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Malaria: Immune Evasion by Parasites
Abstract
Malaria is one of the most life-threatening infectious diseases worldwide. Specific immunity to natural infection is acquired slowly despite a high degree of repeated exposure and rarely continues for a long time even in endemic areas. Malaria parasites have evolved to acquire diverse immune evasion mechanisms that evoke poor immune responses and allow infection of individuals previously exposed. The shrewd schema of malaria parasites also hampers the development of effective vaccines. Furthermore, some of those mechanisms are essential for malaria pathogenesis. In this article, an outline of protective immunity to malaria is given, then strategies used by malaria parasites to evade host immunity, including antigen diversity/polymorphism, antigen variation and total immune suppression, are reviewed. Finally, trials to control malaria based on accumulating insights into the host-parasite relationship are discussed.
... After entering into cells, the process of the nanoparticles is initiated to release antigenic epitopes. Then, MHC classes I and II pathways will be activated to stimulate CD4 + and CD8 + T cell immune responses [44,45]. In the present investigation, vaccination of mice with PfGCS1-SAPN co-administrated with Poly (I:C) prompted a comparatively higher level of IgG1 than IgG2a and IgG2b, and a lower amount of IgG3 in immunized mice groups (except for group C with a higher level of IgG2a than other subclasses). ...
... The greater level of IgG2a (Th1 responses index) in group C in comparison to other subclasses and other immunized mice groups suggests a promising candidate formulation to induce Th1 immune response. The greater measures of IgG1 than IgG2a/c and IgG2b subclass versus nanoparticle peptides replicate a mixed Th1/Th2 response in mice that can be affected by various parameters [44,46,47]. ...
... The intrinsic immunogenicity of the antigen, the selected adjuvants, and the dose of antigen used in the vaccine mixture, exposure times, and methods of immunization influence the induction of immune responses [44,46,47]. In the current investigation, the results confirmed the influence of refolding buffer components on shifting immune responses to Th1 or Th2. ...
Developing a novel class of vaccine is pivotal for eliminating and eradicating malaria. Preceding investigations demonstrated partial blocking activity in malaria transmission against recombinant vaccine PfHAP2-GCS1 and conserved region of the cd loop. The effectiveness of immune response varies with the size and shape of the self-assembly of peptide nanoparticles (SAPNs) displaying antigen, affected by different components in refolding buffers. Plasmodium falciparum Generative Cell Specific 1 (PfGCS1), a promising malaria transmission-blocking vaccine (TBV) candidate, was expressed, purified, and followed by a four-step refolding process to form nanoparticles (PfGCS1-SAPNs). The influence of buffer components on the size and shape of SAPNs was investigated by DLS and FESEM. Furthermore, the immunogenicity of nanostructures was assessed in different mouse groups. The results showed that PfGCS1-SAPN was immunogenic and its administration with Poly (I:C), stimulated humoral and cellular responses in the mouse model. In the immunized mice groups, the level of IgG antibodies against PfGCS1-SAPN was significantly increased in different time points (second and third boost) and heterogeneous boosters. The various IgG-subclasses profile shifted to Th1, Th2, or Th1/Th2 mix responses in mice immunized with PfGCS1-SAPN refolded in different buffers, indicating a prerequisite for further investigations to optimize vaccine formulation to enhance and modulate Th1/cellular responses. Such studies pave the way to improve biophysical features related to the nanoparticles’ size, shape, and conformational epitopes of candidate antigens and T- and B-cells presented on the superficial structure to elicit robust immune responses.
... 7 PfEMP-1 memperantarai perlekatan (adhesi) sel darah merah yang terinfeksi ke berbagai reseptor yang tersebar pada sel-sel endotel berbagai organ. 6,7,9 Kemampuan inilah yang merupakan faktor virulens dari P. falciparum sehingga sering diasosiasikan dengan terjadinya malaria berat. Protein PfEMP-1 merupakan target dari antibodi yang bersifat spesifik, namun karena gen var memiliki kemampuan untuk melakukan perubahan (switching) sekitar 2% per generasi, hal ini menyebabkan sulitnya usaha untuk penemuan vaksin terhadap malaria. ...
... Protein PfEMP-1 merupakan target dari antibodi yang bersifat spesifik, namun karena gen var memiliki kemampuan untuk melakukan perubahan (switching) sekitar 2% per generasi, hal ini menyebabkan sulitnya usaha untuk penemuan vaksin terhadap malaria. 6,9 Dengan adanya variasi antigen ini memungkinkan terjadinya malaria kronik yang dapat mempengaruhi pola transmisi malaria yang terjadi melalui gigitan nyamuk Anopheles betina. 6,9 b. ...
... 6,9 Dengan adanya variasi antigen ini memungkinkan terjadinya malaria kronik yang dapat mempengaruhi pola transmisi malaria yang terjadi melalui gigitan nyamuk Anopheles betina. 6,9 b. Sitoadherens Sitoadherens adalah ikatan anatara eritrosit yang telah terinfeksi parasit malaria (PRBCs, Parasitized Red Blood Cells) dengan endotel vaskuler terutama kapiler postvenula yang menyebabkan terjadinya sekuesterasi parasit pada kapiler-kapiler organ. ...
... Plasmodium falciparum Aotus monkeys became protected [62,63] The parasite's life-cycle complexity is just one challenge to be understood in depth, as it has developed different evasion mechanisms, such as protein variation, antigenic polymorphism, altered peptide ligands (APLs), alternative invasion pathways, cryptic epitopes, immunosuppression, immunological smoke-screens and antigen shedding, thereby inducing long-or short-lived nonprotective immune responses [74][75][76][77][78][79][80]. Repetitive antigens (used erroneously as vaccines) have been targets for strong, but not protective, immune responses. ...
... The parasite's life-cycle complexity is just one challenge to be understood in depth, as it has developed different evasion mechanisms, such as protein variation, antigenic polymorphism, altered peptide ligands (APLs), alternative invasion pathways, cryptic epitopes, immunosuppression, immunological smoke-screens and antigen shedding, thereby inducing long-or short-lived non-protective immune responses [74][75][76][77][78][79][80]. Repetitive antigens (used erroneously as vaccines) have been targets for strong, but not protective, immune responses. ...
... However, HABPs having variable sequences (vHABPs) could induce a highly strain-specific protective immune response [114][115][116][117]. These results agreed with reports showing that antigenic or immunogenic proteins having variable aa sequences had been used as an immunological evasion mechanism (i.e., they induced strain-specific immune protection and repeat aa sequences induced non-protective immune responses) [76,81,118]. These results partly explained the systematic failure arising from using complete X-ray-irradiated or genetically-altered parasites, DNA naked encoding specific proteins or complete recombinant proteins, since practically all of them have been seen to have genetic variability in one or several regions [119][120][121]. ...
Synthetic peptides have become invaluable biomedical research and medicinal chemistry tools for studying functional roles, i.e., binding or proteolytic activity, naturally-occurring regions’ immunogenicity in proteins and developing therapeutic agents and vaccines. Synthetic peptides can mimic protein sites; their structure and function can be easily modulated by specific amino acid replacement. They have major advantages, i.e., they are cheap, easily-produced and chemically stable, lack infectious and secondary adverse reactions and can induce immune responses via T- and B-cell epitopes. Our group has previously shown that using synthetic peptides and adopting a functional approach has led to identifying Plasmodium falciparum conserved regions binding to host cells. Conserved high activity binding peptides’ (cHABPs) physicochemical, structural and immunological characteristics have been taken into account for properly modifying and converting them into highly immunogenic, protection-inducing peptides (mHABPs) in the experimental Aotus monkey model. This article describes stereo–electron and topochemical characteristics regarding major histocompatibility complex (MHC)-mHABP-T-cell receptor (TCR) complex formation. Some mHABPs in this complex inducing long-lasting, protective immunity have been named immune protection-inducing protein structures (IMPIPS), forming the subunit components in chemically synthesized vaccines. This manuscript summarizes this particular field and adds our recent findings concerning intramolecular interactions (H-bonds or π-interactions) enabling proper IMPIPS structure as well as the peripheral flanking residues (PFR) to stabilize the MHCII-IMPIPS-TCR interaction, aimed at inducing long-lasting, protective immunological memory.
... Some of the immunological responses described to occur during the liver stage are: apoptosis of infected cells (Meslin et al., 2007), isolation and targeting of parasites in specific compartments for elimination (Yano and Kurata, 2011), type I IFN production induced by parasite RNA (Liehl et al., 2015) and LC3-mediated autophagy targeting of sporozoites (Risco-Castillo et al., 2015). Nevertheless, several mechanisms such as immune evasion, immune exploitation, and molecular piracy are employed by the parasites to promote their survival in the host (Hisaeda et al., 2005). After the first immunological attack during liver stage, the majority of parasites that survived will replicate within the hepatocytes and amplify their number exponentially leading to the release of hundreds of thousands of merozoites into circulation (Prado et al., 2015). ...
... Within the mosquito, ineffective sporozoites will be kept until the next blood meal, where they will be transmitted to a mammalian host continuing the parasite life cycle (Molina-Cruz et al., 2012). The complexity of the parasite life cycle allows for the use of various immune evasion strategies by Plasmodium, which pose a challenge to the development of a malaria vaccine (Hisaeda et al., 2005). In this review, we discuss some of the immune evasion strategies that have been described for Plasmodium at both the liver and the blood stages. ...
... Some reports have described how Plasmodium RNA could activate the type I interferon (IFN) pathway via the cytosolic Pattern Recognition Receptor (PRR), MDA5 (Liehl et al., 2014). Type I interferons are potent inflammatory cytokines that are known to inhibit growth of exoerythrocytic forms (Hisaeda et al., 2005). Some of the cells that mediate these anti-parasitic effects include Natural Killer and Natural Killer T cells (NK, NKT), and γδT cells. ...
Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins, and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission.
... Parasites have also evolved evasion strategies to avoid the host immune defence and to establish in their host [17][18][19]. For instance, malarial parasites have been suggested to adaptively immuno-deplete their human and mouse hosts by interfering with immune signalling [20][21][22][23]. Therefore, malarial parasites may impose an additional cost to their vertebrate host due to the depletion of immune functions which may increase host susceptibility to other parasites and diseases. ...
... Plasmodium infected individuals tended to have a lower immune response than uninfected ones, yet this difference was not statistically significant. However, parasitaemia increased after immune Plasmodium infected individuals were expected to have a weaker response to a novel antigen than uninfected ones, because Plasmodium parasites may drive host immuno-depletion [23] and because Plasmodium infection may impair host ability to invest in an energetically costly immune response [30]. The results showed no significant differences between uninfected and infected individuals. ...
Background:
Plasmodium parasites are known to impose fitness costs on their vertebrate hosts. Some of these costs are due to the activation of the immune response, which may divert resources away from self-maintenance. Plasmodium parasites may also immuno-deplete their hosts. Thus, infected individuals may be less able to mount an immune response to a new pathogen than uninfected ones. However, this has been poorly investigated.
Methods:
The effect of Plasmodium infection on bird humoral immune response when encountering a novel antigen was tested. A laboratory experiment was conducted on canaries (Serinus canaria) experimentally infected with Plasmodium relictum (lineage SGS1) under controlled conditions. Birds were immune challenged with an intra-pectoral injection of a novel non-pathogenic antigen (keyhole limpet haemocyanin, KLH). One week later they were challenged again. The immune responses to the primary and to the secondary contacts were quantified as anti-KLH antibody production via enzyme-linked immunosorbent assay (ELISA).
Results:
There was no significant difference in antibody production between uninfected and Plasmodium infected birds at both primary and secondary contact. However, Plasmodium parasite intensity in the blood increased after the primary contact with the antigen.
Conclusions:
There was no effect of Plasmodium infection on the magnitude of the humoral immune response. However, there was a cost of mounting an immune response in infected individuals as parasitaemia increased after the immune challenge, suggesting a trade-off between current control of chronic Plasmodium infection and investment against a new immune challenge.
... Acquired or adaptive immunity against malaria arises after infection and the protection it confers depends on the characteristics of the host, place of stay, number of infections suffered etc. It has been graded as anti-disease immunity (that protects against clinical disease), antiparasite immunity (protects against high parasitemia), and sterilizing immunity (protects against new infections by maintaining a low-grade, asymptomatic parasitemia; also called premunition) [21]. An initial infection with malaria parasites commonly induces clinical illness in a non-immune individual with very low levels of parasitemia and the infection may progress to severe disease and death. ...
... The host mounts specific immune response in the presence of genetically and antigenically distinct strains of the parasites in a given locality and the occurrence of clonal antigenic variation during the course of an infection [21]. In this case, the acquisition of immunity against malaria is, therefore, very slow and not very effective and remains species specific and strain specific. ...
Malaria has continued to be a major cause of morbidity and mortality in the Tropical World. Research on its complex immunology has focused more on the host adaptive immunity to the plasmodium parasite. The role of innate immune mechanisms involving myeloid cells has not been given adequate attention. This review highlights the key role of myeloid cells in immunity to malaria through such mechanisms as parasite sensing and elimination, pro inflammatory activities and activation of other immune components.
... However, Plasmodium parasites have evolved various strategies to evade the immune system, such as changing their surface antigens, which allows them to evade detection by antibodies and immune cells [44] . This ability to evade the immune response contributes to the parasite's persistence and the recurrence of malaria infections in individuals living in endemic areas [45] . ...
Malaria remains a significant global health challenge, demanding a deeper understanding of host immune responses for effective clearance of the parasitic infection. Cytokines, as crucial mediators of the immune system, orchestrate a complex interplay during the various stages of malaria infection. Throughout the course of the disease, an intricate balance of pro-inflammatory and anti-inflammatory cytokines dictate the immune response's outcome, influencing parasitic clearance and disease severity. During the initial stages, interleukins such as interleukin-12 (IL-12), interferon-gamma (IFN-γ), and tumour necrosis factor-alpha (TNF-α) play pivotal roles in activating innate immune cells, initiating the anti-parasitic response. Simultaneously, regulatory cytokines like inter-leukin-10 (IL-10) and transforming growth factor-beta (TGF-β) modulate this immune activation, preventing excessive inflammation and tissue damage. As the infection progresses, a delicate shift occurs, characterized by a transition to adaptive immunity, guided by cytokines like interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), promoting antibody production and T-cell responses. Notably, the resolution of malaria infection crucially relies on a fine-tuned balance of cytokine networks. Dysregulation or imbalances in these mediators often result in immune hyperactivation, contributing to severe manifestations and prolonged infection. Understanding the multi-faceted roles of cytokines in malaria clearance offers promising avenues for therapeutic interventions. Targeting cytokine pathways to restore immune equilibrium or bolster protective responses could potentially enhance treatment strategies and vaccine development. In conclusion, the pivotal role of cytokines in immunomodulation during malaria clearance underscores their significance as potential targets for therapeutic interventions, offering promising prospects in the global fight against this infectious disease.
... However, the results indicated a greater recovery ability of the host against Schellackia infection, because the parasitemia of this latter parasite significantly decreased between capture and recapture, whereas that of Karyolysus did not. Parasites can evolve adaptive strategies to evade host defenses (Hisaeda et al., 2005;Schmid-Hempel, 2008. In this sense, Karyolysus blood stages are embedded in a parasitophorous vacuole (see Figure 3d), a structure that is not so obvious, perhaps absent, in ...
Different blood parasites can co‐infect natural populations of lizards. However, our knowledge of the host's ability to recover from them (i.e., significantly reduce parasitemia levels) is scarce. This has interest from an ecological immunology perspective. Herein, we investigate the host recovery ability in males of the lizard Psammodromus algirus infected by parasite genera Schellackia and Karyolysus . The role of lizard hosts is dissimilar in the life cycle of these two parasites, and thus different immune control of the infections is expected by the vertebrate host. As Schellackia performs both sexual and asexual reproduction cycles in lizards, we expect a better immune control by its vertebrate hosts. On the contrary, Karyolysus performs sexual reproductive cycles in vectors, hence we expect lower immune control by the lizards. We carried out a reciprocal translocation experiment during the lizards’ mating season to evaluate both parasitemia and leukocyte profiles in male lizards, being one of the sampling plots close to a road with moderate traffic. These circumstances provide a combination of extrinsic (environmental stress) and intrinsic factors (reproductive vs. immune trade‐offs) that may influence host's recovery ability. We recaptured 33% of the lizards, with a similar proportion in control and translocated groups. Karyolysus infected 92.3% and Schellackia 38.5% of these lizards. Hosts demonstrated ability to significantly reduce parasitemia of Schellackia but not of Karyolysus . This suggests, in line with our predictions, a differential immune relationship of lizards with these parasites, at time that supports that parasites with different phylogenetic origins should be analyzed separately in investigations of their effects on hosts. Furthermore, lizards close to the road underwent a stronger upregulation of lymphocytes and monocytes when translocated far from the road, suggesting a putative greater exposure to pathogens in the latter area.
... Suppression of host T-cell mediated immune response due to Plasmodium spp. infection is reported in humans and murine models of malaria [41]. This was not observed in birds experimentally infected with hemosporidians, however, the long-term costs of maintaining an immune reaction during a chronic infection can impair the building of an efficient response against other agents even more so in wild animals with low food resources and higher stress [42]. ...
Usutu virus (USUV) is a mosquito-borne zoonotic flavivirus causing mortality in Eurasian blackbirds (Turdus merula) in Europe. In dead blackbirds, avian malaria co-infection due to mosquito-borne hemosporidians (e.g., Plasmodium spp.) has been reported. In humans, a similar co-infection of a flavivirus, Dengue virus, and Plasmodium spp. is causing increased severity of clinical disease. Currently, the effects of co-infection of arboviruses and hemosporidians in blackbirds remain unclear. This study investigates the rate of USUV and Plasmodium spp. co-infection in found-dead blackbirds (n = 203) from 2016 to 2020 in the Netherlands. Presence of Plasmodium spp. was evaluated by cytology (43/203; 21,2%), histopathology (94/186; 50,5%) and qPCR (179/203; 88,1%). The severity of histological lesions in USUV and Plasmodium spp. co-infected dead blackbirds (121/203; 59,6%) were compared with those in Plasmodium spp. single-infected cases. Additionally, since no knowledge is present on the infection rate on live birds and mosquitoes in the Netherlands, a small group of live blackbirds (n = 12) and selected in the field-collected mosquito pools (n = 96) in 2020 were tested for the presence of Plasmodium spp. The latter was detected in the tested live blackbirds by qPCR (8/10; 80%), and cytology (3/11; 27,3%) and in the mosquito pools by qPCR (18/96; 18,7%). For this study, co-infection between USUV and Plasmodium spp. was observed only in the dead blackbirds. The high Plasmodium spp. presence, associated with lower lesions score, in single infected found dead birds suggest a predominantly smaller pathogenic role as single agent. On the other hand, the higher histological lesion scores observed in USUV and Plasmodium spp. co-infected birds suggests a major pathogenic role for the virus or an increased severity of the lesions due to a possible interplay of the two agents.
... life cycle. In humans, the immunological response to malaria antigens is mainly regulated through the cooperation of both the innate and adaptive immune systems with the immune attack higher during the erythrocytic stage (Hisaeda et al., 2005;Uchechukwu et al., 2017). Considerable evidence revealed that B cells, antibodies, T cells, cytokines, and their respective receptors, all play crucial roles in the recruitment and activation of different cell types of the immune system thus modulating the complex immunological response against malaria parasites (Deroost et al., 2016; F I G U R E 1 The Plasmodium life cycle et al., 1998). ...
