ArticleLiterature Review

Early Interactions Between Blood-Stage Plasmodium Parasites and the Immune System

February 2005
Current Topics in Microbiology and Immunology 297:25-70

February 2005
297:25-70

DOI:10.1007/3-540-29967-X_2

Source
PubMed

Authors:

Mary Stevenson

McGill University

Accumulating evidence provides strong support for the importance of innate immunity in shaping the subsequent adaptive immune response to blood-stage Plasmodium parasites, the causative agents of malaria. Early interactions between blood-stage parasites and cells of the innate immune system, including dendritic cells, monocytes/macrophages, natural killer (NK) cells, NKT cells, and gamma6 T cells, are important in the timely control of parasite replication and in the subsequent elimination and resolution of the infection. The major role of innate immunity appears to be the production of immunoregulatory cytokines, such as interleukin (IL)-12 and interferon (IFN)-gamma, which are critical for the development of type 1 immune responses involving CD4+ Thl cells, B cells, and effector cells which mediate cell-mediated and antibody-dependent adaptive immune responses. In addition, it is likely that cells of the innate immune system, especially dendritic cells, serve as antigen-presenting cells. Here, we review recent data from rodent models of blood-stage malaria and from human studies, and outline the early interactions of infected red blood cells with the innate immune system. We compare and contrast the results derived from studies in infected laboratory mice and humans. These host species are sufficiently different with respect to the identity of the infecting Plasmodium species, the resulting pathologies, and immune responses, particularly where the innate immune response is concerned. The implications of these findings for the development of an effective and safe malaria vaccine are also discussed.

EFFECT OF MALARIA INFECTION ON BLOOD PARAMETERS AND VIRAL LOAD IN HIV INFECTED CAMEROONIAN PATIENTS UNDER HAART: A HOSPITAL-BASED STUDY

Article

Full-text available

Jun 2017

Co-infections with malaria and HIV infection are common in Sub-Saharan countries. This study aimed at determining the effect of malaria infection on blood parameters and viral load of Cameroonian people living with HIV (PLWHIV) and under antiretroviral treatment. A cross sectional and prospective study took place at the District hospital of Deido. About, 8 mL of venous blood were obtained from each patient by venipuncture for performing complete blood count, thick blood smear and CD4 cells count. Sociodemographic data of participants were sought. In total, 723 patients were enrolled in the study with an average age of 39.49 ± 11.17 years old. The mean count of CD4 lymphocytes was 427 ± 257 (range: 6-1369 cells/µL). The prevalence of malaria was 16.7% (95%CI: 14.2%-19.6%). Hemoglobin and haematocrit were lower in malaria infected individuals (P-value < 0.0001). Viral loads were significantly higher in infected males compared to their uninfected counterparts (65195.20 ± 978.04 versus 540 ± 91.24 copies/µL; P-value < 0.0001). The risk of anemia was twofold and about threefold higher in males (OR = 2.28; 95%CI = 1.58-3.29; P-value < 0.0001) and malaria parasites infected individuals (OR = 2.85; 95%CI = 1.28-4.78; P-value < 0.0001) respectively. It is critical to take into account treatment of malaria episodes in PLWHIV during their management.

Clinical characterization of dengue in a children’s hospital of Cartagena (Colombia)

Article

Full-text available

Dec 2014

Objective: To characterize the clinical manifestations of dengue in pediatric patients in a health institution tertiary Cartagena (Colombia). Materials and methods: Descriptive study by review of medical records of patients hospitalized for dengue at Children's Hospital Napoleon Franco Pareja of Cartagena. We evaluated 136 children with acute fever unapparent etiology. Serology to confirm infection by dengue virus tests was used. Results: 98 cases of children hospitalized with dengue diagnosis were analyzed. Age ranged from under 6 months to 16 years, with the age range with the highest frequency of the disease 10 to 16 years (33.7 %). The most common signs and symptoms were rash (49.0 %), myalgia (35.7 %), headache (33.7 %), arthralgia (33.7 %), anorexia (24.5 %), tourniquet (19.4 %), pruritus (11.2 %), chills (8.2 %), facial erythema (7.1 %) and ocular retro pain (6.1 %). Conclusions: Age remains the predominant factor in the severity of dengue. Therefore urgently needed preventive measures in the pediatric population

CYTOKINES PROFILE AND ANTIBODIES IN RESPONSE TO PLASMODIUM VIVAX INFECTION IN A POPULATION OF THE SOUTH OF BOLIVAR, COLOMBIA (IN SPANISH)

Article

Jun 2013

Revista Ciencias Biomedicas

Introduction: malaria is an important cause of disease and death in tropical countries. Inflammatory cytokines produced by the innate immune system play an important role in the regulation of the adaptive immunity in front of the Malaria blood-stage. However, the role of these mediators in the pathogenesis of the disease by P. vivax is unclear. Objective: determine the serum levels of cytokines and IgG in infected patients with P. vivax and correlate these molecules with the severity of the disease. Methods: cross-sectional pilot study carried out in the municipality of Montecristo, a population of the south of the department of Bolívar, Colombia. Malaria parasite was identified by means of microscopic examination. Patients were distributed in two groups: First infection and reinfection by P. vivax and they were compared with a healthy control group. Serum levels of cytokines and IgG were determined by means of ELISA technique. Results: cytokine and IgG levels were significantly higher in patients with malaria than in healthy control patients (p<0,05). IL-10 levels were significantly higher in the group of first infection when it was compared with the group of reinfection (p<0,05). The quotient IFN-γ/IL-10 was higher in the group of first infection in comparison with the group of reinfection. Conclusion: the severity of the disease is strongly associated to activation of pro-inflammatory and anti-inflammatory cytokines and to the humoral immune response. Rev.cienc.biomed. 2013;4(1):86-97

CYTOKINES PROFILE AND ANTIBODIES IN RESPONSE TO PLASMODIUM VIVAX INFECTION IN A POPULATION OF THE SOUTH OF BOLIVAR, COLOMBIA

Article

Full-text available

May 2013

Carlos Moneriz

RESUMEN Introducción: la malaria es una importante causa de enfermedad y muerte en países tropicales. Las citoquinas inflamatorias producidas por el sistema inmune innato juegan un papel importante en la regulación de la inmunidad adaptativa frente a la etapa sanguínea del Plasmodium. Sin embargo, el papel de estos mediadores en la patogénesis de la enfermedad por P. vivax no es clara. Objetivo: determinar los niveles séricos de citoquinas e IgG en pacientes infectados con P. vivax y correlacionar estas moléculas con la severidad de la enfermedad. Metodología: estudio piloto de corte transversal realizado en el municipio de Montecristo, una población del sur del departamento de Bolívar, Colombia. El parásito de la malaria se identificó mediante examen microscópico. Los pacientes se distribuyeron en dos grupos: primera infección y reinfección por P. vivax y se compararon con un grupo control sano. Los niveles séricos de las citoquinas y de IgG se determinaron mediante la técnica de ELISA. Resultados: los niveles de citoquinas e IgG fueron significativamente mayores en los pacientes con malaria en comparación con los controles sanos (p<0.05). Los niveles de IL-10 fueron significativamente mayores en el grupo de primera infección cuando se comparó con el grupo de reinfección (p<0.05). El cociente de IFN-γ/IL-10 fue mayor en el grupo de primera infección comparado con el grupo de reinfección. Conclusión: la severidad de la enfermedad está fuertemente asociada a activación de citoquinas proinflamatorias y antiinflamatorias y a la respuesta inmune humoral. Rev. cienc.biomed. 2013;4(1):86-97

Regulating the Adaptive Immune Response to Blood-Stage Malaria: Role of Dendritic Cells and CD4 + Foxp3 + Regulatory T Cells

Article

Full-text available

Jan 2011
INT J BIOL SCI

Mary Stevenson

Although a clearer understanding of the underlying mechanisms involved in protection and immunopathology during blood-stage malaria has emerged, the mechanisms involved in regulating the adaptive immune response especially those required to maintain a balance between beneficial and deleterious responses remain unclear. Recent evidence suggests the importance of CD11c+ dendritic cells (DC) and CD4+Foxp3+ regulatory T cells in regulating immune responses during infection and autoimmune disease, but information concerning the contribution of these cells to regulating immunity to malaria is limited. Here, we review recent findings from our laboratory and others in experimental models of malaria in mice and in Plasmodium-infected humans on the roles of DC and natural regulatory T cells in regulating adaptive immunity to blood-stage malaria.

Influence des piqûres de moustiques sur les réponses anticorps spécifiques aux antigènes de Plasmodium falciparum

Thesis

Full-text available

Dec 2021

Kakou Ghislain Aka

Les populations humaines vivant dans les zones endémiques pour le paludisme développent une immunité protectrice qui est majoritairement médiée par les anticorps contre Plasmodium falciparum. Cette immunité peut être modulée par différents facteurs relatifs à l’hôte, au parasite et à l’environnement. Ces populations humaines sont fréquemment exposées aux piqûres des insectes hématophages, notamment aux différentes espèces de moustiques Anopheles, Culex et Aedes. Certains composants salivaires de ces moustiques, contenus dans la salive injectée à l’hôte à chaque repas sanguin, ont des propriétés immunomodulatrices, et sont donc capables de moduler le système immunitaire de l’hôte. Cette thèse s’intéresse aux relations immunologiques hôte-vecteur-pathogène et notre objectif était d’évaluer l’influence de l’exposition aux piqûres de moustiques sur les réponses anticorps spécifiques à Plasmodium falciparum chez des populations humaines qui résident en zone d’endémie pour le paludisme. Pour ce faire, des échantillons sanguins prélevés au cours de deux études multidisciplinaires réalisées à Bouaké (Côte d’Ivoire) nous ont servi pour évaluer les réponses IgG et isotypiques (IgG1 et IgG3) à certains antigènes candidats vaccins (PfAMA1, PfMSP1, PfMSP3 et PfGLURP-R0) et aux extraits de schizontes (Pfshz) de Plasmodium falciparum. L’exposition aux piqûres de moustique a été définie au niveau individuel par une approche sérologique basée sur la quantification de la réponse IgG à certains antigènes salivaires spécifiques de chaque genre de moustique et qui représentent un proxy du niveau d’exposition à ces moustiques. La relation entre les réponses anticorps aux antigènes de P. falciparum et les facteurs démographiques, parasitaires, et les facteurs environnementaux a été réalisée par l’utilisation d’analyses univariées et multivariées.Lors de la première étude transversale, les réponses anticorps anti-Plasmodium falciparum étaient différentes selon le niveau d'exposition des enfants, ceux fortement exposés à Anopheles présentaient des réponses IgG et IgG3 significativement plus faibles à PfMSP1. Nous n'avons pas trouvé d'association entre les réponses anticorps à PfAMA1 et le niveau d’exposition aux Anopheles. La deuxième étude nous a permis de suivre l’évolution de la réponse IgG anti-P. falciparum 42 jours après une infection. Les personnes qui étaient plus exposées aux piqûres d'Anopheles ou d'Aedes (exposition considérée à un genre unique) présentaient une plus forte augmentation de la réponse IgG anti-PfShz en comparaison aux personnes moins exposées. Une association positive entre la réponse IgG à PfShz et le niveau individuel d'exposition aux deux genres de moustiques combinée a également été observé au cours du suivi. L’évolution de cette réponse immune était également associée à l'âge, à la densité parasitaire et à la réponse immunitaire préexistante anti-Plasmodium à l'inclusion de l'étude longitudinale. L’exposition aux moustiques (unique ou combinée) n’était pas associée aux dynamiques d’évolution des réponses spécifiques aux antigènes de mérozoites.L’ensemble de ces résultats suggère que l’exposition aux piqûres de moustiques est associée à l’acquisition et à la dynamique des réponses anticorps dirigées contre certains antigènes de Plasmodium falciparum. Ces observations « de terrain » peuvent constituer le point de départ de travaux complémentaires pour appréhender le rôle de la salive de moustique sur la transmission du paludisme en combinant des études immunologiques sur le terrain et ex-vivo.

Parasite Recognition and Signaling Mechanisms in Innate Immune Responses to Malaria

Article

Full-text available

Dec 2018

Malaria caused by the Plasmodium family of parasites, especially P.falciparum and P. vivax, is a major health problem in many countries in the tropical and subtropical regions of the world. The disease presents a wide array of systemic clinical conditions and several life-threatening organ pathologies, including the dreaded cerebral malaria. Like many other infectious diseases, malaria is an inflammatory response-driven disease, and positive outcomes to infection depend on finely tuned regulation of immune responses that efficiently clear parasites and allow protective immunity to develop. Immune responses initiated by the innate immune system in response to parasites play key roles both in protective immunity development and pathogenesis. Initial pro-inflammatory responses are essential for clearing infection by promoting appropriate cell-mediated and humoral immunity. However, elevated and prolonged pro-inflammatory responses owing to inappropriate cellular programming contribute to disease conditions. A comprehensive knowledge of the molecular and cellular mechanisms that initiate immune responses and how these responses contribute to protective immunity development or pathogenesis is important for developing effective therapeutics and/or a vaccine. Historically, in efforts to develop a vaccine, immunity to malaria was extensively studied in the context of identifying protective humoral responses, targeting proteins involved in parasite invasion or clearance. The innate immune response was thought to be non-specific. However, during the past two decades, there has been a significant progress in understanding the molecular and cellular mechanisms of host-parasite interactions and the associated signaling in immune responses to malaria. Malaria infection occurs at two stages, initially in the liver through the bite of a mosquito, carrying sporozoites, and subsequently, in the blood through the invasion of red blood cells by merozoites released from the infected hepatocytes. Soon after infection, both the liver and blood stage parasites are sensed by various receptors of the host innate immune system resulting in the activation of signaling pathways and production of cytokines and chemokines. These immune responses play crucial roles in clearing parasites and regulating adaptive immunity. Here, we summarize the knowledge on molecular mechanisms that underlie the innate immune responses to malaria infection.