Malaria is one of the most severe infectious diseases affecting humans and it is caused by protozoan pathogens of the species Plasmodium (spp.). The malaria parasite Plasmodium is characterized by a complex, multistage life cycle that requires tight gene regulation which allows for host invasion and defense against host immune responses. Unfortunately, the mechanisms regulating gene expression during Plasmodium infection remain largely elusive, though several lines of evidence implicate a major involvement of non‐coding RNAs (ncRNAs). The ncRNAs have been found to play a key role in regulating transcriptional and post‐transcriptional events in a broad range of organisms including Plasmodium . In Plasmodium ncRNAs have been shown to regulate key events in the multistage life cycle and virulence ability. Here we review recent progress involving ncRNAs (microRNAs, long non‐coding RNAs, and circular RNAs) and their role as regulators of gene expression during Plasmodium infection in human hosts with focus on the possibility of using these molecules as biomarkers for monitoring disease status. We also discuss the surprising function of ncRNAs in mediating the complex interplay between parasite and human host and future perspectives of the field.
This article is categorized under: RNA in Disease and Development > RNA in Disease
... Although the T cell-mediated immune response to initial Plasmodium infection is well described, other immune cells, such as dendritic cells and monocytes/macrophages, have been shown to modulate immune activation and the severity of disease as well (12,13). However, mice lacking tissue-resident macrophages experience increased malaria-related complications, such as disruptions in the blood-brain barrier, increased vascular permeability in the liver, and increased accumulation of hemozoin pigment in the lung (14). ...
Malaria remains a grave concern for humans, as effective medical countermeasures for Plasmodium infection have yet to be developed. Phagocytic clearance of parasitized red blood cells (pRBCs) by macrophages is an important front-line innate host defense against Plasmodium infection. We previously showed that repeated injections of low-dose lipopolysaccharide (LPS) prior to bacterial infection, called LPS preconditioning, strongly augmented phagocytic/bactericidal activity in murine macrophages. However, if LPS preconditioning prevents murine Plasmodium infection is unclear. We investigated the protective effects of LPS preconditioning against lethal murine Plasmodium infection, focusing on CD11b high F4/80 low liver macrophages, which are increased by LPS preconditioning. Mice were subjected to LPS preconditioning by intraperitoneal injections of low-dose LPS for 3 consecutive days, and 24 h later, they were intravenously infected with pRBCs of Plasmodium yoelii 17XL. LPS preconditioning markedly increased the murine survival and reduced parasitemia, while it did not reduce TNF secretions, only delaying the peak of plasma IFN-γ after Plasmodium infection in mice. An in vitro phagocytic clearance assay of pRBCs showed that the CD11b high F4/80 low liver macrophages, but not spleen macrophages, in the LPS-preconditioned mice had significantly augmented phagocytic activity against pRBCs. The adoptive transfer of CD11b high F4/80 low liver macrophages from LPS-preconditioned mice to control mice significantly improved the survival after Plasmodium infection. We conclude that LPS preconditioning stimulated CD11b high F4/80 low liver macrophages to augment the phagocytic clearance of pRBCs, which may play a central role in resistance against Plasmodium infection.
... This also limit the possibilities of development of anti-malarial vaccines (Plebanski et al., 1999). There are several other mechanisms on host side which also aid the malarial parasites to evade immune mechanisms (Hisaeda et al., 2005). ...
Parasitic infections have enormous health, social, and economic influence worldwide, predominantly in tropical and subtropical areas. Diseases caused by protozoan parasites, like malaria, leishmaniasis, trypanosomiasis, toxoplasmosis, giardiasis, etc. have major contributions in the global death rate due to infections. The burden of these parasitic protozoans has increased around the globe due to the lack of effective, commercially-availablevaccines, and the production of less efficacious drugs with poor pharmacokinetics. Unfortunately, in areas with endemic protozoan infections, antiparasitic drugs use and efficacy have been compromised by drug resistance. The development of resistance has been found to be associated with decreased drug uptake, the export of drugs from parasites, genetic modifications, loss of drug activity, and alteration of the drug target. Recently, the isolation and characterization of resistance-related genes and proteins have increased the knowledge about drug resistance greatly and provided a way forward for the identification of new drug candidates. In this chapter, our focus will be on the mode of action and mechanism of resistance development of those drugs used to treat protozoal infections in human including malaria, toxoplasmosis, trypanosomiasis, giardiasis, cystoisosporiasis, babesiosis, and leishmaniasis.
... A previous study suggested that the alteration of immune cells in the peripheral blood was also the cause of leukopenia [48]. Immunity against malaria parasite invasion and the infection of red blood cells is very high during the liver stage or exoerythrocytic stage compared to the erythrocytic stage, and major immune responses for these two stages involve CD8 + T cells and antibodies, respectively [49]. Another possible immune mechanism against malaria infection involves interleukin 12 (IL-12), which is involved in the pathogenesis of malarial pancytopenia, the pathogenesis of low total leukocytes, red blood cells, and platelet production from the bone marrow [50]. ...
Background
Leukocyte alterations are a common hematological alteration among malaria patients.
Objectives
This systematic review and meta-analysis aimed to provide data and evidence comparing alterations in total leukocyte counts in malaria patients compared to febrile/healthy subjects at baseline before treatment. A systematic review was conducted by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analyses.
Data sources
Web of Science (ISI), Scopus, and Medline.
Study eligibility criteria, participants, and interventions
All published articles reporting a total leukocyte count of patients infected with malaria, non-malaria (febrile or healthy group) at baseline before treatment before August 27, 2019, were retrieved, and data were extracted by two main reviewers independently.
Study appraisal and synthesis methods
We used a forest plot, heterogeneity test (Cochran’s Q), and the degree of heterogeneity (I²) to test whether the included studies were heterogeneous. The quality of the included studies was determined by a quality assessment guide based on the quality assessment tool developed by the Newcastle-Ottawa Scale (NOS). Cochran’s Q (Chi-square) and Moran's I² were used to evaluate heterogeneity. Meta-regression using STATA software was conducted to find the source of heterogeneity. A funnel plot with Egger’s test was used to examine the significance of publication bias among the included studies. The mean differences were estimated using a random-effects model.
Results
Out of the 2,261 articles screened, 29 articles were included in this systematic review and meta-analysis. The heterogeneity test indicated that there was heterogeneity among the included studies with no publication bias. The meta-analysis demonstrated that the total leukocyte count was significantly lower in patients with malaria (n = 4,619) than in those without malaria (n = 10,056) (Z = 4.0, P-value < 0.00001, mean difference = -1.38, 95% CI = -2.06-(-0.71)). Leukocyte differential alterations, low lymphocyte counts (P-value <0.0001, mean difference = -1.03, 95% CI = -1.53-(-0.53)) and a high NL ratio were found in the malaria group (n = 1,579) compared to the non-malaria group (n = 4,991) (P-value <0.0001, mean difference = 0.6, 95% CI = 0.32–0.88). The subgroup analysis indicated that there was a significantly lower total leukocyte count in the malaria group (n = 3,545) than in the febrile group (n = 8,947) (Z = 1.33, P-value < 0.0001, mean difference = -1.76, 95% CI = -2.56-(-0.96)), but no significant difference was found between the malaria group (n = 1,232) and the healthy group (n = 1,679) (P-value > 0.05).
Limitations
As the specific diagnoses in the febrile groups were not reported in the included studies so that the results of the present study need to be carefully interpreted.
Conclusions and implications of key findings
This systematic review demonstrated that the total leukocyte count was affected by malarial infection at baseline despite the heterogeneity of the included studies. Future work must aim to understand the treatment-related total leukocyte reduction during follow-up or post-treatment outcomes in malaria-endemic settings.
... L'ARN plasmodial serait ainsi reconnu très tôt par MDA5 au sein des hépatocytes infectés pour aboutir à la synthèse d'IFN-I (208), afin d'induire l'inhibition de la croissance des formes parasitaires exoérythrocytaires (209). Au stade érythrocytaire, les PRRs impliqués dans la reconnaissance plasmodiale appartiennent à la famille des TLRs (210). ...
Le vaccin vivant rougeole a été atténué dans les années 1960 par passages successifs en culture de cellules embryonnaires de poulet. C’est un vaccin très sûr et efficace qui confère une protection à vie. L’essor de la génétique inverse a permis son développement comme vecteur vaccinal, et ouvre de nouvelles perspectives vaccinales pour la prévention des maladies émergentes ou négligées, comme le paludisme, problème de santé publique mondial mais également pour les forces armées françaises. Les bases moléculaires de l’atténuation restent encore partiellement incomprises, mais impliquent des modifications de stimulation de la voie interféron de type I (IFN-I) et du tropisme cellulaire. La stimulation de la voie IFN-I par les souches vaccinales apparaît comme étroitement liée à la présence de génomes défectifs interférents (DI-RNA). Nous avons ainsi recherché et caractérisé de façon systématique les DI-RNAs produits par la plateforme vaccinale rougeole, puis validé leurs fonctions immunostimulatrices par leur liaison spécifique aux récepteurs cytosoliques de l’immunité innée RIG-I et LGP2. La modification du tropisme cellulaire a été décrite comme dépendante du récepteur humain ubiquitaire CD46. Cependant, nous avons montré in vivo sur modèle murin que ce récepteur n’est pas essentiel et que seule la barrière IFN-I restreint la réplication virale. Enfin, nous avons développé une stratégie vaccinale antipaludique vectorisée par la rougeole reposant sur l’effet adjuvant des DI-RNAs produits par les vaccins recombinants rougeole.
... Certain of the immunological responses described to take place during the liver stage are: apoptotic death of infected cells (Meslin et al., 2007), sequestration and targeting of parasites in definite compartments for elimination (Yano and Kurata, 2011), type I IFN production prompted by parasite RNA (Liehl et al., 2015) as well as LC3-mediated autophagy targeting of sporozoites (Risco-Castillo et al., 2015). Nevertheless, several other mechanisms such as immune exploitation, immune evasion, and molecular piracy are engaged by the parasites to ensure their survival in the host (Hisaeda et al., 2005). Following the first immunological attack during liver stage, most of the parasites that survived replicates within hepatocytes and exponentially amplify their number resulting in the release of hundreds of thousands of merozoites into systemic circulation (Prado et al., 2015). ...
A review of the contribution of nutrition in management and control of Malaria was conducted. Nutrition has been confirmed as one factors that can be used to suppress the effect of malaria infection before clinical treatment is received by the patient. For the body to function normally, its nutritional demand must be met in the right proportions. Diet rich in vitamins, minerals, micronutrients are required for the metabolic functioning of the body, hence effective or adequate nutrition has health benefits to the human body. Living on quality diet has a way of improving the body defense mechanism against infectious diseases such as malaria.
... Each stages has a different visual appearance that can be detected using the microscope. It has several phases of life in the human body, including ring, trophozoites, schizonts, and gametocytes [2], [3], [4]. The rapid parasite ...
Malaria, as a dangerous disease globally, can bereduced its number of victims by finding a method of infectiondetection that is fast and reliable. Computer-based detectionmethods make it easier to identify the presence of plasmodiumin blood smear images. This kind of methods is suitable for usein locations far from the availability of health experts. Thisstudy explores the use of two methods of machine learning onColor Cascading Framework, i.e. Backpropagation NeuralNetwork and Support Vector Machine. Both methods wereused as classifier in detecting malaria infection. From theexperimental results it was found that Color CascadingFramework improved the classifier performance for both inSupport Vector Machine and Backpropagation Neural Network.
... Immunogenicity and protection assays in Aotus monkeys have shown that high activity binding peptides (HABPs) [12] having a conserved sequence (cHABP) have not induced an immune response, suggesting that despite the importance of their biological role, they are immunologically silent [4,5]. By contrast, HABPs having a variable sequence (vHABPs) have induced a nonprotective immune response (or only a short-term one) [4,13], an immune evasion mechanism for these sequences (smokescreens distracting the immune response) [14][15][16]. However, when some cHABP residues [17,18] have been replaced by amino acids (aa) having similar mass and volume, but different polarity, modified analogues (mHABPs) have been seen to induce a protective immune response in Aotus monkeys against experimental challenge [5,13,[19][20][21][22]. ...
Malaria continues being a high-impact disease regarding public health worldwide; the WHO report for malaria in 2018 estimated that ~219 million cases occurred in 2017, mostly caused by the parasite Plasmodium falciparum . The disease cost the lives of more than 400,000 people, mainly in Africa. In spite of great efforts aimed at developing better prevention (i.e., a highly effective vaccine), diagnosis, and treatment methods for malaria, no efficient solution to this disease has been advanced to date. The Fundación Instituto de Inmunología de Colombia (FIDIC) has been developing studies aimed at furthering the search for vaccine candidates for controlling P. falciparum malaria. However, vaccine development involves safety and immunogenicity studies regarding their formulation in animal models before proceeding to clinical studies. The present work has thus been aimed at evaluating the safety and immunogenicity of a mixture of 23 chemically synthesised, modified peptides (immune protection-inducing protein structure (IMPIPS)) derived from different P. falciparum proteins. Single and repeat dose assays were thus used with male and female BALB/c mice which were immunised with the IMPIPS mixture. It was found that single and repeat dose immunisation with the IMPIPS mixture was safe, both locally and systemically. It was observed that the antibodies so stimulated recognised the parasite’s native proteins and inhibited merozoite invasion of red blood cells in vitro when evaluating the humoral immune response induced by the IMPIPS mixture. Such results suggested that the IMPIPS peptide mixture could be a safe candidate to be tested during the next stage involved in developing an antimalarial vaccine, evaluating local safety, immunogenicity, and protection in a nonhuman primate model.
... The blood-stage antimalarial vaccine candidates' immunogenicity results described here (mainly based on P. falciparum protein conserved regions) have indicated that although moderate Ab titers are induced after a first immunization, they do not induce long-lasting protective immunity. This is consistent with our research demonstrating that, although conserved regions are functionally important for target cell binding, they are poorly recognized by host immune system due to being located far from the highly polymorphic regions used by the parasite as an evasion mechanism to distract the immune system (Patarroyo et al., 2017b); such polymorphic regions are immunodominant but confer just strain-specific immunity (Hisaeda et al., 2005;Curtidor et al., 2017). ...
Plasmodium falciparum malaria is a disease causing high morbidity and mortality rates worldwide, mainly in sub-Saharan Africa. Candidates have been identified for vaccines targeting the parasite’s blood stage; this stage is important in the development of symptoms and clinical complications. However, no vaccine that can directly affect morbidity and mortality rates is currently available. This review analyzes the formulation, methodological design, and results of active clinical trials for merozoite-stage vaccines, regarding their safety profile, immunological response (phase Ia/Ib), and protective efficacy levels (phase II). Most vaccine candidates are in phase I trials and have had an acceptable safety profile. GMZ2 has made the greatest progress in clinical trials; its efficacy has been 14% in children aged less than 5 years in a phase IIb trial. Most of the available candidates that have shown strong immunogenicity and that have been tested for their protective efficacy have provided good results when challenged with a homologous parasite strain; however, their efficacy has dropped when they have been exposed to a heterologous strain. In view of these vaccines’ unpromising results, an alternative approach for selecting new candidates is needed; such line of work should be focused on how to increase an immune response induced against the highly conserved (i.e., common to all strains), functionally relevant, protein regions that the parasite uses to invade target cells. Despite binding regions tending to be conserved, they are usually poorly antigenic and/or immunogenic, being frequently discarded as vaccine candidates when the conventional immunological approach is followed. The Fundación Instituto de Inmunología de Colombia (FIDIC) has developed a logical and rational methodology based on including conserved high-activity binding peptides (cHABPs) from the main P. falciparum biologically functional proteins involved in red blood cell (RBC) invasion. Once appropriately modified (mHABPs), these minimal, subunit-based, chemically synthesized peptides can be used in a system covering the human immune system’s main genetic variables (the human leukocyte antigen HLA-DR isotype) inducing a suitable, immunogenic, and protective immune response in most of the world’s populations.
... The response of the immune system to Plasmodium parasites is complex and targets different stages of its life cycle. Immune attack involvement is high in the erythrocytic stage in contrast to pre-erythrocytic stage, and major immune players in the pre erythrocytic and erythrocytic stages are CD8+ T cells and antibodies, respectively [7]. ...
... Plasmodium parasites stimulate their host by various pathways, leading to an assortment of responses on the cellular and molecular level, dependent on the degree and timing of malaria infection. e T-cell response to initial malaria infection is well described; however, other immune cells, including dendritic cells and monocyte/macrophages, have been shown to modulate immune activation and the severity of disease as well [16,17]. For example, in mice, modest levels of Plasmodium infection lead to increased expression of CD40, a marker of immune activation induced by Toll-like receptors (TLRs) in dendritic cells and macrophages, which in turn enhances the expression of stimulator of interferon genes (STING), key regulators of the innate immune response pathway, and ultimately leads to augmented type I interferon (IFN) (such as IFNα and IFNβ) production during early infection. ...
Malaria is a significant cause of global morbidity and mortality. The Plasmodium parasite has a complex life cycle with mosquito, liver, and blood stages. The blood stages can preferentially affect organs such as the brain and placenta. In each of these stages and organs, the parasite will encounter monocytes and tissue-specific macrophages—key cell types in the innate immune response. Interactions between the Plasmodium parasite and monocytes/macrophages lead to several changes at both cellular and molecular levels, such as cytokine release and receptor expression. In this review, we summarize current knowledge on the relationship between malaria and blood intervillous monocytes and tissue-specific macrophages of the liver (Kupffer cells), central nervous system (microglia), and placenta (maternal intervillous monocytes and fetal Hofbauer cells). We describe their potential roles in modulating outcomes from infection and areas for future investigation.
... The innate immune genes such as TLRs, PRRs, and inflammatory cytokines are already upregulated, and these lead to elevate the level of TNF, IFN, and IL-12 from plasmodium-infected peripheral blood mononuclear cells (PBMCs) up to 48 h of infection [32,33]. These inflammatory responses are associated with the pathophysiological condition and clinical symptoms of malaria including anemia, cerebral malaria, and ultimate death [34]. Cerebral malaria is caused due to overexpression and binding of adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), endothelial/leukocyte adhesion molecule (ELAM-1), and CD36 [35] on brain endothelial cell receptors. ...
... Thus, cases introduced from an external reservoir likely contributed to the increased diversity [28]. Because changing antigenicity is a major strategy for parasites to be protected from host immunity, antigenic diversity/polymorphism, which links the expression of different alleles of a gene in different parasite populations with outcomes of selection under immune pressure, would selectively expand [49]. ...
Plasmodium vivax is more challenging to control and eliminate than P. falciparum due to its more asymptomatic infections with low parasite densities making diagnosis more difficult, in addition to its unique biological characteristics. The potential re-introduction of incidence cases, either through borders or via human migrations, is another major hurdle to sustained control and elimination. The Republic of Korea has experienced re-emergence of vivax malaria in 1993 but is one of the 32 malaria-eliminating countries to-date. Despite achieving successful nationwide control and elimination of vivax malaria, the evolutionary characteristics of vivax malaria isolates in the Republic of Korea have not been fully understood. In this review, we present an overview of the genetic variability of such isolates to increase understanding of the epidemiology, diversity, and dynamics of vivax populations in the Republic of Korea.