Natural cocoa ingestion reduced liver damage in mice infected with Plasmodium berghei (NK65)

Article

Full-text available

Sep 2012

Purpose: This study tested whether natural cocoa powder ingestion could mitigate hepatic injury coincident with murine malaria. Plasmodium berghei infection causes liver damage including hepatic sinusoidal distension, and elevated serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. According to literature, these pathologies largely result from activity of reactive oxygen species (ROS) and may be extenuated by antioxidants. Animals and methods: Thirty Balb/c mice were randomly assigned to three equal groups. One of two groups of mice inoculated with 0.2 mL of P. berghei-parasitized red blood cells (RBCs) was given unrestricted 24-hour access to a natural cocoa powder beverage (2% by weight) in place of water. The third group of mice were neither infected nor given cocoa. All mice were fed the same standard chow. After 6 days, mice were sacrificed and their livers processed for histomorphometric assessment of mean hepatic sinusoidal diameter as a quantitative measure of altered morphology. Serum ALT and AST were measured as a gauge of functional impairment. Results: Compared with uninfected mice, hepatic sinusoidal diameter in P. berghei-infected mice not given cocoa increased by 150%, whereas a smaller increase of 83% occurred in infected mice that ingested cocoa. Mean serum ALT increased by 127% in infected mice not given cocoa and 80% in infected mice that consumed cocoa, compared with the value for uninfected mice. Similarly, mean serum AST was raised by 141% in infected mice not given cocoa and 93% in infected mice that drank cocoa. Conclusion: Distension of hepatic sinusoidal diameter in P. berghei-infected mice was reduced by 67%, whereas respective elevations of serum ALT and AST concentrations were reduced by 47% and 48% via ingestion of cocoa. Anti-inflammatory and antioxidant components of cocoa probably mediated the demonstrated hepatoprotective benefit by blunting pernicious ROS activity in P. berghei-infected mice.

Cellular correlates of immunity and risk of disease in semi-immune Papua New Guinean children.

Conference Paper

Jan 2008
Int J Parasitol

Plasmodium yoelii surface-related antigen (PySRA) modulates the host pro-inflammatory responses via binding to CD68 on macrophage membrane

Article

Full-text available

Apr 2024
INFECT IMMUN

Malaria, one of the major infectious diseases in the world, is caused by the Plasmodium parasite. Plasmodium antigens could modulate the inflammatory response by binding to macrophage membrane receptors. As an export protein on the infected erythrocyte membrane, Plasmodium surface-related antigen (SRA) participates in the erythrocyte invasion and regulates the immune response of the host. This study found that the F2 segment of P. yoelii SRA activated downstream MAPK and NF-κB signaling pathways by binding to CD68 on the surface of the macrophage membrane and regulating the inflammatory response. The anti-PySRA-F2 antibody can protect mice against P. yoelii, and the pro-inflammatory responses such as IL-1β, TNF-α, and IL-6 after infection with P. yoelii are attenuated. These findings will be helpful for understanding the involvement of the pathogenic mechanism of malaria with the exported protein SRA.

Mushroom‐Derived Products as an Alternative Antimalarial Therapeutics: A Review

Chapter

Oct 2022

Edible and medicinal mushrooms have been highlighted to contain potent antiparasitic activity, due to their vast phytochemical content. Mushroom can be defined as a macro‐fungus with a fruiting body that can be either above or below the ground which can be seen and picked by hands. A number of researchers have documented potent antimalarial effects of crude extracts and isolated compounds derived from medicinal and edible mushrooms. The continued discovery of drug‐resistant malaria‐causing parasites has necessitated the requirement for novel antimalarial drugs. However, literature on mushrooms as potential antimalarials has not been fully provided; hence, this chapter focuses majorly on the antiparasitic effects of mushroom‐derived products and their potential antimalarial capabilities and the possible mechanism of action.

Selective expression of variant surface antigens enables Plasmodium falciparum to evade immune clearance in vivo

Article

Full-text available

Jul 2022

Plasmodium falciparum has developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based on in vitro studies of individual parasite variant surface antigens and how this relates to the processes in vivo is not well-understood. Here, we have used a humanized mouse model to identify parasite factors important for in vivo growth. We show that upregulation of the specific PfEMP1, VAR2CSA, provides the parasite with protection from macrophage phagocytosis and clearance in the humanized mice. Furthermore, parasites adapted to thrive in the humanized mice show reduced NK cell-mediated killing through interaction with the immune inhibitory receptor, LILRB1. Taken together, these findings reveal new insights into the molecular and cellular mechanisms that the parasite utilizes to coordinate immune escape in vivo. Identification and targeting of these specific parasite variant surface antigens crucial for immune evasion provides a unique approach for therapy. During the erythrocyte (RBC) stage of P. falciparum infection variant surface antigens (VSAs) such as PfEMP1s and RIFINs expressed on RBCs are important for infection and evasion of host innate immune system. Here, Chew et al. use a NSG mouse model, which is deficient in B, T and NK cells but retains macrophages, to show that PfEMP1 surface expression is required for in vivo adaptation as well as in vitro evasion of macrophage phagocytosis.

Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria

Article

Full-text available

Jan 2022
eLife

Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here, we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. Plasmodium yoelii 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between the different host species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. These data will aid the selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.

Impact of malaria infection on renal and liver functions in patients living with HIV/AIDS on HAART in Douala, Cameroon

Article

Full-text available

Feb 2016

Malaria and HIV (Human immunodeficiency virus) infection are known overlap in Sub-Saharan Africa countries. Thus, it is likely in this context that the burden inflicted by these both diseases is more important. This study was designed to determine the prevalence of malaria and its impact on renal and hepatic profiles in people living with HIV (PLWHIV) on HAART (Highly active antiretroviral therapy) and living in Douala. Between August 2015 and March 2016 a prospective and cross-sectional study was carried out at the District hospital of Deido in the town of Douala. Questionnaire form was used to document sociodemographic, clinic and biological data of participants. Blood samples were collected by venipuncture into tubes for biological analyses. These allowed to performed thick blood films for malaria diagnosis. Sera were obtained and used to measure transaminases and creatinine levels. A total of 723 patients were included in the study. The mean age of the population was 39.49 ± 11.17 years old. The malaria prevalence was 16.7% (95%CI = 14.2%-19.6%). AST (aspartate aminotransferase) and ALT (alanine aminotransferase) were higher in malaria positive patients on average. In addition, the difference was statistically significant for ALT (p-value = 0.0403). In addition, creatinine levels were lower in malaria positive patients compared to their negative counterparts. Renal and liver functions were both further impaired in malaria positive patients especially ALT which is more specific of liver function. This study outlines the need for appraising the measurement of transaminases and creatinine especially in PLWHIV during their management.

A single-nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor alters the development of host immunity

Article

Full-text available

Feb 2020

The acquisition of malaria immunity is both remarkably slow and unpredictable. At present, we know little about the malaria parasite genes that influence the host’s ability to mount a protective immune response. Here, we show that a single-nucleotide polymorphism (SNP) resulting in a single amino acid change (S to F) in an ApiAP2 transcription factor in the rodent malaria parasite Plasmodium berghei ( Pb ) NK65 allowed infected mice to mount a T helper cell 1 (T H 1)–type immune response that controlled subsequent infections. As compared to Pb NK65 S , Pb NK65 F parasites differentially expressed 46 genes, most of which are predicted to play roles in immune evasion. Pb NK65 F infections resulted in an early interferon-γ response and a later expansion of germinal centers, resulting in high levels of infected red blood cell–specific T H 1-type immunoglobulin G2b (IgG2b) and IgG2c antibodies. Thus, the Pb ApiAP2 transcription factor functions as a critical parasite virulence factor in malaria infections.

Serum Levels of Interleukin-10 and Interferon Gamma Among Patients with Plasmodim Falciparum EL-DAMAZIEN-BLUE NILE STATE

Article

Full-text available

Feb 2019

Cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. In malaria, blood concentrations of cytokines were influent by the infection, such as interleukin (IL-10) and interferon-γ (IFN-γ). In this study serum levels of interleukin-10 (IL-10) and interferon-γ (IFN-γ) were determined in 52 patients and 7 healthy volunteers as controls in El-Damazien, Blue Nile State-Sudan. Blood samples were collected from both patients and control candidates in (EDTA) containers for parasitological and immunological tests. Microscopic examination for Geimsa stained thick and thin blood films were used to detect the positive samples for Plasmodium falciparum. Enzyme linked Immunosorbant Assay (ELISA), was used for the determination of IL-10 and IFN-γ levels. Serum levels of IL-10 and IFN-γ were markedly elevated in patients with malaria (118.99 ± 62.21 ng/ml versus 12.08± 7.77 ng/ml in healthy controls; 40.45 ± 35.31 ng/ml versus 12.33 ± 5.00 ng/ml, respectively; mean ± SD). These results were found to be statistically significant (P= 0.007). Furthermore the levels of these cytokines had significant correlation within parasitemia (0.001 and 0.022 respectively). Thus suggest that stimulatory and inhibitory cytokines for macrophage activation and/or antibody production (i.e., TH1-and TH2-type immunoreaction, respectively) are coexpressed during acute P. falciparum infection and stress the multifactorial network between host and parasite in malaria immunology. Further studies are needed to examine whether serum concentrations of these cytokines also parallel their concentrations at the tissue sites of their production and action.

Serum Levels of Interferon-gamma in Patients with

Article

Full-text available

Feb 2019

A complex parasite such as human Plasmodium is likely to generate a variety of substances that injure the hosts directly or cause immunopathology. In malaria, a blood concentration of anti-inflammatory cytokines, such as interferon-gamma (IFN-γ) is increased. The present study was performed to analyze IFN-γ levels in patients with certain conditions of malaria with healthy controls and correlate with malaria density infection as well as age groups. It is a cross-sectional study was carried out in Khartoum State/ Sudan, a total of 49 febrile patients and 10 healthy volunteers as controls were included in this study. Blood samples were collected from both patients and control candidates in (EDTA) containers for parasitological and immunological tests. Microscopical examination of thick and thin blood films rather than immunochromatography test (ICT) were used to detect the positive samples for Plasmodia. Enzyme linked Immunosorbant Assay (ELISA) was used for the determination of IFN-γ levels. The results showed that the prevalence was occurred among all age groups and P.falciparum was the predominant species with P.vivax mono or co-infections. Furthermore IFN-γ levels in malaria patients were 65.14and SD 64.56 while the levels in healthy participants were 12.33 and SD was 4.11. The difference was found to be statistically significant (P= 0.001). The levels of cytokine mentioned above were observed to be raised in malaria individual compared to healthy control candidates. Acknowledgment We would like to express our immense gratitude and appreciation to the Deanship of Scientific Research-Sudan University of Science and Technology who sponsored this project.

Induction of Plasmodium-Specific Immune Responses Using Liposome-Based Vaccines

Article

Feb 2019

Aloysious Ssemaganda

Induction of Plasmodium-Specific Immune Responses Using Liposome-Based Vaccines

Article

Full-text available

Feb 2019

In the development of vaccines, the ability to initiate both innate and subsequent adaptive immune responses need to be considered. Live attenuated vaccines achieve this naturally, while inactivated and sub-unit vaccines generally require additional help provided through delivery systems and/or adjuvants. Liposomes present an attractive adjuvant/delivery system for antigens. Here, we review the key aspects of immunity against Plasmodium parasites, liposome design considerations and their current application in the development of a malaria vaccine.

Biochemical effects of ethanolic extract from root bark of Salacia nitida L. benth in Plasmoduim berghei-malaria infected mice.

Article

Full-text available

Jan 2019

Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway

Article

Full-text available

Oct 2018
PLOS PATHOG

Natural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population. Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed. Knockout of MDA5 in responding human NK cells by CRISPR/cas9 abolished NK cell activation, IFN-γ secretion, lysis of iRBCs. Similarly, inhibition of TBK1/IKKε, an effector molecule downstream of MDA5, also inhibited activation of responding NK cells. Conversely, activation of MDA5 by liposome-packaged poly I:C restored non-responding NK cells to lyse iRBCs. We further show that microvesicles containing large parasite RNAs from iRBCs activated NK cells by fusing with NK cells. These findings suggest that NK cells are activated through the MDA5 pathway by parasite RNAs that are delivered to the cytoplasm of NK cells by microvesicles from iRBCs. The difference in MDA5 expression between responding and non-responding NK cells following exposure to iRBCs likely contributes to the variation in NK cell responses to malaria infection in the human population.

PERAN INTERLEUKIN-10 PADA INFEKSI MALARIA

Article

Full-text available

Feb 2015

Mechanism of splenic cell death and host mortality in a Plasmodium yoelii malaria model

Article

Full-text available

Dec 2017

Malaria is a fatal disease that displays a spectrum of symptoms and severity, which are determined by complex host-parasite interactions. It has been difficult to study the effects of parasite strains on disease severity in human infections, but the mechanisms leading to specific disease phenotypes can be investigated using strains of rodent malaria parasites that cause different disease symptoms in inbred mice. Using a unique mouse malaria model, here we investigated the mechanisms of splenic cell death and their relationship to control of parasitemia and host mortality. C57BL/6 mice infected with Plasmodium yoelii nigeriensis N67C display high levels of pro-inflammatory cytokines and chemokines (IL-6, IFN-γ, TNF-α, CXCL1, and CCL2) and extensive splenic damage with dramatic reduction of splenic cell populations. These disease phenotypes were rescued in RAG2−/−, IFN-γ−/−, or T cell depleted mice, suggesting IFN-γ and T cell mediated disease mechanisms. Additionally, apoptosis was one of the major pathways involved in splenic cell death, which coincides with the peaks of pro-inflammatory cytokines. Our results demonstrate the critical roles of T cells and IFN-γ in mediating splenic cell apoptosis, parasitemia control, and host lethality and thus may provide important insights for preventing/reducing morbidity associated with severe malaria in humans.