... Malaria is a disease in humans caused by parasitic protozoan of the genus Plasmodium and it is a severe public health problem in most countries of the tropics and subtropics. 1 Malaria causes a major public health problem in people living in the highly affected areas of India In the present study, the serum levels of TC, HDL, and LDL cholesterols in P. falciparum malaria-infected patients were lower than controls. This finding is in contrast to data reported in other studies that showed elevated levels of lipoproteins in patients suffering from malaria infection. ...
Background: Malaria is a major public health problem in India with wide-ranging haematological and biochemical alterations. Plasmodium falciparum (P. falciparum) is one of four distinct species of the malaria parasite that afflict humans and pose a threat to public health. Under normal physiological conditions, liver ensures homeostasis of lipid and lipoprotein metabolism. Therefore, the aim of this study was to assess malaria infection and its association with lipid parameters changes. Hepatocellular damage often associated with severe and acute P. falciparum infections impairs these processes, leading to alteration in plasma lipid profile and lipoprotein patterns. An observation on the nature of dyslipidaemia in confirmed cases of P. falciparum malaria patients with reference to correlation if any that exists between malaria and lipid profile in these patients was performed.Methods: A case-control study was carried out on clinically and laboratory confirmed P. falciparum malaria positive patients attending the outpatient and inpatient department of RIMS Ranchi for a period of six months i.e. from January 2018 to June 2018, 100 participants were enrolled for the present study. 50 participants were P. falciparum malaria confirmed cases and 50 participants were without any clinical or laboratory evidence of malaria served as the control.Results: It revealed that the total cholesterol, HDL and LDL were significantly decreased -(P ≤0.05) while triglyceride and VLDL were not significantly changed in P. falciparum malaria patients (P ≥0.05).Conclusions: It can be concluded that alteration in lipid profile can be an index of severe malaria infection that may leads to poor prognosis, but specificity of malaria infection with lipid changes is questionable and need further studies.
... Probably, the parasite produces this antigen to make the host produce antiglycan antibodies to block the site of effective antibodies such as IgE (blocking antibodies). [37,38] In an investigation, sera of patients with hydatid cyst reacted with several bands of cyst wall in Western blotting. [39] In another work, cross-reaction of sera of patients with breast cancer with a 27 KDa antigen of hydatid cyst wall has been shown. ...
Background:
Recent studies have shown that similar host glycan antigens are expressed by helminths such as Echinococcus granulosus hydatid cysts to evade from host immune system. In this work to investigate these antigens further, immunological cross-reactivity between human sera and hydatid cyst wall antigens has been investigated.
Materials and methods:
Hydatid cyst wall antigens were used in enzyme-linked immunosorbent assay and Western immunoblotting and probed with pooled sera of hydatidosis patients and healthy controls. Sodium metaperiodate treatment was used to investigate glycan antigens.
Results:
A band with molecular weight about 53 KDa reacted with both hydatid patients' sera and also normal human sera. It has been shown that this band was a glycan antigen.
Conclusions:
A 53 KDa glycan antigen of hydatid cyst wall that reacted with all human sera may have an important role for evasion from host immune system.
... Studies show that the parasite initially affected gorillas [14]. Among all the species of Plasmodium known to affect humans this is the most virulent species and is majorly responsible for mortality [15]. The Malaria Vaccine Advisory Committee of WHO in 2006 proposed a "Malaria Vaccine Technology Roadmap" to develop and license a malaria vaccine with a target of 50% protective efficacy against mortality and severe infection with a lasting period of more than a year and to be developed by 2015 [14]. ...
... The response is complex and targets at different stages of plasmodium parasites. Immune attack involvement is high in the erythrocytic stage in contrast to preerythrocytic stage, and major immune players in the preerythrocytic and erythrocytic stages are CD8 + T cells and antibodies, respectively [23]. ...
Malaria causes approximately 212 million cases and 429 thousand deaths annually. Plasmodium falciparum is responsible for the vast majority of deaths (99%) than others. The virulence of P. falciparum is mostly associated with immune response-evading ability. It has different mechanisms to evade both Anopheles mosquito and human host immune responses. Immune-evading mechanisms in mosquito depend mainly on the Pfs47 gene that inhibits Janus kinase-mediated activation. Host complement factor also protects human complement immune attack of extracellular gametes in Anopheles mosquito midgut. In the human host, evasion largely results from antigenic variation, polymorphism, and sequestration. They also induce Kupffer cell apoptosis at the preerythrocytic stage and interfere with phagocytic functions of macrophage by hemozoin in the erythrocytic stage. Lack of major histocompatibility complex-I molecule expression on the surface red blood cells also avoids recognition by CD8 ⁺ T cells. Complement proteins could allow for the entry of parasite into the red blood cell. Intracellular survival also assists the escape of malarial parasite. Invading, evading, and immune response mechanisms both in malaria vector and human host are critical to design appropriate vaccine. As a result, the receptors and ligands involved in different stages of malaria parasites should be elucidated.
... Major clinical symptoms in malaria patients are partly due to sequestration of infected red blood cells in the brain microvasculature. The sequestration is due to the binding of infected red blood cells to the host endothelial receptors such as intracellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), endothelial/leukocyte adhesion molecule (ELAM-1) and CD36 [33]. The increase of proinflammatory cytokine release is responsible for the overexpression of adhesion molecules on brain endothelial cells causing the development of cerebral malaria [34]. ...
Despite a global effort to develop an effective vaccine, malaria is still a significant health problem. Much of the pathology of malaria is immune mediated. This suggests that host immune responses have to be finely regulated. The innate immune system initiates and sets the threshold of the acquired immune response and determines the outcome of the disease. Yet, our knowledge of the regulation of innate immune responses during malaria is limited. Theoretically, inadequate activation of the innate immune system could result in unrestrained parasite growth. Conversely, hyperactivation of the innate immune system, is likely to cause excessive production of proinflammatory cytokines and severe pathology. Toll-like receptors (TLRs) have emerged as essential receptors which detect signature molecules and shape the complex host response during malaria infection. This review will highlight the mechanisms by which Plasmodium components are recognized by innate immune receptors with particular emphasis on TLRs. A thorough understanding of the complex roles of TLRs in malaria may allow the delineation of pathological versus protective host responses and enhance the efficacy of anti-malarial treatments and vaccines.
... The genome has been deciphered from a large number of parasitic species as well as mutations related to drug resistance (Ersfeld, 2003;Ivics, 2009;Jackson, 2015). They have also been deciphered complicated mechanisms of adaptation of the parasites or mechanisms of evasion to the immune response of the host (Hisaeda et al. 2005;Schmid-Hempel, 2009;Cressler et al. 2015). ...
In this article, the trends in human parasitology have been studied through the analysis of the number of publications in this area. The parameters studied were: number of articles, language, countries and institutions with the highest number of publications, and keywords with greater presence in the articles of human parasitology. The results of the analysis confirm the growing interest in this area, observing an exponential growth in the number of publications in the last decades. We also verified that the main country in terms of scientific production is the USA, although among the most important institutions, we find non-US centres such as the Oswaldo Cruz Foundation and the London School of Hygiene and Tropical Medicine. For observing the relative importance of the journals that publish articles in this specific topic, an index has been created based on the h -index of the journal with publications related to human parasitology and divided by every 100 items. This rank is led fist by ‘Journal of Medical Entomology’ closely followed by ‘Parasitology’. The analysis of the keywords allows to draw conclusions about the great importance of malaria in the current world research. A change in analytical methodology is also observed, and molecular techniques are now being imposed. These techniques, in the near future, have to influence in an improvement in the treatments and prevention of the diseases caused by parasites. Finally, it can be seen that diseases traditionally studied as helminthiasis and amebiasis are currently as well studied as others such as toxoplasmosis or leishmaniasis.
... These antigens may have an important role for the parasite to evade from the human immune system. Probably the parasite may elaborate these glycan antigens to raise antibodies that may block the specific sites for effective antibodies (32,33). So, these antigens may have the potential to abolish production of specific immune responses. ...
Background: Hydatid disease is characterized by long-term growth of hydatid cysts in the human. The glycan antigens have an important role in the immunology of hydatid cyst. In this study immunological reaction of host sera to different glycan antigens of the cyst, has been investigated.
Methods: The antibody responses were tested to glycoprotein and glycolipid of the laminated layer (LL), cyst fluid (CF) and protoscolex (PS) antigens of E. Granulosus using ELISA and western immunoblotting tests. Thin-layer chromatography and ß-elimination were used for glycan purification.
Results: Both hydatid cyst and normal human sera reacted with hydatid cyst fluid, protoscolices, laminated layer, glycoprotein and glycolipid antigens. The most antigen-antibody reaction was related to CF and PS antigens, and LL antigens had the minimal reaction with the sera. Thin layer chromatography (TLC) of the antigens showed presence of many glycan bands in the laminated layer.
Conclusion: The parasite may elaborate different glycan antigens in LL to evade host immune response.
... Despite the emerging resistance, drug discovery program is struggling to avoid the spread of resistance [2]. Similarly, insecticide resistance and immune evasion mechanisms by the parasite are the major threats to malaria control [3]. These all problems call for the development and deployment of new malaria drugs and vaccines to prevent the clinical disease and transmission, and to break off the phases in parasite life cycle. ...