Influence of host genetic factors on erythrocyte phase of malarial infection caused by Plasmodium falciparum

Thesis

May 2017

Severe forms of malaria in humans is caused by Plasmodium falciparum and Plasmodium vivax.Malaria infection is the results of complex membrane sorting and signaling. Erythrocyte membrane lipid rafts proteins regulate membrane sorting and signaling processes and hence lipid raft proteins (Gαs and β2AR) and the interacting proteins (ADORA2A and GRK5) can influence pathogen entry and consequently the erythrocyte phase of the infection that is crucial to the pathogenesis of malaria. It is also known that the entry of malaria parasite in patients induces the synthesis of inflammatory cytokines such as TNF-a, IL-1, IL-6 and IL-10 and altered gene expression known to be regulated by epigenetic mechanisms. We demonstrated that malaria susceptibility or its severity may be influenced by the SNPs in GNAS, ADRB2, ADORA2A, GRK5and ABCB1genes; and epigenetic changes at the critical CpG sites in the promoter region of ABCB1and ADRB2genes. We also showed that global DNA methylation variants could discriminate the malaria phenotypes. Our study provides evidence for the proposed role of host genes mediated mechanisms in the etiology of malaria susceptibility. For the effective control of malaria, the development of sensitive, accurate and rapid assay is essential. We developed the single-step amplification and non-amplification based assays with better sensitivity than existing assays. Thesis link: http://hdl.handle.net/10603/148259

art 10.1186 s12936-017-1781-4(1)

Data

Full-text available

Mar 2017

Sangdao Somsri

A novel in vitro model reveals distinctive modulatory roles of Plasmodium falciparum and Plasmodium vivax on na?ve cell-mediated immunity

Article

Full-text available

Mar 2017
MALARIA J

Background To date, human peripheral blood mononuclear cells (PBMCs) have been used mainly in immune stimulation assays and the interpretation of data can be influenced by the previous immunological history of donors and cross reactivity with other infectious agents. Resolving these limitations requires an alternative in vitro model to uncover the primary response profiles. MethodsA novel in vitro model of mononuclear cells (MNCs) generated from haematopoietic stem cells (HSCs) was developed and these cells were then co-cultured with various antigens from Plasmodium falciparum and Plasmodium vivax to investigate the response of na?ve immune cells to malaria antigens by flow cytometry. ResultsIn vitro stimulation of na?ve lymphocytes showed that CD4+ and CD8+ T lymphocytes were significantly reduced (P < 0.01) by exposure to lysates of infected erythrocytes or intact erythrocytes infected with P. falciparum. The depletion was associated with the expression of CD95 (Fas receptor) on the surface of T lymphocytes. Maturation of T lymphocytes was affected differently, showing elevated CD3+CD4+CD8+ and CD3+CD4?CD8? T lymphocytes after stimulation with cell lysates of P. falciparum and P. vivax, respectively. In addition, antigen presenting monocytes and dendritic cells derived from haematopoietic stem cells showed impaired HLA-DR expression as a consequence of exposure to different species of malaria parasites. Conclusion These results suggest that na?ve mononuclear cells differentiated in vitro from HSCs could provide a valid model for the assessment of immunity. P. falciparum and P. vivax malaria parasites could modulate various populations of immune cells starting from newly differentiated mononuclear cells.

Prevalence of Malaria Infection and Reliability of ACCUCARE One Step Malaria Test® for Diagnosing Malaria in People Living with Human Immunodeficiency Virus Infection in Cameroon

Article

Full-text available

Jan 2017
INT J INFECT DIS

Protozoan Parasites and Type I IFNs

Article

Full-text available

Jan 2017

For many years, the role of interferon (IFN)-I has been characterized primarily in the context of viral infections. However, regulatory functions mediated by IFN-I have also been described against bacterial infections and in tumor immunology. Only recently, the interest in understanding the immune functions mediated by IFN-I has dramatically increased in the field of protozoan infections. In this review, we discuss the discrete role of IFN-I in the immune response against major protozoan infections: Plasmodium, Leishmania, Trypanosoma, and Toxoplasma.

Effects of Invariant NKT Cells on Parasite Infections and Hygiene Hypothesis

Article

Full-text available

Jan 2016

Invariant natural killer T (iNKT) cells are unique subset of innate-like T cells recognizing glycolipids. iNKT cells can rapidly produce copious amounts of cytokines upon antigen stimulation and exert potent immunomodulatory activities for a wide variety of immune responses and diseases. We have revealed the regulatory effect of iNKT cells on autoimmunity with a serial of publications. On the other hand, the role of iNKT cells in parasitic infections, especially in recently attractive topic “hygiene hypothesis,” has not been clearly defined yet. Bacterial and parasitic cell wall is a cellular structure highly enriched in a variety of glycolipids and lipoproteins, some of which may serve as natural ligands of iNKT cells. In this review, we mainly summarized the recent findings on the roles and underlying mechanisms of iNKT cells in parasite infections and their cross-talk with Th1, Th2, Th17, Treg, and innate lymphoid cells. In most cases, iNKT cells exert regulatory or direct cytotoxic roles to protect hosts against parasite infections. We put particular emphasis as well on the identification of the natural ligands from parasites and the involvement of iNKT cells in the hygiene hypothesis.

Malaria-Cutaneous Leishmaniasis Co-infection: Influence on Disease Outcomes and Immune Response

Article

Full-text available

Jun 2016

Malaria and Cutaneous Leishmaniasis are co-endemic throughout large regions in tropical countries and co-infection may impact the evolution of host-parasite interactions. In the present study, we evaluate Malaria/Leishmaniasis disease outcome, Th1/Th2 cytokine levels and the CD4 and CD8 T-cell profiles in a co-infection murine model (BALB/c) of P. yoelii 17XNL (Py) and L. amazonensis (La) or L. braziliensis (Lb). Malaria parasitaemia was assessed through blood strains stained with Giemsa. Leishmania lesions were monitored with a digital caliper and parasite loads determined by limiting-dilution assay. Serum levels of IFN-γ, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17 were determined using multiplexed bead assay and expression of CD3, CD4 and CD8 T-cells markers were determined by Flow Cytometry in the thymus, spleens and lymph nodes. Parasitaemia in Lb+Py co-infected group was lower than in Py single-infected group, suggesting a protective effect of Lb co-infection in Malaria progression. In contrast, La+Py co-infection increased parasitaemia, patent infection and induced mortality in non-lethal Malaria infection. Regarding Leishmaniasis, Lb+Py co-infected group presented smaller lesions and less ulceration than Lb single-infected animals. In contrast, La+Py co-infected group presented only a transitory delay on the development of lesions when compared to La single-infected mice. Decreased levels of IFN-, TNF, IL-6 and IL-10 were observed in the serum of co-infected groups, demonstrating a modulation of Malaria immune response by Leishmania co-infections. We observed an intense thymic atrophy in Py single-infected and co-infected groups, which recovered earlier in co-infected animals. The CD4 and CD8 T cell profiles in thymus, spleens and lymph nodes did not differ between Py single and co-infected groups, except for a decrease in CD4+CD8+ T cells which also increased faster in co-infected mice. Our results suggest that Py and Leishmania co-infection may change disease outcome. Interestingly Malaria outcome can be altered according to the Leishmania specie involved. Alternatively Malaria infection reduced the severity or delayed the onset of leishmanial lesions. These alterations in Malaria and Cutaneous Leishmaniasis development seem to be closely related with changes in the immune response as demonstrated by alteration in serum cytokine levels and thymus/spleens T cell phenotypes dynamics during infection.

Pre-infection administration of asiatic acid retards parasitaemia induction in Plasmodium berghei murine malaria infected Sprague-Dawley rats

Article

Full-text available

Apr 2016
MALARIA J

Background Malaria prevention has remained a critical area in the absence of efficacious vaccines against malaria. Drugs currently used as chemotherapeutics are also used in chemoprophylaxis increasing possible drug resistance. Asiatic acid is a natural phytochemical with oxidant, antioxidant and anti-inflammatory properties with emerging anti-malarial potential. The influence of asiatic acid administration prior to Plasmodium berghei infection of Sprague-Dawley rats on parasitaemia induction is here reported. Methods Sprague-Dawley rats (90–120 g) were administered with asiatic acid (10 mg/kg) 48 h before intraperitoneal infection with P. berghei. Parasitaemia induction and progression, food and water intake as well as weight were compared to 30 mg/kg chloroquine-treated and infected control rats during sub-chronic studies (21 days). Results Asiatic acid pre-infection administration preserved food and water intake as well as increase in percentage weight gain of infected animals. In pre-infection treated animals, the pre-patent period was extended to day 6 from 72 h. Asiatic acid suppressed parasitaemia while oral chloroquine (30 mg/kg) did not influence malaria induction. Conclusions Per-oral, pre-infection, asiatic acid administration influenced parasitaemia patency and parasitaemia progression, food, water, and weight gain percentage. This may suggest possible chemoprophylaxis effects of asiatic acid in malaria.

Diarylheptanoids Rich Fraction of Alnus nepalensis Attenuates Malaria Pathogenesis: In-vitro and In-vivo Study

Article

Mar 2016
PHYTOTHER RES

Diarylheptanoids from Alnus nepalensis leaves have been reported for promising activity against filariasis, a mosquito-borne disease, and this has prompted us to investigate its anti-malarial and safety profile using in-vitro and in-vivo bioassays. A. nepalensis leaf extracts were tested in-vitro against chloroquine-sensitive Plasmodium falciparum NF54 by measuring the parasite specific lactate dehydrogenase activity. Among all, the chloroform extract (ANC) has shown promising anti-plasmodial activity (IC50 8.06 ± 0.26 µg/mL). HPLC analysis of ANC showed the presence of diarylheptanoids. Efficacy and safety of ANC were further validated in in-vivo system using Plasmodium berghei-induced malaria model and acute oral toxicity in mice. Malaria was induced by intra-peritoneal injection of P. berghei infected red blood cells to the female Balb/c mice. ANC was administered orally at doses of 100 and 300 mg/kg/day following Peter's 4 day suppression test. Oral administration of ANC showed significant reduction of parasitaemia and increase in mean survival time. It also attributed to inhibition of the parasite induced pro-inflammatory cytokines as well as afford to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. In-vivo safety evaluation study revealed that ANC is non-toxic at higher concentration. Copyright © 2016 John Wiley & Sons, Ltd.

Phagosomal acidification prevents macrophage inflammatory cytokine production to malaria and DCs are the major source at the early stages of infection: implication for malaria protective immunity development

Article

Full-text available

Aug 2015
J BIOL CHEM

Inflammatory cytokines produced at the early stages of malaria infection contribute to shaping protective immunity and pathophysiology. To gain mechanistic insight into these processes, it is important to understand the cellular origin of cytokines since both cytokine input and cytokine-producing cells play key roles. Here, we determined cytokine responses by monocytes, macrophages, and dendritic cells (DCs) to purified P. falciparum and P. berghei ANKA, and by spleen macrophages and DCs from P. yoelii 17NXL- and P. berghei ANKA-infected mice. The results demonstrate that monocytes and macrophages do not produce inflammatory cytokines to malaria parasites, and that DCs are the primary source early during infection and DC subsets differentially produce cytokines. Importantly, blocking of phagosomal acidification by inhibiting vacuolar-type H(+)-ATPase enabled macrophages to elicit cytokine responses. Since cytokine responses to malaria parasites are mediated primarily through endosomal TLRs, our data indicate that the inability of macrophages to produce cytokines is due to the phagosomal acidification that disrupts endosomal ligand-receptor engagement. Macrophages efficiently produced cytokines to LPS upon simultaneously internalizing parasites, and to heat-killed E. coli, demonstrating that phagosomal acidification affects endosomal receptors-mediated, but not cell surface receptors-mediated, recognition of TLR agonists. Enabling monocytes/macrophages to elicit immune responses to parasites by blocking endosomal acidification can be a novel strategy for the effective development of protective immunity to malaria. The results have important implications for enhancing the efficacy of a whole parasite-based malaria vaccine, and designing strategies for protective immunity development to pathogens that induce immune responses primarily through endosomal receptors. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.

ChemInform Abstract: Ferroquine and Its Derivatives: New Generation of Antimalarial Agents

Article

Jul 2015

Plasmodium cellular effector mechanisms and the hepatic microenvironment

Article

Full-text available

May 2015

Plasmodium falciparum malaria remains one of the most serious health problems globally. Immunization with attenuated parasites elicits multiple cellular effector mechanisms capable of eliminating Plasmodium liver stages. However, malaria liver stage immunity is complex and the mechanisms effector T cells use to locate the few infected hepatocytes in the large liver in order to kill the intracellular liver stage parasites remain a mystery to date. Here, we review our current knowledge on the behavior of CD8+ effector T cells in the hepatic microvasculature, in malaria and other hepatic infections. Taking into account the unique immunological and lymphogenic properties of the liver, we discuss whether classical granule-mediated cytotoxicity might eliminate infected hepatocytes via direct cell contact or whether cytokines might operate without cell-cell contact and kill Plasmodium liver stages at a distance. A thorough understanding of the cellular effector mechanisms that lead to parasite death hence sterile protection is a prerequisite for the development of a successful malaria vaccine to protect the 40% of the world’s population currently at risk of Plasmodium infection.

Antiplasmodial Efficacy of Crude Cocoa Powder Extract on CD4+ T-Cell Counts of Plasmodium berghei Infected BALB/c Mice

Article

Full-text available

Jan 2013

Splenic CD11c(+) cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria

Article

Full-text available

Jan 2015
MALARIA J

Background Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells. Previously, mice semi-immune to malaria was developed. Three cycles of infection and cure (`three-cure¿) were required to protect mice against Plasmodium berghei (ANKA strain) infection.MethodsC57BL/6 J mice underwent three cycles of P. berghei infection and drug-cure to become semi-immune. The spleens of infected semi-immune mice were collected for flow cytometry analysis. CD11c(+) cells of semi-immune mice were isolated and transferred into naïve mice which were subsequently challenged and followed up by survival and parasitaemia.ResultsThe percentages of splenic CD4(+) and CD11c(+) cells were increased in semi-immune mice on day 7 post-infection. The proportion and number of B220(+)CD11c(+)low cells (plasmacytoid dendritic cells, DCs) was higher in semi-immune, three-cure mice than in their naïve littermates on day 7 post-infection (2.6 vs 1.1% and 491,031 vs 149,699, respectively). In adoptive transfer experiment, three months after the third cured P. berghei infection, splenic CD11c(+) DCs of non-infected, semi-immune, three-cure mice slowed Plasmodium proliferation and decreased the death rate due to neurological pathology in recipient mice. In addition, anti-P. berghei IgG1 level was higher in mice transferred with CD11c(+) cells of semi-immune, three-cure mice than mice transferred with CD11c(+) cells of naïve counterparts.ConclusionCD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

Oxidant-induced cell death in lymphocytes – mechanisms of induction and resistance

Article

Full-text available

Fredrik B Thorén

Reactive oxygen species (oxidants, oxygen radicals) produced by the phagocytic NADPH oxidase have pivotal roles in immunity. Patients lacking a functional NADPH oxidase suffer from chronic granulomatous disease, which is characterized by recurring bacterial infections and thus manifesting the importance of reactive oxygen species in host defense against bacteria. However, NADPH oxidase-derived radicals also efficiently inhibit lymphocyte-mediated immunity. Oxidant-induced inactivation of lymphocytes is reportedly a control mechanism for autoreactive lymphocytes and hence prevents autoimmunity. In malignant diseases, oxygen radicals have been proposed to contribute to the characteristic state of anergy of cytotoxic lymphocytes, which prevents immune-mediated rejection of the tumor. Studies of the mechanisms of radical-induced inactivation of lymphocytes may therefore be helpful in understanding the pathophysiology of important disease entities. The first paper in this thesis shows that oxidant-induced functional inhibition and cell death in cytotoxic lymphocytes is critically dependent on cooperation between a nuclear enzyme involved in DNA repair, PARP-1, and a mitochondrion-derived protein, AIF. The results presented in Paper II demonstrate that pharmacological inhibition of the PARP-1 enzyme not only prevents oxidant-induced cell death, but also preserves functions of cytotoxic lymphocytes, such as cytotoxicity against malignant cells, cytokine production, and proliferation. Paper III shows that subsets of natural killer (NK) cells display differential sensitivity to oxygen radicals: the cytotoxic CD56dimCD16+ NK cells were found to be highly sensitive to oxidative inactivation and apoptosis, while the immunoregulatory, cytokine-producing CD56brightCD16- NK cells were highly resistant to the toxicity of oxidants. These data were extended in Paper IV, in which the effect of oxygen radical-producing phagocytes on the expression of the activating NK cell receptors, NKp46 and NKG2D, was investigated. The expression of both receptors was efficiently downregulated on CD56dim NK cells, while the expression remained intact on CD56bright cells. Recent data imply that reciprocal interactions between NK cells and dendritic cells (DCs) are important for the development of adaptive immunity. The results presented in Paper V demonstrate that DCs are equipped with an antioxidative system that efficiently protects cytotoxic cells from oxidant-induced inactivation.

TATIANA KARLA DOS SANTOS BORGES

Article

Placental Cytokine and Chemokine Profiles Reflect Pregnancy Outcomes in Women Exposed to Plasmodium falciparum Infection

Article

Full-text available

Aug 2014
INFECT IMMUN

Pregnancy-associated malaria (PAM) can lead to severe complications for both mother and baby. Certain placental cytokine/chemokine profiles have been shown to reflect poor pregnancy outcomes, including maternal anemia and low birth weight. In intervillous plasma samples from 400 Beninese women living in an area where Plasmodium falciparum is endemic, we quantified 16 cytokines/chemokines. We assessed their profiles in groups with PAM, with maternal anemia, with preterm births, or with a low birth weight for gestational age. Repeated ultrasound measurements ensured that prematurity and low birth weight were highly accurate. Preliminary analyses revealed trends for lower cytokine/chemokine concentrations in placental plasma associated both with babies with low birth weight for gestational age and with P. falciparum infection during pregnancy, while, as a function of the latter, the concentration of gamma interferon (IFN-γ)-inducible protein 10 (IP-10) was higher. Multivariate analyses showed that (i) higher placental plasma interleukin-10 (IL-10) levels were associated with P. falciparum infections and (ii) independently of P. falciparum infections, lower concentrations of both IFN-γ and IL-5 were associated with low birth weight for gestational age. Our data further strengthen the idea that IL-10 and IP-10 could be useful diagnostic markers of P. falciparum infection during pregnancy. The concentrations of cytokines/chemokines in placental plasma may represent previously unrecognized markers of poor fetal growth.

Immunomodulatory effects of recombinant BCG expressing MSP-1C of Plasmodium falciparum on LPS- or LPS plus IFN-gamma-stimulated J774A.1 cells

Article

Apr 2014

Macrophage phagocytosis is the first line of defense of the innate immune system against malaria parasite infection. This study evaluated the immunomodulatory effects of BCG and recombinant BCG (rBCG) strains expressing the C-terminus of the merozoite surface protein-1 (MSP-1C) of Plasmodium falciparum on mouse macrophage cell line J774A.1 in the presence or absence of lipopolysaccharide (LPS) or LPS + IFN-γ. The rBCG strain significantly enhanced phagocytic activity, production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nitric oxide (NO), and inducible nitric oxide synthase (iNOS) as compared with parental BCG strain, and these activities increased in the presence of LPS and LPS+IFN-γ. Furthermore, the rBCG strain also significantly reduced the macrophage viability as well as the rBCG growth suggesting the involvement of macrophage apoptosis. Taken together, these data indicate that the rBCG strain has an immunomodulatory effect on macrophages, thus strengthen the rational use of rBCG to control malaria infection.

Extracellular Vesicles Derived from Plasmodium -infected Hosts as Stimuli of “Trained” Innate Immunity

Article

Feb 2023
CURR MED CHEM

Although the burden of malaria has been successfully controlled globally, this disease remains a major public health issue. To date, neither existing drugs nor vaccines against malaria are sufficient in eliminating malaria worldwide. To achieve the eradication of malaria by 2040, effective interventions targeting all Plasmodium species are urgently needed. As the cornerstone of vaccine design, immune memory serves a significant role in the host's defense against Plasmodium infections. It has long been considered that innate immunity is non-specific and lacks immunologic memory. However, emerging evidence has suggested that innate immunity can be trained following exposure of the body to infectious agents, such as Plasmodium or its products, which, in turn, promotes the onset of a type of memory in innate immune cells. The above ''trained'' innate immune cells, whose phenotype is modified in response to epigenetic modifications, metabolic recombination, or cytokine secretion, exhibit differential pathophysiology after the exposure of the body to a pathogen. In addition, Plasmodium-infected red blood cells and other host cells can secrete exosomes that contain conserved parasite-specific information, such as proteins, RNA, non-coding RNA molecules, and nucleic acids. These molecules can act as stimuli for promoting the establishment of ''trained'' innate immunity against malaria, thereby altering the onset and progression of the parasitic disease. A deeper understanding of the role of exosomes in the development of ''trained'' innate immunity during Plasmodium infection could provide novel therapeutic and prevention strategies against malaria infections.

Toll‐Like Receptor‐Based Adjuvants: A Gateway Toward Improved Malaria Vaccination

Chapter

Oct 2022

Understanding the mode of action of adjuvants and their ability to evoke immune responses is paramount to develop a constructive adjuvant for a vaccine. In the blood stages of malarial pathogenesis, an antibody‐mediated response is pivotal in controlling the parasitemia. However, the variability in patient group, age, and exposure to previous infections results in different B cell responses. Neonates and infants tend to develop slower responses, thus requiring booster doses in comparison with the adults, while exposed individuals at endemic areas develop sterile immunity. A protective malaria vaccine hence requires immunostimulants to promote prolonged B and T cell responses. Utilization of toll‐like receptor (TLR) adjuvants may provoke appropriate stimuli, priming the immune cells for an elicited response. TLR agonist‐based adjuvants may also utilize the property of these receptors being biphasic. Complicated malaria patients with TLR9 activation induce Tregs by suppressing the effector cells. This tends to develop an immunosuppressive environment. While regulated priming of plasmacytoid dendritic cells (pDCs) and macrophages enables pro‐ and anti‐inflammatory responses kindling cellular and humoral responses. These properties can be intensified by strategically using a combination of synthetic TLR adjuvants against malaria. In this chapter, we focus on enlightening the TLR agonists and the rationale behind the use of synthetic TLR‐based adjuvants for malaria vaccines.

References

Article

Apr 2014

Irwin Sherman

Selective Expression of Variant Surface Antigens Enables Plasmodium falciparum to Evade Immune Clearance in vivo

Preprint

Full-text available

Jul 2020

Plasmodium falciparum has developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based on in vitro studies of individual parasite variant surface antigens and how this relates to the processes in vivo is not well-understood. Here, we have used a humanized mouse model to identify parasite factors important for in vivo growth. We show that upregulation of the specific PfEMP1, VAR2CSA and the RIFIN PF3D7_1254800 provides the parasite with protection from macrophage phagocytosis and natural killer cell mediated killing. Taken together, these findings reveal new insights on the molecular and cellular mechanisms that coordinate the immune escape process the parasite utilizes in vivo . As immune evasion may be particularly important during the establishment of the blood stage infection when parasite numbers are still relatively small, identification of specific parasite variant surface antigens provides targets for developing more effective vaccines by targeting parasite immune evasion.

Malaria

Article

Sep 2013

Dendritic Cells subsets mediated immune response during Plasmodium berghei ANKA and Plasmodium yoelii infection. Cytokine. 2015. Doi 10.1016/j.cyto.2015.02.023

Article

Feb 2015

The roles of Dendritic cells (DCs) in mediating immunity against Plasmodium infection have been extensively investigated, but immune response during pathogenesis of malaria is still poorly understood. In the present study, we compared the splenic DCs phenotype and function during P. berghei ANKA (PbA) or P. yoelii (P.yoelii) infection in Swiss mice. We observed that PbA-infected mice developed more myeloid and mature DCs capable of secreting IL-12, while P. yoelii-infected mice had more plasmacytoid and immature DCs secreting higher levels of IL-10. Expression of FoxP3, IL-17, TGF-β and IL-6 were also different between these two infections. Thus, these results suggest that the phenotypic and functional subsets of splenic DCs are key factors for regulating immune responses to PbA and P. yoelii infections.

Tarun Keswani, Anirban Sengupta, Samrat Sarkar, Arindam Bhattacharyya. Dendritic Cells subsets mediated immune response during Plasmodium berghei ANKA and Plasmodium yoelii infection. Cytokine. 2015. Doi 10.1016/j.cyto.2015.02.023

Article

Feb 2015

Tarun Keswani

In Vivo Approaches Reveal a Key Role for DCs in CD4+ T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria

Article

Full-text available

Feb 2015

Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence sug-gesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first en-counter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasite-mia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during

Studies evaluating the possible evolution of malaria parasites in response to blood-stage vaccination

Article

Jan 2009

Victoria Charlotte Barclay

Drug resistance is one of the most medically relevant forms of pathogen evolution. To date, vaccines have not failed with the same depressing regularity as drugs. Does that then make vaccines evolution-proof? In the face of vaccination, pathogens are thought to evolve in two ways: by evolving epitope changes at the antigenic target of vaccination (epitope evolution); or by evolving changes at other antigenic loci, some of which may involve virulence (virulence evolution). The fundamental difference between these two forms of evolution is that virulence evolution could lead to disease outcomes in unvaccinated people that are more severe than would have been seen prior to evolution. One of the theoretical assumptions of virulence evolution is that more virulent parasites will have a selective advantage over less virulent parasites in an immunized host, and are thus more likely to be transmitted. The assumption is that more virulent parasites may be competitively more superior in mixed infections, or may be better able to evade/modulate the host immune response. Thus, the aim of this thesis was to experimentally test whether more virulent parasites have a within-host selective advantage in an immunized host or whether vaccine efficacy is more likely to depend on genetic differences at the targeted sites of vaccination. I used clones (genotypes) of the rodent malaria Plasmodium chabaudi originally derived from wild-caught Thicket (Thamnomys rutilans) rats to infect laboratory mice and a rodent analogue of the candidate blood-stage malaria vaccine apical membrane antigen 1 (AMA-1). I found that within-host selection did not depend on parasite virulence, and that protective efficacy depended on genotype-specific differences at the vaccine target. Vaccine-induced protection was not enhanced by including a number of allelic variants. However, such genotype-specific responses were only observed when the vaccine was tested against genetically distinct P. chabaudi parasites. When one P. chabaudi genotype was serially passaged through naïve mice the derived line was more virulent and was subsequently less well controlled by vaccine-induced immunity. In other experiments I found within host competition not to be immune-mediated. Thus my results suggest that vaccination has the potential to select for more virulent parasites but that the selective advantage is likely to be independent of competition. The selective advantage may be attributable to the enhanced immune evasion of more virulent parasites. However, without genetic markers of virulence, the mechanisms that mediate this selection remain unknown. My thesis contributes towards a growing body of evidence that vaccines have the potential to differently alter the within-host parasite dynamics of particular pathogen genotypes and that the selection imposed is likely to be system specific, depending on the fine specificity of the vaccine-induced responses and the identity of infecting parasites. Although vaccine potency may not be enhanced by including more than one allelic variant of an antigen, multi-valent vaccines may be one of the best ways to avoid the inadvertent selection for more virulent malaria parasites.