Although malaria control efforts have currently reduced much of the morbidity and mortality, yet malaria remains a hard problem in many parts of Africa. Together with the existing malaria control efforts, an effective malaria vaccine is expected to act as an important weapon to fight against malaria burden. Developing an efficacious malaria vaccine is a top priority in the agenda of global health program. However, the multi-stage life cycle, antigenic variation, and vast genetic diversity of malaria parasites made malaria vaccine development difficult for years. This study was conducted with the aim of reviewing the status of malaria vaccine development through different obstacles in the path. Vaccine trials currently upgraded to yield a partially effective and short-lived immunity with the pre-erythrocytic subunit vaccine, RTS,S/AS01, which is likely to be the first vaccine to be licensed for malaria control and elimination in sub-Saharan Africa. A promising result was also observed in the early trials with parenteral administration of the whole sporozoite vaccine in malaria-naive adults, where a complete protection against malaria was demonstrated. The subunit vaccines may not develop a strong sterile immunity among the malaria endemic community. Therefore, moving forward to the multi-stage vaccine comprising antigens from the pre-erythrocytic, erythrocytic and sexual stages of parasite lifecycle could be the best tool to neutralize the merozoites emerging from hepatocytes and red blood cells, and to break the sexual stage transmission. Furthermore, deep understanding of the potential vaccine targets and how immunity acts is a key roadmap to develop a fully effective vaccine against malaria.
... The complex, multistage life cycle of malaria parasites typically induce suboptimal immune responses that develop slowly over time (7). The development and maintenance of immunity is complicated by the presence of multiple mechanisms of immune evasion employed by malaria parasites (8)(9)(10). When some level of immunity is achieved, it is thought to rapidly wane in the absence of parasite exposure (7,8,(11)(12)(13). ...
The development of vaccines to protect against parasites is difficult, in large part due to complex host-parasite interactions that have evolved over millennia. Parasitic factors such as antigenic variation and host factors such as age, transmission intensity, and genetic influences are all thought to contribute to the limited efficacy of parasite vaccines. A developing theme in field studies investigating antiparasitic immunity is the emergence, establishment, and maintenance of immunoregulatory networks that shape the immune responses to new infections, as well as vaccines, thereby influencing disease outcome. In this review, we will examine why parasite vaccine candidates perform poorly in target populations and, in particular, the role of immunoregulatory networks in influencing antimalarial immunity and vaccine efficacy. We will focus our discussion on malaria, the most important parasitic disease of humans, but also highlight the broader impact of immunoregulatory networks on vaccine efficacy.
... Previous studies have suggested that tandem repeats could play an important role as host immune response evasion mechanism [68][69][70][71]. In this study, 21 haplotypes were identified in PvRON4 when the InDels were [86] for simplifying interpretation of the network. ...
Background
Designing a vaccine against Plasmodium vivax has focused on selecting antigens involved in invasion mechanisms that must have domains with low polymorphism for avoiding allele-specific immune responses. The rhoptry neck protein 4 (RON4) forms part of the tight junction, which is essential in the invasion of hepatocytes and/or erythrocytes; however, little is known about this locus’ genetic diversity. MethodsDNA sequences from 73 Colombian clinical isolates from pvron4 gene were analysed for characterizing their genetic diversity; pvron4 haplotype number and distribution, as well as the evolutionary forces determining diversity pattern, were assessed by population genetics and molecular evolutionary approaches. Resultsron4 has low genetic diversity in P. vivax at sequence level; however, a variable amount of tandem repeats at the N-terminal region leads to extensive size polymorphism. This region seems to be exposed to the immune system. The central region has a putative esterase/lipase domain which, like the protein’s C-terminal fragment, is highly conserved at intra- and inter-species level. Both regions are under purifying selection. Conclusionspvron4 is the locus having the lowest genetic diversity described to date for P. vivax. The repeat regions in the N-terminal region could be associated with immune evasion mechanisms while the central region and the C-terminal region seem to be under functional or structural constraint. Bearing such results in mind, the PvRON4 central and/or C-terminal portions represent promising candidates when designing a subunit-based vaccine as they are aimed at avoiding an allele-specific immune response, which might limit vaccine efficacy.
... Malaria is a disease in humans caused by parasitic protozoan of the genus Plasmodium and it is a severe public health problem in most countries of the tropics and sub tropics. 1 According to World Health Organization 2012 estimation, there were about submit your manuscript | www.dovepress.com ...
Solomon Sirak,1,* Abebe Alemu Fola,2 Ligabaw Worku,3 Belete Biadgo4,* 1Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia; 2Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; 3Department of Medical Parasitology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 4Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia *These authors contributed equally to this work Background: Malaria is a major public health problem in Ethiopia with wide-ranging hematological and biochemical alterations. Therefore, the aim of this study was to assess malaria parasitemia and its association with lipid and hematological parameters. Methods: A comparative cross-sectional study was conducted from April 1 to June 30, 2014. Of 200 study participants, 100 were confirmed malaria patients and 100 healthy controls. Study participants were included based on systematic random sampling techniques. Seven milliliters of blood samples were collected for investigation of hematological and lipid parameters. Data were entered and analyzed using SPSS-20 statistical software. Independent t-test and one-way analysis of variance were run to compare mean differences. A P<0.05 was considered as statistically significant. Results: A total of 200 study participants (78.5% males and 21.5% females) were included with a mean age of 24.67±11.2 years. A majority of malaria patients were infected with Plasmodium falciparum (66%). According to parasitic load, 38%, 52%, and 10% patients were reported with low, moderate, and high malaria parasitemia, respectively. There were statistically significant mean differences in white blood cells count ([6.875±3.20 vs 5.835±2.01]×103/µL), neutrophil (63.1%±8.7% vs 56.0%±12.7%), hemoglobin (11.9±2.0 vs 14.5±3.0 gm/dL), hematocrit (36.2%±7.8% vs 42.4%±8.3%), platelet count ([175.3±136 vs 193.4±81.9]×103/µL), high-density lipoprotein (19.6±13.7 vs 35.5±12.3 mg/dL), low-density lipoprotein (34.7±23.5 vs 64.5±29.3 mg/dL), triglyceride (118.0±61.3 vs 101.7±36.8 mg/dL), and total cholesterol (88.0±36.3 vs 148.7±39.1 mg/dL) for cases and controls, respectively (P<0.05). In patients with different densities of malaria parasitemia there were statistically significant differences in total red blood cells count ([4.4±0.8 vs 4.8±0.8 vs 5.3±0.7] ×106/µL), hemoglobin concentration ([11.9±1.8 vs 11.6±1.8 vs 13.4±3.0] gm/dl), and platelet count ([227.1±131 vs 186.8±175 vs 156.9±100] ×103/uL) among low, moderate, and high parasitemia, respectively. Conclusion: This study revealed that routinely used laboratory tests such as lipid and hematological parameters could be good and reliable adjunct in the early diagnosis of malaria-infected patients with mild-to-severe parasitemia in malaria endemic areas. Keywords: malaria parasitemia, hematological parameters, lipid parameters, Ethiopia
... Despite the high prevalence of P. vivax, few studies have investigated the genetic diversity of natural P. vivax populations in India. The P. vivax genome exhibits greater diversity compared with P. falciparum [18] and displays high levels of antigenic polymorphisms, which indicates the presence of sophisticated mechanisms to evade the human immune system [19]. However, recurrent infections that arise from recrudescence, re-infection or relapses make it difficult to interpret the results of clinical P. vivax studies that aim to determine the efficacy of treatment strategies. ...
Background
Plasmodium vivax is the most widely distributed human malaria parasite and accounts for approximately the same number of malaria cases as Plasmodium falciparum in India. Compared with P. falciparum, P. vivax is difficult to eradicate because of its tendency to cause relapses, which impacts treatment and control strategies. The genetic diversity of these parasites, particularly of the merozoite surface protein-3 alpha (msp-3α) gene, can be used to help develop a potential vaccine. The present study aimed to investigate the genetic diversity of P. vivax using the highly polymorphic antigen gene msp-3α and to assess the suitability of using this gene for population genetic studies of P. vivax isolates and was carried out in 2004–06. No recent study has been reported for MSP 3α in the recent decade in India. Limited reports are available on the genetic diversity of the P. vivax population in India; hence, this report aimed to improve the understanding of the molecular epidemiology of the parasite by studying the P. vivax msp-3α (Pvmsp-3α) marker from P. vivax field isolates from India.
Methods
Field isolates were collected from different sites distributed across eight states in India. A total of 182 blood samples were analysed by a nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique using the HhaI and AluI restriction enzymes to determine genetic msp-3α variation among clinical P. vivax isolates.
Results
Based on the length variants of the PCR products of Pvmsp-3α gene, three allele sizes, Type A (1.8 kb), Type B (1.5 kb) and Type C (1.2 kb) were detected among the 182 samples. Type A PCR amplicon was more predominant (75.4 %) in the samples compared with the Type B (14.3 %) and Type C (10.0 %) polymorphisms. Among all of the samples analysed, 8.2 % were mixed infections detected by PCR alone. Restriction fragment length polymorphism (RFLP) analysis involving the restriction enzymes AluI and HhaI generated fragment sizes that were highly polymorphic and revealed substantial diversity at the nucleotide level.
Conclusions
The present study is the first extensive study in India using the Pvmsp-3α marker. The results indicated that Pvmps-3α, a polymorphic genetic marker of P. vivax, exhibited considerable variability in infection prevalence in field isolates from India. Additionally, the mean multiplicity of infection observed at all of the study sites indicated that P. vivax is highly diverse in nature in India, and Pvmsp-3α is likely an effective and promising epidemiological marker.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-016-1524-y) contains supplementary material, which is available to authorized users.
... The released merozoites initiate next round of erythrocytic cycle by infecting fresh erythrocytes (Gilson and Crabb, 2009). The survival of parasite inside the host cell is difficult, ascribed to which Plasmodium adapts various strategies to avoid the host immune response (Miller et al., 1994;Hisaeda et al., 2005). The strategies encompass the secretion of hitherto of proteins against infected RBC (iRBC) surface and beyond it into the host plasma (Singh et al., 2009). ...
Plasmodium falciparum is the causative agent of deadly malaria disease. It is an intracellular eukaryote and completes its multi-stage life cycle spanning the two hosts viz, mosquito and human. In order to habituate within host environment, parasite conform several strategies to evade host immune responses such as surface antigen polymorphism or modulation of host immune system and it is mediated by secretion of proteins from parasite to the host erythrocyte and beyond, collectively known as, malaria secretome. In this review, we will discuss about the deployment of parasitic secretory protein in mechanism implicated for immune evasion, protein trafficking, providing virulence, changing permeability and cyto-adherence of infected erythrocyte. We will be covering the possibilities of developing malaria secretome as a drug/vaccine target. This gathered information will be worthwhile in depicting a well-organized picture for host-pathogen interplay during the malaria infection and may also provide some clues for the development of novel anti-malarial therapies.
... Human malaria infection can lead to a wide range of clinical symptoms that are influenced by epidemiological and immunological factors [1] along with the mechanisms of immune evasion of the parasite [2]. Protective humoral response against Plasmodium falciparum can be acquired after repeated infections of malaria; however, it does not persist over long periods of time and it is generally incomplete [1]. ...
Vaccines blocking malaria parasites in the blood-stage diminish mortality and morbidity caused by the disease. Here, we isolated antigens from total parasite proteins by antibody affinity chromatography to test an immunization against lethal malaria infection in a murine model. We used the sera of malaria self-resistant ICR mice to lethal
Plasmodium yoelii yoelii
17XL for purification of their IgGs which were subsequently employed to isolate blood-stage parasite antigens that were inoculated to immunize BALB/c mice. The presence of specific antibodies in vaccinated mice serum was studied by immunoblot analysis at different days after vaccination and showed an intensive immune response to a wide range of antigens with molecular weight ranging between 22 and 250 kDa. The humoral response allowed delay of the infection after the inoculation to high lethal doses of
P. yoelii yoelii
17XL resulting in a partial protection against malaria disease, although final survival was managed in a low proportion of challenged mice. This approach shows the potential to prevent malaria disease with a set of antigens isolated from blood-stage parasites.
... It has been previously postulated that IDPs, and tandem repeat regions in particular, may play an important role in the immune evasion of various parasites including Plasmodium [37,69,70], Trypanosoma [32], Leishmania [33,71] and Ehrlichia [34]. Tandem repeat regions may induce immunodominant responses that act as immunological decoys, masking responses against functionally important epitopes. ...
Malaria remains a significant global health burden. The development of an effective malaria vaccine remains as a major challenge with the potential to significantly reduce morbidity and mortality. While Plasmodium spp. have been shown to contain a large number of intrinsically disordered proteins (IDPs) or disordered protein regions, the relationship of protein structure to subcellular localisation and adaptive immune responses remains unclear. In this study, we employed several computational prediction algorithms to identify IDPs at the proteome level of six Plasmodium spp. and to investigate the potential impact of protein disorder on adaptive immunity against P. falciparum parasites. IDPs were shown to be particularly enriched within nuclear proteins, apical proteins, exported proteins and proteins localised to the parasitophorous vacuole. Furthermore, several leading vaccine candidates, and proteins with known roles in host-cell invasion, have extensive regions of disorder. Presentation of peptides by MHC molecules plays an important role in adaptive immune responses, and we show that IDP regions are predicted to contain relatively few MHC class I and II binding peptides owing to inherent differences in amino acid composition compared to structured domains. In contrast, linear B-cell epitopes were predicted to be enriched in IDPs. Tandem repeat regions and non-synonymous single nucleotide polymorphisms were found to be strongly associated with regions of disorder. In summary, immune responses against IDPs appear to have characteristics distinct from those against structured protein domains, with increased antibody recognition of linear epitopes but some constraints for MHC presentation and issues of polymorphisms. These findings have major implications for vaccine design, and understanding immunity to malaria.
Malaria is considered as a systemic syndrome caused by infection of the red blood cells by intracellular protozoan parasites of the genus Plasmodium and is transmitted by the bite of infected and physiologically excited female anopheline mosquito, which feeds on mamamalian blood to produce and mature its eggs. Vaccination is believed to be one of the most effective approaches to tackle morbidity and mortality related malaria and its approach targets the malaria life stage factors like the pre-erythrocyticproteins (RTSs, ChAd63/MVA, METRAP, PSPZ, PfceITos…), the blood stage proteins (EBA175, AMA1, GMZ1, P27A, MSP3, MSP1, RH5, sexual stage proteins ( Pfs25, Pfs48, Pfs230 and Multi-stage /multi-epitope/antigen combination vaccines ((PfCP-2. 9 chimeric (AMA1 and MSP1–19)). Even if the vaccine trials against malaria was began early in 1930s, currently the one most advanced pre-erythrocyticvaccine, RTS, S vaccine has been launched with good safety profile ( efficacy of 30-50%). New approaches like combining different types of adjuvants into antigen‐specific formulations improved efficacy of a particular vaccine and its formulations offer a wide spectrum of opportunities in malaria vaccine research. Frequent and multiple infections gradually lead to the development of anti-parasite immunity which results in very low or undetectable parasitemia in malaria-infected individuals. Sterilizing immunity against malarial parasite, though never fully achieved, results in a high degree of immune response, low levels of parasitemia, and an asymptomatic carrier status For unsuccessful trials of malaria vaccine, there are so many challenges that are associated to logistic (high cost-effective public health intervention to control and regulate pathway complicity ), immunologic (polymorphism of the malaria parasite antigens in each life stage, the immune evasion strategy of the parasite… ), and technical challenges related to miss identification of malaria vaccine candidates, selection adjuvants and route of administration. Although there were tackles to malarial vaccine trials, it was reported that there are fine opportunities to proceed on the track
The endoparasitic pathogen, Plasmodium falciparum (Pf), modulates protein-protein interactions to employ post-translational modifications like SUMOylation to establish successful infections. The interaction between E1 and E2 (Ubc9) enzymes governs species specificity in the Plasmodium SUMOylation pathway. Here, we demonstrate that a unidirectional cross-species interaction exists between Pf-SUMO and Human-E2, whereas Hs-SUMO1 failed to interact with Pf-E2. Biochemical and biophysical analyses revealed that surface-accessible Aspartates of Pf-SUMO determine the efficacy and specificity of SUMO-Ubc9 interactions. Furthermore, we demonstrate that critical residues of the Pf-Ubc9 N-terminal are responsible for diminished Hs-SUMO1 and Pf-Ubc9 interaction. Mutating these residues to corresponding Hs-Ubc9 residues restore electrostatic, π-π, and hydrophobic interactions and allow efficient cross-species interactions. We suggest that in comparison to human counterparts, Plasmodium SUMO and Ubc9 proteins have acquired critical changes on their surfaces as nodes, which Plasmodium can use to exploit the host SUMOylation machinery.
Plasmodium infection causes inflammation in the host. A combination of herbs like Azadirachta indica and Curcuma longa may have beneficial effect in remediating inflammation in malaria disease. The aim of this study is to investigate the immunomodulatory and synergistic effects of the association of Azadirachta indica and Curcuma longa in experimental Plasmodium berghei infection. Fifty male Swiss mice were infected with chloroquine susceptible (NK 65) strain of Plasmodium berghei intraperitoneally. Parasitemia was confirmed using microscopy and the animals were grouped (n = 5), treated once daily and orally for 7 days with 200 and 400 mg/kg of A. indica and C. longa methanol extracts. Four hundred milligrams per kilogram A. indica was combined with the two doses of C. longa methanol extract and fractions. Negative control was treated with 10 mL/kg 5% (v/v) dimethyl sulfoxide (DMSO, vehicle) while positive control was treated with artemether–lumefantrine (10 mg/kg) and normal control not infected with parasites was treated with distilled water only. Animals were sacrificed on day 7, and blood serum was obtained. Serum immunoglobulins G (IgG) and immunoglobulin M (IgM), C-reactive protein (CRP), tumour necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) were assayed using ELISA techniques. Combination of A. indica and C. longa significantly increased (P < 0.05) IgG and TNF-α than separate treatment while IgM increased albeit insignificantly (P < 0.05); CRP and IL-1β decreased significantly relative to control (P < 0.05) while IL-6 levels was modulated both in separate and combined therapy. Separate administration and combinations of A. indica and C. longa have immunomodulatory effects in malaria-infected mice.
The endoparasitic pathogen, Plasmodium falciparum (Pf), modulates protein-protein interactions to employ post-translational modifications like SUMOylation in order to establish successful infections. The interaction between E1 and E2 (Ubc9) enzymes governs species specificity in the Plasmodium SUMOylation pathway. Here, we demonstrate that a unidirectional cross-species interaction exists between Pf-SUMO and Human-E2, whereas Hs-SUMO1 failed to interact with Pf-E2. Biochemical and biophysical analysis revealed that surface-accessible Aspartates of Pf-SUMO determine the efficacy and specificity of SUMO-Ubc9 interactions. Furthermore, we demonstrate that critical residues of the Pf-Ubc9 N-terminal are responsible for the lack of interaction between Hs-SUMO1 and Pf-Ubc9. Mutating these residues to corresponding Hs-Ubc9 residues restore electrostatic,pi-pi, and hydrophobic interactions and allows efficient cross-species interactions. We suggest that the critical changes acquired on the surfaces of Plasmodium SUMO and Ubc9 proteins as nodes can help Plasmodium exploit the host SUMOylation machinery. Thus, Pf-SUMO interactions can be targeted for developing antimalarials.