Dendritic Cells Induce Immunity and Long-Lasting Protection against Blood-Stage Malaria despite an In Vitro Parasite-Induced Maturation Defect

Article

Full-text available

Sep 2004
INFECT IMMUN

Dendritic cells (DC) suffer a maturation defect following interaction with erythrocytes infected with malaria parasites and become unable to induce protective malaria liver-stage immunity. Here we show that, by contrast, maturation-arrested DC in vitro are capable of the successful induction of antigen-specific gamma interferon (IFN-γ) and interleukin 4 (IL-4) T-cell responses, antibody responses, and potent protection against lethal blood-stage malaria challenge in vivo. Similar results were found with DC pulsed with intact parasitized Plasmodium yoelii or Plasmodium chabaudi erythrocytes. Cross-strain protection was also induced. High levels of protection (80 to 100%) against lethal challenge were evident from 10 days after a single immunization and maintained up to 120 days. Interestingly, correlation studies versus blood-stage protection at different time points suggest that the immune effector mechanisms associated with protection could change over time. Antibody-independent, T-cell- and IL-12-associated protection was observed early after immunization, followed by antibody and IL-4-associated, IFN-γ-independent protection in long-term studies. These results indicate that DC, even when clearly susceptible to parasite-induced maturation defect effects in vitro, can be central to the induction of protection against blood-stage malaria in vivo.

Transcriptional profiling of gamma delta T cells

Article

Full-text available

Nov 2003

High frequency of circulating gammadelta T cells with dominance of the Vdelta1 subset in a healthy population

Article

Full-text available

Jun 2000
INT IMMUNOL

Lars Hviid

TCR γδ cells constitute <5% of all circulating T cells in healthy, adult Caucasians, and V δ 1 cells constitute a minority of these cells. In contrast to TCR αβ cells, their repertoire is selected extrathymically by environmental antigens. Although increased frequencies of V δ 1 cells are found in several diseases, their function remains obscure. Here we show that the frequency of peripheral blood γδ T cells in healthy West Africans is about twice that of Caucasians, mainly due to a 5-fold increase in V δ 1 cells, which is consequently the dominant subset. No age dependency of V δ 1 frequencies was identified and the V δ 1 cells in the African donors did not show preferential V γ chain usage. Analysis of the CDR3 region size did not reveal any particular skewing of the V δ 1 repertoire, although oligoclonality was more pronounced in adults compared to children. The proportions of CD8 , CD38 and CD45RA hi CD45RO – cells within the V δ 1 subset were higher in the African than in the European donors, without obvious differences in expression of activation markers. No significant correlations between levels of V δ 1 cells and environmental antigens or immunological parameters were identified. Taken together, the evidence argues against a CDR3-restricted, antigen-driven expansion of V δ 1 cells in the African study population. Our study shows that high frequencies of TCR γδ cells with dominance of the V δ 1 subset can occur at the population level in healthy people, raising questions about the physiological role of V δ 1 T cells in the function and regulation of the immune system.

Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment [published erratum appears in J Exp Med 1993 Mar 1;177(3):following 873]

Article

Full-text available

Oct 1992

Evelin Schwarzer

Human monocyte-derived macrophages ingest diamide-treated red blood cells (RBC), anti-D immunoglobulin (Ig)G-opsonized RBC, or Plasmodium falciparum ring-stage parasitized RBC (RPRBC), degrade ingested hemoglobin rapidly, and can repeat the phagocytic cycle. Monocytes fed with trophozoite-parasitized RBC (TPRBC), which contain malarial pigment, or fed with isolated pigment are virtually unable to degrade the ingested material and to repeat the phagocytic cycle. Monocytes fed with pigment display a long-lasting oxidative burst that does not occur when they phagocytose diamide-treated RBC or RPRBC. The phorbol myristate acetate-elicited oxidative burst is irreversibly suppressed in monocytes fed with TPRBC or pigment, but not in monocytes fed with diamide-treated or IgG-opsonized RBC. This pattern of inhibition of phagocytosis and oxidative burst suggests that malarial pigment is responsible for the toxic effects. Pigment iron released in the monocyte phagolysosome may be the responsible element. 3% of total pigment iron is labile and easily detached under conditions simulating the internal environment of the phagolysosome, i.e., pH 5.5 and 10 microM H2O2. Iron liberated from pigment could account for the lipid peroxidation and increased production of malondialdehyde observed in monocytes fed with pigment or in RBC ghosts and liposomes incubated at pH 6.5 in presence of pigment and low amounts of H2O2. Removal of the labile iron fraction from pigment by repeated treatments with 0.1 mM H2O2 at pH 5.5 reduces pigment toxicity. It is suggested that iron released from ingested pigment is responsible for the intoxication of monocytes. In acute and chronic falciparum infections, circulating and tissue-resident phagocytes are seen filled with TPRBC and pigment particles over long periods of time. Moreover, human monocytes previously fed with TPRBC are unable to neutralize pathogenic bacteria, fungi, and tumor cells, and macrophage responses decline during the course of human and animal malaria. The present results may offer a mechanistic explanation for depression of cellular immunity in malaria.

CD4−CD8αα Subset of CD1d-Restricted NKT Cells Controls T Cell Expansion1

Article

Full-text available

Jun 2004

Vα24 invariant (Vα24i) CD1d-restricted NKT cells are widely regarded to have immune regulatory properties. They are known to have a role in preventing autoimmune diseases and are involved in optimally mounted immune responses to pathogens and tumor cells. We were interested in understanding how these cells provide protection in autoimmune diseases. We first observed, using EBV/MHC I tetrameric complexes, that expansion of Ag-specific cells in human PBMCs was reduced when CD1d-restricted NKT cells were concomitantly activated. This was accompanied by an increase in a CD4−CD8αα+ subset of Vα24i NKT cells. To delineate if a specific subset of NKT cells was responsible for this effect, we generated different subsets of human CD4− and CD4+ Vα24i NKT clones and demonstrate that a CD4−CD8αα+ subset with highly efficient cytolytic ability was unique among the clones in being able to suppress the proliferation and expansion of activated T cells in vitro. Activated clones were able to kill CD1d-bearing dendritic or target cells. We suggest that one mechanism by which CD1d-restricted NKT cells can exert a regulatory role is by containing the proliferation of activated T cells, possibly through timely lysis of APCs or activated T cells bearing CD1d.

IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells

Article

Full-text available

Apr 2000

The cellular and humoral immune system is critically dependent upon CD40-CD154 (CD40 ligand) interactions between CD40 expressed on B cells, macrophages, and dendritic cells, and CD154 expressed primarily on CD4 T cells. Previous studies have shown that CD154 is transiently expressed on CD4 T cells after T cell receptor engagement in vitro. However, we found that stimulation of PBLs with maximal CD28 costimulation, using beads coupled to Abs against CD3 and CD28, led to a very prolonged expression of CD154 on CD4 cells (>4 days) that was dependent upon autocrine IL-2 production. Previously activated CD4 T cells could respond to IL-2, or the related cytokine IL-15, by de novo CD154 production and expression without requiring an additional signal from CD3 and CD28. These results provide evidence that CD28 costimulation of CD4 T cells, through autocrine IL-2 production, maintains high levels of CD154 expression. This has significant impact on our understanding of the acquired immune response and may provide insight concerning the mechanisms underlying several immunological diseases.

Cutting Edge: Differentiation of Human NK Cells into NK1 and NK2 Subsets1

Article

Full-text available

Dec 1998

Human NK cells cultured in the presence of IL-12 or IL-4 differentiate into cell populations with distinct patterns of cy- tokine secretion similar to Th1 and Th2 cells. NK cells grown in IL-12 (NK1) produce IL-10 and IFN-g, whereas NK cells grown in IL-4 (NK2) produce IL-5 and IL-13. Although these NK cell subsets do not differ in cytotoxic activity, NK1 cells express higher levels of cell surface CD95 (Fas) Ag than NK2 cells and are more sensitive to Ab or chemically induced apo- ptosis. Like Th1 cells, NK1 cells accumulate much higher levels of the IL-12Rb2-chain mRNA and are significantly more re- sponsive to IL-12 than NK2 cells at the level of activation of STAT4 transcription factor. The identification of NK cell sub- sets that are analogous to T cell subsets suggests a new role for NK cells in innate inflammatory responses and in their effect on adaptive immunity. The Journal of Immunology, 1998, 161: 5821-5824.

A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses

Article

Full-text available

Jun 2000

New strategies are required to identify the most important targets of protective immunity in complex eukaryotic pathogens. Natural selection maintains allelic variation in some antigens of the malaria parasite Plasmodium falciparum 1, 2, 3. Analysis of allele frequency distributions could identify the loci under most intense selection4, 5, 6, 7. The merozoite surface protein 1 (Msp1) is the most-abundant surface component on the erythrocyte-invading stage of P. falciparum 8, 9, 10. Immunization with whole Msp1 has protected monkeys completely against homologous11 and partially against non-homologous12 parasite strains. The single-copy msp1 gene, of about 5 kilobases, has highly divergent alleles13 with stable frequencies in endemic populations14, 15. To identify the region of msp1 under strongest selection to maintain alleles within populations, we studied multiple intragenic sequence loci in populations in different regions of Africa and Southeast Asia. On both continents, the locus with the lowest inter-population variance in allele frequencies was block 2, indicating selection in this part of the gene. To test the hypothesis of immune selection, we undertook a large prospective longitudinal cohort study. This demonstrated that serum IgG antibodies against each of the two most frequent allelic types of block 2 of the protein were strongly associated with protection from P. falciparum malaria.

Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, and Colonna M. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 5: 919-923

Article

Full-text available

Aug 1999

We have identified two cell subsets in human blood based on the lack of lineage markers (lin−) and the differential expression of immunoglobulin-like transcript receptor 1 (ILT1) and ILT3. One subset (lin −/ILT3+/ILT1+) is related to myeloid dendritic cells. The other subset (lin−/ILT3+ /ILT1−) corresponds to 'plasmacytoid monocytes'. These cells are found in inflamed lymph nodes in and around the high endothelial venules. They express CD62L and CXCR3, and produce extremely large amounts of type I interferon after stimulation with influenza virus or CD40L. These results, with the distinct cell phenotype, indicate that plasmacytoid monocytes represent a specialized cell lineage that enters inflamed lymph nodes at high endothelial venules, where it produces type I interferon. Plasmacytoid monocytes may protect other cells from viral infections and promote survival of antigen-activated T cells.

Immunobiology of Dendritic Cells

Article

Full-text available

Apr 2000
ANNU REV IMMUNOL

Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cellâ€“mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria

Article

Full-text available

Jan 2000

Infection with Plasmodium falciparum during pregnancy leads to the accumulation of parasite-infected erythrocytes in the placenta, and is associated with excess perinatal mortality, premature delivery and intrauterine growth retardation in the infant, as well as increased maternal mortality and morbidity. P. falciparum can adhere to specific receptors on host cells, an important virulence factor enabling parasites to accumulate in various organs. We report here that most P. falciparum isolates from infected placentae can bind to hyaluronic acid, a newly discovered receptor for parasite adhesion that is present on the placental lining. In laboratory isolates selected for specific high-level adhesion, binding to hyaluronic acid could be inhibited by dodecamer or larger oligosaccharide fragments or polysaccharides, treatment of immobilized receptor with hyaluronidase, or treatment of infected erythrocytes with trypsin. In vitro flow-based assays demonstrated that high levels of adhesion occurred at low wall shear stress, conditions thought to prevail in the placenta. Our findings indicate that adhesion to hyaluronic acid is involved in mediating placental parasite accumulation, thus changing the present understanding of the mechanisms of placental infection, with implications for the development of therapeutic and preventative interventions.

γδ+ T Cells Preferentially Respond to Live Rather than Killed Malaria Parasites

Article

Full-text available

May 1998

We have compared the in vitro responses of peripheral blood T cells from malaria-unexposed donors to live Plasmodium falciparum schizonts, freeze-thawed schizont extracts (P. falciparum schizont extracts [PfSE]), and parasite culture supernatants. We show that the cells responding to PfSE and parasite culture supernatants are predominantly CD4+ TCR alphabeta+ while in the presence of live schizonts there is an additional activation of TCR gammadelta+ cells. Activation of TCR gammadelta+ cells in response to PfSE was seen only when irradiated autologous feeder cells or recombinant interleukin-2 (IL-2) was added to the cultures. Live schizonts but not PfSE induced significant IL-2 production in vitro in the first 5 days after stimulation, suggesting that induction of early IL-2 by live parasites may contribute to the marked activation of the TCR gammadelta+ population.

Phagocytosis of the Malarial Pigment, Hemozoin, Impairs Expression of Major Histocompatibility Complex Class II Antigen, CD54, and CD11c in Human Monocytes

Article

Full-text available

Apr 1998

In Plasmodium falciparum malaria, large proportions of resident macrophages and circulating monocytes and leukocytes contain massive amounts of the malarial pigment, hemozoin. Previous studies have shown that important functions (e.g., the generation of the oxidative burst, the ability to repeat phagocytosis, and protein kinase C activity) were severely impaired in hemozoin-loaded monocytes. Expression of membrane antigens directly involved in the immune response and in the phagocytic process, and/or under protein kinase C control, in hemozoin-loaded human monocytes was studied. Expression of major histocompatibility complex (MHC) class II after gamma interferon stimulation was blocked in hemozoin-loaded monocytes at the protein expression and gene transcription levels but was preserved in control monocytes loaded with opsonized latex beads or anti-D(Rho)-immunoglobulin G (IgG)-opsonized human erythrocytes. Expression of CD54 (intracellular adhesion molecule 1) and CD11c (p150,95 integrin) was also decreased in hemozoin-loaded monocytes. Expression of MHC class I, CD16 (low-affinity Fc receptor for aggregated IgG), CD32 (low-affinity Fc receptor for aggregated IgG), CD64 (high-affinity receptor for IgG), CD11b (receptor for complement component iC3b [CR3]), CD35 (receptor for complement components C3b and C4b [CR1]), and CD36 (non-class-A scavenger receptor) was not specifically affected by hemozoin loading. These results suggest that hemozoin loading may contribute to the impairment of the immune response and the derangement of antigen presentation reported in previous studies of P. falciparum malaria.

Risk of Severe Malaria among African Infants: Direct Evidence of Clinical Protection during Early Infancy

Article

Full-text available

Mar 1998

Little empirical evidence from field-based studies exists on the relative magnitude or duration of clinical protection from Plasmodium falciparum malaria in infancy. A prospective study was undertaken to examine the age distribution of hospital admissions in four geographically and demographically well-defined areas with differing intensities of P. falciparum transmission. Where transmission was perennial, significant clinical protection from severe morbidity was observed up to the third month of life; in the seasonal transmission area, disease rates rose after the sixth month of life. Infants exposed to the highest rates of P. falciparum exposure demonstrated significant declines in the risks of severe malaria from 6 months of age. These data provide direct evidence for the very early acquisition of clinical immunity and for the existence of a period of clinical protection, which together may explain why, in these communities, the cumulative risk of malarial disease throughout childhood appears to decline with increasing transmission intensity.

Rich SM, Ayala FJ. Population structure and recent evolution of Plasmodium falciparum. Proc Natl Acad Sci USA 97: 6994-7001

Article

Full-text available

Jul 2000

Plasmodium falciparum is the agent of malignant malaria, one of mankind's most severe maladies. The parasite exhibits antigenic polymorphisms that have been postulated to be ancient. We have proposed that the extant world populations of P. falciparum have derived from one single parasite, a cenancestor, within the last 5,000–50,000 years. This inference derives from the virtual or complete absence of synonymous nucleotide polymorphisms at genes not involved in immune or drug responses. Seeking to conciliate this claim with extensive antigenic polymorphism, we first note that allele substitutions or polymorphisms can arise very rapidly, even in a single generation, in large populations subject to strong natural selection. Second, new alleles can arise not only by single-nucleotide mutations, but also by duplication/deletion of short simple-repeat DNA sequences, a process several orders of magnitude faster than single-nucleotide mutation. We analyze three antigenic genes known to be extremely polymorphic: Csp, Msp-1, and Msp-2. We identify regions consisting of tandem or proximally repetitive short DNA sequences, including some previously unnoticed. We conclude that the antigenic polymorphisms are consistent with the recent origin of the world populations of P. falciparum inferred from the analysis of nonantigenic genes.

An Immunohistochemical Study of the Pathology of Fatal Malaria: Evidence for Widespread Endothelial Activation and a Potential Role for Intercellular Adhesion Molecule-1 in Cerebral Sequestration

Article

Full-text available

Dec 1994

The sequestration of parasitized erythrocytes in the microvasculature of vital organs is central to the pathogenesis of severe Plasmodium falciparum malaria. This process is mediated by specific interactions between parasite adherence ligands and host receptors on vascular endothelium such as intercellular adhesion molecule-1 (ICAM-1) and CD36. Using immunohistochemistry we have examined the distribution of putative sequestration receptors in different organs from fatal cases of P. falciparum malaria and noninfected controls. Receptor expression and parasite sequestration in the brain were quantified and correlated. Fatal malaria was associated with widespread induction of endothelial activation markers, with significantly higher levels of ICAM-1 and E-selectin expression on vessels in the brain. In contrast, cerebral endothelial CD36 and thrombospondin staining were sparse, with no evidence for increased expression in malaria. There was highly significant co-localization of sequestration with the expression of ICAM-1, CD36, and E-selectin in cerebral vessels but no cellular inflammatory response. These results suggest that these receptors have a role in sequestration in vivo and indicate that systemic endothelial activation is a feature of fatal malaria.

Plasmodium falciparum rosetting is associated with malaria severity in Kenya

Article

Full-text available

Jun 1995

Rosette formation in 154 fresh Plasmodium falciparum isolates from Kenyan children with mild (n = 54), moderate (n = 64), or severe (n = 36) malaria was studied to determine whether the ability to form rosettes in vitro is correlated with malaria severity. There was a wide distribution of rosette frequencies within each clinical category; however, a clear trend towards higher rosette frequency with increasing severity of disease was seen, with the median rosette frequency of the mild-malaria group (1%; range, 0 to 82%) being significantly lower than those of the moderate-malaria group (5%; range, 0 to 45%; Mann-Whitney U test, P < 0.02) and the severe-malaria group (7%; range, 0 to 97%; Mann-Whitney U test, P < 0.003). Within the severe-malaria category there was no difference in rosetting among isolates from cerebral malaria patients or those with other forms of severe malaria. We also examined the ABO blood groups of the patients from whom isolates were obtained and found that isolates from group O patients (median rosette frequency, 2%; range 0 to 45%) rosetted less well than those from group A (median, 7%; range 0 to 82%; Mann-Whitney U test, P < 0.01) or group AB (median, 11%; range 0 to 94%; Mann-Whitney U test, P < 0.03). We therefore confirm that rosetting is associated with severe malaria and provide further evidence that rosetting is influenced by ABO blood group type. Whether rosetting itself plays a direct role in the pathogenesis of severe malaria or is a marker for some other causal factor remains unknown.

CD4POS, NK1.1POS T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3

Article

Full-text available

May 1994

Injection of anti-CD3 antibodies causes prompt expression of interleukin (IL)-4, IL-2, and interferon gamma (IFN-gamma) mRNA among spleen cells. The optimal dose of anti-CD3 for such induction was 1.33 microgram/animal; lymphokine mRNA was first observed at 30 min, peaked at 90 min, and was undetectable (for IL-4) or had declined markedly by 4 h. Cells harvested from spleens of mice injected with anti-CD3 90 min earlier secreted IL-4, IL-2, and IFN-gamma without further stimulation. By contrast, in vitro stimulation with anti-CD3 of spleen cell suspensions or splenic fragments from noninjected donors failed to cause prompt production of IL-4 and, even after 24 h of stimulation, the amount of IL-4 produced in such cells was substantially less than that secreted within 1 h by spleen cell suspensions or splenic fragments from mice injected with anti-CD3 90 min earlier. Production of IL-4 by spleen cells from anti-CD3-injected mice was not inhibited by pretreatment with anti-IL-4 antibody or with IFN-gamma or tumor growth factor beta nor enhanced by treatment with IL-4. By contrast, CTLA-4 immunoglobulin (Ig) treatment clearly diminished IL-4 production in response to in vivo anti-CD3, indicating that cellular interactions involving CD28 (or related molecules) were important in stimulation. Cell sorting analysis indicated that the cells that produced IL-4 in response to in vivo injection of anti-CD3 were highly enriched in CD4pos cells with the phenotype leukocyte cell adhesion molecule-1 (LECAM-1)dull, CD44bright, CD45RBdull, NK1.1pos. Indeed, the small population of CD4pos, NK1.1pos cells had the great majority of the IL-4-producing activity of this population. Injection with Staphylococcal enterotoxin B also caused prompt induction of IL-4 mRNA; the cells that were principally responsible for production also had the phenotype of CD4pos, NK1.1pos. These results suggest that possibility that this rare population of T cells may be capable of secreting IL-4 at the outset of immune responses and thus may act to regulate the pattern of priming of naive T cells, by providing a source of IL-4 to favor the development of T cell helper 2-like IL-4-producing cells.

Clearance kinetics of parasite and pigment-containing leukocytes in severe malaria

Article

Full-text available

Dec 1996

In tropical areas, where unsupervised use of antimalarial drugs is common, patients with an illness consistent clinically with severe malaria but with negative blood smears pose a management dilemma. Malaria pigment is evident in peripheral blood leukocytes in greater than 90% of patients with severe malaria. To characterize the clearance kinetics of parasitized erythrocytes and malaria pigment-containing leukocytes, sequential peripheral blood and intradermal smears were assessed in 27 adult Vietnamese patients with severe falciparum malaria. The clearance of parasitized erythrocytes and pigment-containing monocytes (PCMs) followed first order kinetics. The elimination of pigment-containing neutrophils (PCNs) was first order initially, but deviated from this when counts were low. Clearance of peripheral blood PCMs (median clearance time, 216 hours; range, 84 to 492 hours) was significantly slower than that of parasitized erythrocytes (median, 96 hours; range, 36 to 168 hours) or PCNs (median, 72 hours; range, 0 to 168 hours; P < .0001). Intradermal PCM clearance times were the longest of all (median, 12 days; range, 6 to 23 days; significantly longer than peripheral blood PCM clearance, P < .001). Twenty-one (88%) patients still had signs, symptoms, or laboratory features of severe malaria after parasite clearance but before phagocyte pigment clearance. Sixteen of the 23 surviving patients (70%; 95% confidence interval, 50% to 87%) still had intraleukocytic malaria pigment on peripheral blood films 72 hours after parasite clearance. Thus, by determining the distribution of malaria pigment in peripheral blood and intradermal phagocytes, the time since effective antimalarial treatment started can be estimated. Microscopy for intraleukocytic pigment is valuable in the differential diagnosis of severe febrile illnesses in malarious areas where uncontrolled use of antimalarial drugs is widespread.

Early gamma interferon responses in lethal and nonlethal murin blood-stage malaria

Article

Full-text available

Jun 1997

This study was undertaken to explore early differences in cytokine production during nonlethal and lethal blood-stage murine malaria infections. Cytokine analysis of spleens during these infections showed that the principal difference between two nonlethal and two lethal Plasmodium species was the production of gamma interferon 24 h after infection with nonlethal parasites. In contrast, no increases in interleukin-4 production were observed in the first 24 h and tumor necrosis factor alpha levels increased equally in both nonlethal and lethal infections. During the later phase of infection with nonlethal parasites, both gamma interferon and interleukin-4 levels increased markedly a few days before parasite clearance. Early increases in gamma interferon production in nonlethal infections of Plasmodium yoelii and Plasmodium chabaudi were dose related and increased significantly with the size of the inoculum. Studies with the nonlethal P. yoelii suggest that the early gamma interferon response is mediated by T cells and natural killer cells, as it was reduced in athymic mice and in mice depleted of their natural killer cells by treatment with specific antiserum. Infecting mice with increasing numbers of lethal P. yoelii and Plasmodium berghei parasites did not increase the amount of gamma interferon, interleukin-4, and tumor necrosis factor alpha produced in a dose-dependent fashion. We conclude that one consequence of the early production of gamma interferon and tumor necrosis factor-alpha, particularly after nonlethal P. yoelii infection, may be to adjust the balance of T-helper cell subset activation, and probably that of other immune responses, so as to enhance the mechanisms that are essential for elimination of the parasites. This suggests that a successful vaccine should contain antigens capable of inducing such responses.

In vivo removal of malaria parasites from red blood cells without their destruction in acute

Article

Full-text available

Oct 1997

During acute falciparum malaria infection, red blood cells (RBC) containing abundant ring-infected erythrocyte surface antigen (Pf 155 or RESA), but no intracellular parasites, are present in the circulation. These RESA-positive parasite negative RBC are not seen in parasite cultures in vitro. This indicates that in acute falciparum malaria there is active removal of intraerythrocytic parasites by a host mechanism in vivo (probably the spleen) without destruction of the parasitized RBC. This may explain the observed disparity between the drop in hematocrit and decrease in parasite count in some hyperparasitemic patients. The fate of these "once-parasitized" RBC in vivo is not known.

Hemozoin is a key factor in the induction of malaria-associated immunosuppression

Article

Jan 1999

Toll-like receptor expression reveals CpG DNA aa a unique microbial stimulus for plasmacytoid dendritic edla which synergizes with CD40L to induce high amounts of IL-I 2

Article

Jan 2001

Malaria and the red cell

Article

Jul 2004

Susceptibility to malaria as a complex trait: big pressure from a tiny creature

Article

Oct 2002
HUM MOL GENET

A. Fortin

Malaria, which is a major infectious disease worldwide, is caused by the Plasmodium parasite, one of the longest-known parasites infecting humans. The malaria situation is complicated by the emergence of drug resistance and the lack of an effective vaccine. Genetic factors play a key role in disease susceptibility, progression and outcome. Interestingly, an increasing large number of polymorphisms associated with resistance and susceptibility in humans have been found in proteins from erythrocytes, the site of Plasmodium replication. Some of these deleterious alleles have been selected by direct genetic pressure from the parasite in endemic areas of malaria. A number of additional gene effects have been mapped both in humans and in mice using population studies and experimental models of malaria, respectively. These recent studies have started to reveal additional aspects of the complex host-parasite interactions.

Malaria and the Red Cell

Article

Jan 2002

David J. Weatherall

Because of the breakdown of malaria control programs, the constant emergence of drug resistant parasites, and, possibly, climatic changes malaria poses a major problem for the developing countries. In addition, because of the speed of international travel it is being seen with increasing frequency as an imported disease in non-tropical countries. This update explores recent information about the pathophysiology of the disease, its protean hematological manifestations, and how carrier frequencies for the common hemoglobin disorders have been maintained by relative resistance to the malarial parasite. In Section I, Dr. Louis Miller and colleagues consider recent information about the pathophysiology of malarial infection, including new information about interactions between the malarial parasite and vascular endothelium. In Section II, Dr. David Roberts discusses what is known about the complex interactions between red cell production and destruction that characterize the anemia of malaria, one of the commonest causes of anemia in tropical countries. In Section III, Dr. David Weatherall reviews recent studies on how the high gene frequencies of the thalassemias and hemoglobin variants have been maintained by heterozygote advantage against malaria and how malaria has shaped the genetic structure of human populations.

An analysis of the geographical distribution of severe malaria in children in Kilifi District, Kenya

Article

Apr 1998
INT J EPIDEMIOL

J.R.M.Armstrong Schellenberg

Background Although malaria is known to be a major cause of child mortality and morbidity throughout sub-Saharan Africa there are few detailed studies of malaria mortality rates and incidence of severe malarial disease in defined communities. We have studied the geographical pattern of admissions to hospital with severe malaria and the stability of this pattern over time in Kilifi District on the Kenyan Coast. Methods Over a 2-year period all children under 5 years of age with severe malaria admitted to the district hospital and living in a rural study population of about 50 000 people were identified. Annual censuses were carried out in the study area, and all households were mapped using a hand-held satellite navigation system. The resulting databases were linked using a geographical information system (GIS). Results Using methods originally developed for the study of the geographical distribution of childhood leukaemia we assessed the spatial pattern of hospital admission rates for severe malaria. As expected, admission rates were significantly higher in children with easier access to the hospital. For example, those living more than 25 km from the hospital had admission rates which were about one-fifth of those for children living within 5 km of the hospital. Those living more than 2.5 km from the nearest road had admission rates that were about half of those for children living within 0.5 km of a road. We also investigated short-term local fluctuations in severe malaria and found evidence of space-timeclusteringof severe malaria. Conclusions Hospital admission rates for severe malaria are higher in households with better access to hospital than in those further away. The finding of space-time clusters of severe malaria suggests that it would be of value to conduct case-control studies of environmental, genetic and human behavioural factors involved in the aetiology of the disease.

Contact-dependent Stimulation and Inhibition of Dendritic Cells by Natural Killer Cells

Article

Feb 2002

Diego Piccioli

Natural killer (NK) cells and dendritic cells (DCs) are two distinct cell types of innate immunity. It is known that the in vitro interaction of human NK cells with autologous DCs results in DC lysis. Here we show that contact-dependent interactions between activated human NK cells and immature DCs (iDCs) provides a “control switch” for the immune system. At low NK/DC ratios, this interaction dramatically amplifies DC responses, whereas at high ratios it completely turns off their responses. Specifically, culture of activated human NK cells with iDCs, at low NK/DC ratios (1:5), led to exponential increases in DC cytokine production, which were completely dependent on cell-to-cell contact. DC maturation was also driven by cognate interactions with NK cells and maturation was dependent on endogenously produced TNF-α in the culture. At slightly higher NK/DC ratios (5:1), inhibition of DC functions was the dominant feature due to potent killing by the autologous NK cells. Resting NK cells also stimulated autologous DC maturation in a TNF-α/contact-dependent manner, however, increasing the NK/DC ratio only led to an enhancement of this effect.

Critical role of IL15–IL15R for antigen-presenting cell functions in the innate immune response

Article

Nov 2001

Activation of dendritic cells (DCs) and macrophages by infectious agents leads to secretion of interleukin 12 (IL-12), which subsequently induces interferon-γ (IFN-γ) production by multiple cell types that include DCs and macrophages. In turn, IFN-γ acts on macrophages to augment IL-12 secretion and to produce nitric oxide (NO), which eradicates infected microbes. We show here that in cytokine common γ subunit–deficient and/or IL-2 receptor β–deficient mice, production of IL-12, IFN-γ and NO by DCs and macrophages was severely impaired, as was up-regulation of major histocompatibility complex class II and CD40. Similar phenotypes were observed in DCs and macrophages from IL-15–deficient mice but not in those from IL-2–deficient mice. This shows that the IL-15–IL-15R interaction is critical in early activation of antigen-presenting cells and plays an important role in the innate immune system.

Basic Immunology Human γδT Cells that Inhibit the In Vitro Growth of the Asexual Blood Stages of the Plasmodium falciparum Parasite Express Cytolytic and Proinflammatory Molecules

Article

Dec 1999

Marita Troye-Blomberg

The functional properties, regarding parasite growth inhibition in vitro , the cytotoxic potential and cytokine profiles of human γδ ⁺ and αβ ⁺ T cells, T‐cell lines and clones stimulated with Plasmodium falciparum‐ antigen‐or T‐cell mitogen in vitro were investigated. Using reverse transcriptase‐polymerase chain reaction (RT‐PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the γδ‐ and the αβT cells. Despite this fact, only γδT cells inhibited, both Vδ1 ⁺ and Vδ2 ⁺ , the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell‐to‐cell contact and was not observed until the second parasite replication implied that the likely γδT‐cell target was the extracellular merozoite or schizont. The failure of αβT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the γδT cells. Both the γδ‐ and αβT cells expressed mRNA for a large number of cytokines. Interferon (IFN)‐γ, interleukin (IL) IL‐5, IL‐6, IL‐8, tumour necrosis factor alpha (TNFα), tumour necrosis factor beta (TNF‐β)/lymphotoxin (LT) and T‐cell growth factor beta‐1 (TGF‐β1) were observed in all activated clones tested. No IL‐3 was detected, while IL‐1β, IL‐2, IL‐4, IL‐10 and GM‐CSF were variably expressed. In conclusion, our data show that γδT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated αβT cells do not. Thus, it is likely that the γδT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.

The response of γδ T cells in malaria infections: a hypothesis

Article

Dec 1994
Res Immunol

Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset

Article

May 2001
BLOOD

Megan A. Cooper

During the innate immune response to infection, monocyte-derived cytokines (monokines), stimulate natural killer (NK) cells to produce immunoregulatory cytokines that are important to the host's early defense. Human NK cell subsets can be distinguished by CD56 surface density expression (ie, CD56bright and CD56dim). In this report, it is shown that CD56bright NK cells produce significantly greater levels of interferon-γ, tumor necrosis factor-β, granulocyte macrophage–colony-stimulating factor, IL-10, and IL-13 protein in response to monokine stimulation than do CD56dim NK cells, which produce negligible amounts of these cytokines. Further, qualitative differences in CD56bright NK-derived cytokines are shown to be dependent on the specific monokines present. For example, the monokine IL-15 appears to be required for type 2 cytokine production by CD56bright NK cells. It is proposed that human CD56bright NK cells have a unique functional role in the innate immune response as the primary source of NK cell–derived immunoregulatory cytokines, regulated in part by differential monokine production.

Malaria susceptibility and CD36 mutation

Article

Jun 2000

A critical step in infection by Plasmodium falciparum, the microorganism that causes the most severe form of malaria, is the adhesion of parasitized red blood cells to capillary endothelium. The human protein CD36 is a major receptor for P. falciparum-infected red blood cells1, 2 and may contribute to the disease by sequestering infected red blood cells1, 2 and inhibiting the immune response to the parasite3. We have found that African populations contain an exceptionally high frequency of mutations in CD36. Unexpectedly, these mutations that cause CD36 deficiency are associated with susceptibility to severe malaria, suggesting that the presence of distinct CD36 mutations in Africans and Asians4, 5, 6 is due to some selection pressure other than malaria.

Involvement of interleukin-18 in severe Plasmodium falciparum malaria

Article

Mar 2003

Serum levels of interleukin-18 (IL-18), interferon-gamma (IFN-gamma), and immunoglobulin E (IgE) were determined for 96 patients with Plasmodium falciparum malaria admitted to hospital, Bangkok, Thailand in the period 1998-2000. The patients were divided into 3 groups, i.e. uncomplicated, severe and cerebral malaria according to WHO criteria (2000). Elevation of IL-18 levels was observed in all 3 groups, with a tendency for higher levels in cases with severe malaria throughout the course of the disease. Moreover, there was a significant correlation between IL-18 levels and the extent of parasitaemia among patients with severe malaria. However, IL-18 levels decreased more significantly in patients with cerebral malaria compared with the other groups in the late stage of the disease. Elevated levels of IFN-gamma were also observed in all groups of patients, especially in those with severe or cerebral malaria, and the levels in patients with cerebral malaria remained significantly higher than in those with uncomplicated malaria during days 4-7 post-treatment, suggesting the involvement of IFN-gamma in disease severity. Meanwhile, no significant difference was observed in IgE levels between the severe and uncomplicated groups of patients with helminth infection, although IgE levels were significantly higher in helminth-infected patients than uninfected patients. These results suggest that IL-18 plays a key role in inducing severe malaria through another pathway, such as elevation of IFN-gamma, rather than its IgE inducing activity.

The Passive Transfer of Human Malarial Immunity

Article

Jan 1964

I.A. McGregor

Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells

Article

Apr 1996
EUR J IMMUNOL

Interleukin-12 (IL-12), a 70-kDa heterodimeric cytokine composed of covalently linked p35 and p40 chains, is to date the most critical factor for skewing the immune response towards a T helper 1 (Th1) of cytokine profile [high interferon-γ (IFN-γ), low IL-4]. Established sources of IL-12 are stimulated macrophages, neutrophils and B cells. As dendritic cells (DC) process antigen in the periphery and then migrate to lymphoid organs to sensitize T cells and induce cell-mediated immunity, we reasoned that DC should constitute a critical source of IL-12. The criteria used to detect IL-12 in DC were the demonstration of p40 and p35 mRNA (semiquantitative polymerase chain reaction, Northern blotting, and in situ hybridization) as well as IL-12 protein (p70 enzyme-linked immunosorbent assay, p70 antigen capture followed by IFN-γ bioassay, free p40 chain radioimmunoassay or immunoprecipitation). We found that conventional stimuli such as Staphylococcus aureus induced production of IL-12 bymurine as well as human DC in amounts comparable to spleen cells, peritoneal macrophages or peripheral blood mononuclear cells. DC exhibited, however, features that had not been seen with other antigen-presenting cells: they produced bioactive IL-12 upon antigen-specific interaction with T cells without any other stimuli; in an allogeneic mixed leukocyte reaction model, neutralizing anti-IL-12 antibodies showed that DC-derived IL-12 was critical for optimal proliferation and IFN-γ production by activated Th1 blasts; and finally, the priming of resting, naive allogeneic T cells by DC, followed by restimulation of primed T blasts by DC, skewed the response to Th1 without the need for any exogenous cytokines or stimuli such as microorganisms. This skewing to Th1 cytokine production, which depended on DC-derived IL-12, but did not require anti-IL-4, exogenous IL-12, or microbes, might be a major function of DC.

γδ T cells in malaria infections

Article

May 1996
Parasitol Today

Jean Langhorne

The association of a pronounced γδ T-cell response with Plasmodium infections is intriguing. The ability of parasite material to activate γδ T cells in vitro, and the localization of these cells in vivo in the red pulp of the spleen, suggests that these cells could play a role in the killing of bloodstage malaria parasites. However, the magnitude, the response and the predominance of inflammatory cytokines secreted by these cells may also indicate a role in the pathology of malaria infections. In this article, Jean Langhorne reveiws the current status of γδ T cells in malaria in the context of what is known about the function and specificity of γδ T cells in general.

Modulation of host responses to blood-stage malaria by interleukin-12: from therapyto adjuvant activity

Article

Jan 2001

This review focuses on the role of interleukin (IL)-12, a proinflammatory cytokine with pleiotropic effects as a potent immunoregulatory molecule and hematopoietic growth factor, in infection with Plasmodium parasites, the causative agents of malaria. IL-12 has been demonstrated to have profound effects on the immune response to blood-stage malaria, to induce protection, and to alleviate malarial anemia. In combination with an anti-malarial drug, IL-12 is effective in an established malaria infection. This cytokine also has potent immune effects as a malaria vaccine adjuvant. However, IL-12 can also mediate pathology during blood-stage malaria.

Periodicity and space-time clustering of severe childhood malaria on the coast of Kenya

Article

Jul 1993

Traditionally malaria epidemiology has focused on factors such as parasite rates and vector dynamics without specific reference to disease. There are limited comprehensive data on malaria as a life-threatening event in African children. We have identified, through hospital surveillance, 581 episodes of severe malaria in residents of a defined area on the Kenya coast over a period of 3 years. This represents an absolute minimum risk of developing severe malaria by the fifth birthday of 1 in 15. The presentation of severe malaria showed marked seasonality, but the timing and magnitude of these fluctuations varied considerably between years. A satellite navigational system was used to define the exact location of the home of each severe malaria case. Space-time clustering of severe malaria was evident in this community. Seasonal peaks in incidence of severe malaria may comprise discrete mini-epidemics. In contrast, parasite rates in the community varied little during the course of the surveillance. The monitoring of disease, as opposed to parasitization, in children may result in more effective targeting of intervention resources.

Malarial immunodepression in vitro. Adherent spleen cells are functionally defective as accessory cells in the response to horse erythrocytes

Article

Nov 1976

The basis for the depressed response of malarial infected mice to horse red blood cells (HRBC) has been studied in vitro. Results presented show that the adherent spleen cells from infected mice (a) are defective in their ability to allow nonadherent spleen cells of both normal and infected mice to respond to HRBC whereas a response does occur with adherent spleen cells from normal mice (b) do not suppress the response of unfractionated spleen cells from normal mice to HRBC (c) contain phagocytic cells as measured by the uptake of neutral red in numbers which are of the same order of magnitude as in adherent spleen cells from normal mice, but which are unable to take up HRBC. We conclude that a splenic adherent cell, probably the macrophage is functionally defective as an accessory cell in the response to HRBC of mice infected with Plasmodium berghei yoelii.

Cytotoxicity of human natural killer (NK) cell subsets for Plasmodium falciparum erythrocytic schizonts: Stimulation by cytokines and inhibition by neomycin

Article

Nov 1991

Quantification of human peripheral blood NK subsets has been made in a group of Kenyan adults and children with acute P. falciparum malaria. Results were compared with data obtained from three age- and sex-matched control cohorts: parasitaemic but asymptomatic children; aparasitaemic children and adults; and adult Caucasians with no previous history of malaria. Separated NK subsets were tested in vitro for cytotoxicity to erythrocytic schizonts of P. falciparum in the presence and absence of cytokines. There was a statistically significant quantitative and qualitative depression of the CD3-CD56+ subset in patients with acute malaria and this was accompanied by an expansion of the 'non-functional' CD3-CD57+CD16-CD56- subset. Both CD3-CD16+ and CD3-CD56+ NK cells from all patients and donors lysed schizonts, and this cytotoxicity was enhanced by the addition of recombinant interferon-alpha and/or IL-2, notably with the CD3-CD56+ subset. Interestingly, asymptomatic donors had the highest levels of CD3-CD56+ NK cells, which also demonstrated an enhanced response to cytokine stimulation. Cytotoxicity to schizonts was accompanied by the release of soluble NK cell lytic factors. Neomycin suppressed cytotoxicity in a dose-dependent manner, indicating that the lysis of schizonts by NK cells involves phospholipase C-mediated phosphoinositide metabolism. Our findings define a role for NK cells in immunity to malaria through the lysis of infected erythrocytes as a first-line defence against the parasite.

Immune response to soluble exoantigens of Plasmodium falciparum may contribute to both pathogenesis and protection in clinical malaria: Evidence from a longitudinal, prospective study of semi-immune African children

Article

Apr 1991

Some soluble exoantigens of Plasmodium have lipopolysaccharide (LPS)-like properties and are believed to contribute to the pathogenesis of acute malaria. We have studied cellular and humoral immune responses to several purified exoantigens of Plasmodium falciparum in a cohort of children and compared these responses with their subsequent susceptibility to malaria infection and clinical disease. We found no evidence that either lymphoproliferative or interferon-gamma (IFN-gamma) responses to these antigens were associated with protective immunity. On the contrary, children whose cells produced IFN-gamma after in vitro activation with one of the soluble antigens (Ag7) were more likely to experience clinical manifestations of malaria infection (fever and malaise) than were children whose cells did not produce IFN-gamma. It is possible that exoantigen-induced IFN-gamma may exacerbate the LPS-like effects of these antigens. However, serum antibodies to another antigen (Ag2) were more prevalent in children with asymptomatic infections or low parasitemia than in children with fever and higher parasitemia (confirmed clinical malaria), suggesting that these antibodies may contribute to the development of protective immunity.

Lymphocyte-T interferon-gamma production induced by Plasmodium-falciparum antigen is high in recently infected non-immune and low in immune subjects

Article

Feb 1990

Interferon (IFN) alpha and gamma were measured by radio-immunoassays in supernatants from cultures of peripheral blood mononuclear cells (PBMC) or purified T cell subsets incubated with either Plasmodium falciparum schizont-enriched malaria antigen (mAg), uninfected red blood cells (RBC) or pokeweed mitogen (PWM). Cell donors were 24 clinically immune, healthy African adult native residents of a P. falciparum-endemic region, Haut-Ogooué, Gabon, and seven non-immune, European temporary residents with a history of a single to a few malaria infections during the previous 1 to 9 months. When PBMC were cultured in medium alone or with RBC antigen no or low titres of IFN-gamma were detected. PBMC proliferation and IFN-gamma production observed in the presence of mAg were dose dependent and significantly correlated. When cultured with mAg, PBMC from non-immune Europeans produced significantly higher levels of IFN-gamma than did PBMC from clinically immune Africans. No such difference was found when PBMC were cultured with PWM. The mAg-induced IFN-gamma production was due mainly to CD4+ T cells and was not enhanced by CD8+ T cell depletion. No IFN-alpha was detected in culture supernatants. Thus, P. falciparum antigens are able to induce in vitro production of IFN-gamma by CD4+ T cells; however, in this sample, individuals considered to be clinically resistant to malaria were low producers of IFN-gamma.

Immunosuppression in Malaria: Effect of Hemozoin Produced by Plasmodium berghei and Plasmodium falciparum

Article

Feb 1988

To a considerable degree, malaria-induced immunosuppression has been attributed to an inhibition of macrophage accessory cell function. In this study hemozoin, a plasmodium hemoglobin degradation product which readily accumulates in phagocytic cells and tissues during infection, was examined for its influence on immune responses. Hemozoin-laden liver and splenic macrophages from Plasmodium berghei-infected mice, displayed accessory cell dysfunction which was likely due to hemozoin loading by these phagocytic cells. This indicated by the observation that hemozoin obtained from livers and spleens of infected mice as well as from Plasmodium falciparum cultures greatly inhibited splenic plaque-forming cell responses to sheep red blood cells. The results of the present study strongly suggest that the inhibition of macrophage accessory cell activity is due, at least in part, to the uptake and accumulation of hemozoin in their cytoplasms.

Murine malaria: Resistance of AXB/BXA recombinant inbred mice to Plasmodium chabaudi

Article

Mar 1985

The level of resistance to infection with Plasmodium chabaudi is genetically controlled. We have previously reported that a single dominant gene is responsible for the variation in host resistance to malaria between susceptible A/J- and resistant C57BL-derived mice. In the present study, recombinant inbred strain analysis was performed with AXB/BXA recombinant inbred strains derived from A/J and C57BL/6 progenitors. Typing of 17 AXB/BXA recombinant inbred strains confirmed the unigenic control of inheritance in this particular strain combination and allowed us to demonstrate genetic linkage between the traits of resistance (defined as a prolonged survival and a low peak parasitemia) and the magnitude of splenomegaly. The influence of sex on the course of infection, which we previously reported in the examination of segregating populations (Stevenson et al., Infect. Immun. 38:80-88, 1982), was again demonstrated in the survey of RI strains.

Role of macrophage-derived nitric oxide in suppression of lymphocyte proliferation during blood-stage malaria

Article

Aug 1995

Examination of the proliferative responses in vitro to mitogens (concanavalin A, phytohemagglutinin, lipopolysaccharide) of spleen cells recovered from C57BL/6 mice during blood-stage Plasmodium chabaudi AS infection revealed that the most severe suppression occurred during the first 14 days post infection, that is, during the acute phase of infection. Coincidently, inducible nitric oxide synthase gene expression was found to be up-regulated in the spleens of infected mice, and both splenic and peritoneal macrophages produced high levels of NO in vitro in response to stimulation with lipopolysaccharide (LPS). The roles of NO, a molecule recently found to mediate immunosuppression during parasitic infections, and of the well-recognized immunosuppressive molecule prostaglandin were, therefore, investigated in the suppression of proliferation to mitogens and specific antigen of spleen cells from 7- and 14-day P. chabaudi AS-infected mice. Addition of either 0.5 mM NG-monomethyl-L-arginine (L-NMMA) or 0.5 mM aminoguanidine (AG), inhibitors of NO synthase, or 10 micrograms/ml indomethacin (INDO), a prostaglandin inhibitor, partially but significantly abrogated the suppression in response to concanavalin A (Con A) and phytohemagglutinin (PHA). Only the addition of INDO significantly increased the responses to LPS. Addition of L-NMMA or AG in combination with INDO partially but significantly abrogated the suppression in response to Con A and completely abrogated the suppression in response to PHA. The addition of L-NMMA or AG also significantly increased proliferation in response to parasite antigen. The contribution of NO to suppression of lymphoproliferation was confirmed by adding 3-morpholino-sydnonimine-hydrochloride (SIN-1), a chemical generator of NO, to mitogen-stimulated splenocyte cultures prepared from normal mice. The mechanism of NO-mediated suppression was investigated in coculture experiments using spleen cells from normal mice and peritoneal macrophages from either normal or day 7 infected mice. The addition of 5-10 x 10(4) peritoneal macrophages from infected mice significantly and consistently suppressed Con A- or PHA-stimulated proliferation of normal splenocytes. Moreover, suppression correlated with production of NO and could be reversed by the addition of L-NMMA or AG. These results suggest that, in addition to prostaglandin, increased NO production by macrophages within the first 2 weeks after infection with P. chabaudi AS contributes to immunosuppression associated with blood-stage malaria.

Gamma delta T cells function in cell-mediated immunity to acute blood-stage Plasmodium chabaudi adami malaria

Article

May 1995

To determine whether gamma delta T cells are essential for the resolution of acute Plasmodium chabaudi adami (P. c. adami) malaria, we depleted gamma delta T cells from C57BL/6 mice with hamster monoclonal anti-TCR gamma delta Ab treatment. During the period in which control mice that had received normal hamster IgG completely resolved infections, gamma delta T cell-depleted mice were unable to suppress their infections. Because the number of splenic CD4+ alpha beta T cells in these anti-TCR-gamma delta-treated mice with nonresolving malaria was similar to control mice, it appears that CD4+ alpha beta T cells alone cannot mediate early resolution even though they are known to play a critical role in immunity to blood-stage malaria. Mice treated with anti-CD4 mAb also failed to resolve P. c. adami malaria. Depletion of CD4+ alpha beta T cells from the spleens of infected mice resulted in minimal expansion of the splenic CD4- gamma delta T cell subset compared with infected control mice. Together, these findings indicate that activation of the gamma delta T cell subset, which requires the presence of CD4+ alpha beta T cells, is essential for resolution of acute P. c. adami malaria. To determine whether gamma delta T cells require either Abs or B cells to achieve their protective activity, B cell-deficient JHD mice were treated with the same depleting anti-TCR-gamma delta Abs. Whereas control JHD mice injected with hamster IgG resolved acute P. c. adami malaria, JHD mice depleted of gamma delta T cells failed to do so. We conclude that gamma delta T cells suppress P. c. adami parasitemia by mechanisms of immunity independent of Ab and B cells.

Intraleucocyte malaria pigment and prognosis in severe malaria

Article

Mar 1995

The quantity of malaria pigment liberated into the circulation at schizogony reflects the pathogenic sequestered parasite burden in Plasmodium falciparum malaria, and may therefore be a measure of disease severity. Among 300 consecutive adult patients with severe falciparum malaria, the 40 who died had significantly higher proportions of malaria pigment-containing neutrophils on admission (mean = 7·7%, standard deviation (sd) = 5·9%) and pigment-containing monocytes (mean = 8·6%, SD = 5·9%) than did survivors (mean 3·2%, sd = 4·1% and mean 4·8%, sd = 4·6%, respectively) (P < 0·0001): This proved a better indicator of prognosis than the peripheral parasite count. A count of peripheral neutrophils containing visible pigment ⩾5% predicted a fatal outcome with 73% sensitivity and 77% specificity (relative risk 6·2, 95% confidence interval (CI) 3·2–11·8) compared to 60% sensitivity and 57% specificity for parasitaemia >100 000/μL (relative risk 1·8, 95% CI 1·0–3·3). The peripheral blood count of pigment-containing neutrophils in severe malaria is a rapid, simple, and practical prognostic test.

Severe childhood malaria in two areas of markedly different falciparum transmission in East Africa

Article

Oct 1994
ACTA TROP

Malaria remains a major public health challenge in sub-Saharan Africa, yet our knowledge of the epidemiology of malaria in terms of patterns of mortality and morbidity is limited. We have examined the presentation of severe, potentially life-threatening malaria to district hospitals in two very different transmission settings: Kilifi, Kenya with low seasonal transmission and Ifakara, Tanzania with high seasonal transmission. The minimum annual rates of severe disease in children below five years in both populations were similar (46 per 1000 children in Kilifi and 51 per 1000 children in Ifakara). However, there were important differences in the age and clinical patterns of severe disease; twice as many patients were under one year of age in Ifakara compared with Kilifi and there was a four fold higher rate of cerebral malaria and three fold lower rate of malaria anaemia among malaria patients at Kilifi compared with Ifakara. Reducing malaria transmission in Ifakara by 95%, for example with insecticide-treated bed nets, would result in a transmission setting comparable to that of Kilifi and although this reduction may yield early successes in reducing severe malaria morbidity and mortality in young, immunologically naive children, place these same children at increased risk at older ages of developing severe and potentially different manifestations of malaria infection hence producing no net cohort gain in survivorship from potentially fatal malaria.

Soluble products of inflammatory reactions are not induced in children with asymptomatic Plasmodium falciparum infections

Article

Aug 1996

A proportion of children with Plasmodium falciparum infection have a high parasitaemia without accompanying fever, indicative of different clinical thresholds of parasitaemia. Higher levels of IL-10, IL-1Ra and sIL-4R but not sIL-2R were found in children with P. falciparum malaria, compared with levels in children with asymptomatic P. falciparum infections and in healthy children. Concentrations of IL-10 and IL-1Ra were correlated with levels of parasitaemia, but the association of cytokine levels with disease was independent of the association with parasitaemia. Children may tolerate a high parasitaemia by neutralizing the parasite-derived toxins. When studying potential anti-toxic molecules we found that children with symptomatic infections had lower concentrations of a phospholipid-binding molecule, beta 2-glycoprotein I (beta 2-GPI), compared with children with asymptomatic infections or healthy children. In conclusion, cytokines were found in much higher concentrations in children with symptomatic P. falciparum malaria than in children with asymptomatic infections, whilst the former had lower concentrations of beta 2-GPI.

Early Interactions Between Blood-Stage Plasmodium Parasites and the Immune System

Abstract

No full-text available

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