Malaria remains a grave concern for humans, as effective medical countermeasures for malaria infection have yet to be developed. Phagocytic clearance of parasitized red blood cells (pRBCs) by macrophages is an important front-line innate host defense against malaria infection. We previously showed that repeated injections of low-dose lipopolysaccharide (LPS) prior to bacterial infection, called LPS preconditioning, strongly augmented phagocytic/bactericidal activity in murine macrophages. However, how LPS preconditioning prevents murine malaria infection is unclear. We investigated the protective effects of LPS preconditioning against lethal murine malaria infection, focusing on CD11b high F4/80 low liver macrophages, which are increased by LPS preconditioning. Mice were subjected to LPS preconditioning by intraperitoneal injections of low-dose LPS for 3 consecutive days, and 24 h later, they were intravenously infected with pRBCs of Plasmodium yoelii 17XL. LPS preconditioning markedly increased the murine survival and reduced parasitemia, while it did not reduce TNF secretions, only delaying the peak of plasma IFN-γ after malaria infection in mice. An in vitro phagocytic clearance assay of pRBCs showed that the CD11b high F4/80 low liver macrophages of the LPS-preconditioned mice had significantly augmented phagocytic activity against pRBCs. The adoptive transfer of CD11b high F4/80 low liver macrophages from LPS-preconditioned mice to control mice significantly improved the survival after malaria infection. We conclude that LPS preconditioning stimulated CD11b high F4/80 low liver macrophages to augment the phagocytic clearance of pRBCs, which may play a central role in resistance against malaria infection. LPS preconditioning may be an effective tool for preventing malaria infection.
Malaria is a life-threatening disease and is a concern of global health threat. The standard way of diagnosing the malaria is by visually examining them under microscope and is very lengthy and tedious task. In this paper, the authors has purposed custom Convolutional Neural Network model for detection of malaria on blood smear slide images. The images are available on website of U.S. National Library of Medicine. The proposed model uses various deep learning layers like convolution layer, max pooling layer, batch normalization layer and fully connected layer. The model achieves 99.71% accuracy in training and 98.23% accuracy on the test data. The study purposes a robust CNN models for detecting infected cell. The training and testing were performed on the 27,558 single cell images.
Malaria disease has severely affected the economics of tropical underdeveloped regions and a primary cause of child mortality in such regions. This mosquito carried protozoan infectious disease can take pandemic conditions in remote rural areas within a very short time. Controlling the propagation of disease vector is often futile. The disease can only be managed with early detection, confirmation of species type, stage and density of parasites within the human blood. Manual microscopy has remained the gold standard though contemporary techniques have proved themselves to be more accurate. But considering the cost and maintenance associated with modern equipment, it is impractical to implement such technology in remote areas. Manual microscopy has a number of limitations, but to overcome these limitations, technological advancements in computer science , digital electronics and microscope optics have been utilized. Digital microscopy for malaria detection is a pragmatic and cost-effective solution. The Computer Aided Diagnosis based approach with digital microscopy and advanced image processing techniques coupled with the intelligent system is the best cost effective diagnostic solution. Such software is being developed to assist pathologists and hematologist. These will reduce the time of observation, analysis, and inference and will provide a second unbiased, consistent opinion. The development of new algorithms for CAD development is an ongoing process and it is vital to understand the different methods that have already been employed. It is similarly important to assess the effectiveness of these proposed algorithms and their limitations. This review citation has critically surveyed different CAD methods. Moreover, the effectiveness of digital microscopy has been studied and compared with other methods of diagnosis.
The antiplasmodial activity of the aqueous leaf extract of Mucuna pruriens (M. pruriens) was evaluated against Plasmodium berghei NK-65 strain in mice. The plant was selected based on their traditional claims for treatment of fever and other malaria related diseases in southeastern region of Nigeria. An aqueous leaf extract (90 - 270 mg/kg) was investigated for antiplasmodial activity against Chloroquine-sensitive Plasmodium berghei infections in mice. The antiplasmodial activity during early and established infections as well as prophylactic action of the plant in blood was investigated. Chloroquine (10 mg/kg) and pyrimethamine (1.2 mg/kg) were used as positive controls. The extract (90 - 270 mg/kg) dose dependently reduced parasitaemia induced by Chloroquine sensitive Plasmodium berghei infection in suppressive, prophylactic and curative models in mice. The extract at these doses caused 60.06 - 71.75% inhibition of parasitaemia in the suppressive test, 65.97 - 84.38% parasitaemia inhibition in prophylactic test and a mean survival time of 16 - 30 days representing 64.41- 89.71% inhibition of parasitaemia in the curative test. These reductions were statistically significant (P<0.05) comparable to that of the standard drug used (Chloroquine and Pyrimethamine). These results show that the aqueous leaf extract of M. pruriens possesses significant (P<0.05) antiplasmodial activity which confirms its use in folkloric medicine in the treatment of fever and other malaria-related disease.
Introduction:
Obtaining an effective antimalarial vaccine has represented one of the biggest public health challenges over the last 50 years. Despite efforts by many laboratories around the world using whole-organism, recombinant proteins and genome-based approaches, the results have been disappointing. One of the main problems when designing an antimalarial vaccine is the poor immunogenicity induced by the functionally relevant and conserved protein regions of the parasite. Areas covered: This review focuses on the logical and rational methodology followed to identify Plasmodium falciparum conserved functional regions with the ability to bind to target cells conserved high activity binding peptides (cHABPs) and the physicochemical and immunological characteristics that should be taken into account for modifying them into highly immunogenic and protection-inducing peptides (mHABPs) into highly immunogenic and protection-inducing in Aotus monkeys. Expert opinion: The functional approach taken to develop a fully protective, minimal subunit-based, multiantigenic, multistage and synthetic peptide-based antimalarial vaccine has shown promising results. The clear relationship observed between mHABPs structure and their immunological properties highlights the challenges and opportunities arising from this methodology, as well as the universal principles and rules derived therefrom.
Plasmodium falciparum expresses on the host erythrocyte surface clonally variant antigens and ligands that mediate adherence to endothelial receptors. Both are central to pathogenesis, since they allow chronicity of infection and lead to concentration of infected erythrocytes in cerebral vessels. Here we show that expression of variant antigenic determinants is correlated with expression of individual members of a large, multigene family named var. Each var gene contains copies of a motif that has been previously shown to bind diverse host receptors; expression of a specific var gene correlated with binding to ICAM-1. Thus, our findings are consistent with the involvement of var genes in antigenic variation and binding to endothelium.
One approach towards the development of a vaccine against malaria is to immunize against the parasite sexual stages that mediate transmission of the parasite from man to mosquito. Antibodies against these stages, ingested with the blood meal, inhibit the parasite development in the mosquito vector, constituting "transmission blocking immunity." Most epitopes involved in transmission-blocking immunity depend on the tertiary conformational structure of surface antigens. However, one of the transmission-blocking monoclonal antibodies we have raised against Plasmodium vivax reacts with a linear epitope on both asexual stages and gametes. This monoclonal antibody (A12) is capable of totally blocking development of the parasite in the mosquito host when tested in membrane feeding assays with gametocytes from P. vivax-infected patients. Immune screening of a P. vivax lambda gt11 genomic expression library with A12 led to the isolation of a clone to which was mapped the six-amino acid epitope recognized by A12. Antisera raised in mice against a 12-mer synthetic peptide containing this epitope coupled to bovine serum albumin not only had high titers of antipeptide antibodies as measured by enzyme-linked immunosorbent assay, but in addition recognized the same 24- and 57-kD parasite components as A12 on Western blots and reacted with the parasite by immunofluorescence. When tested in membrane feeding assays, these antibodies have significant suppressive effects on parasite development in the mosquito.
Plasmodium falciparum causes the most severe form of human malaria, which kills approximately 1.5-2.7 million people every year, but the molecular mechanisms underlying the clinical symptoms and the host-parasite interaction remain unclear. We show here that P. falciparum produces prostaglandins (PGs) D2, E2, and F2alpha. After incubation with 1 mM arachidonic acid (AA), cell homogenates of P. falciparum produced PGs as determined by enzyme immunoassay and gas chromatography-selected ion monitoring. PG production in the parasite homogenate was not affected by the nonsteroidal antiinflammatory drugs aspirin and indomethacin, and was partially heat resistant, whereas PG biosynthesis by mammalian cyclooxygenase was completely inhibited by these chemicals and by heat treatment. Addition of AA to the parasite cell culture markedly increased an ability of the parasite cell homogenate to produce PGs and of parasitized red blood cells to accumulate PGs in the culture medium. PGD2 and PGE2 accumulated in the culture medium at the stages of trophozoites and schizonts more actively than at the ring stage. These findings are the first evidence of the direct involvement of a malaria parasite in the generation of substances that are pyrogenic and injurious to the host defenses. We will discuss a possible contribution of the parasite-produced PGs to pathogenesis and host-parasite interaction of P. falciparum.
The malaria parasite Plasmodium falciparum is one of the most successful human pathogens. Specific virulence factors remain poorly defined, although the adhesion of infected erythrocytes to the venular endothelium has been associated with some of the syndromes of severe disease. Immune responses cannot prevent the development of symptomatic infections throughout life, and clinical immunity to the disease develops only slowly during childhood. An understanding of the obstacles to the development of protective immunity is crucial for developing rational approaches to prevent the disease. Here we show that intact malaria-infected erythrocytes adhere to dendritic cells, inhibit the maturation of dendritic cells and subsequently reduce their capacity to stimulate T cells. These data demonstrate both a novel mechanism by which malaria parasites induce immune dysregulation and a functional role beyond endothelial adhesion for the adhesive phenotypes expressed at the surface of infected erythrocytes.
Malaria is today a disease of poverty and underdeveloped countries. In Africa, mortality remains high because there is limited access to treatment in the villages. We should follow in Pasteur's footsteps by using basic research to develop better tools for the control and cure of malaria. Insight into the complexity of malaria pathogenesis is vital for understanding the disease and will provide a major step towards controlling it. Those of us who work on pathogenesis must widen our approach and think in terms of new tools such as vaccines to reduce disease. The inability of many countries to fund expensive campaigns and antimalarial treatment requires these tools to be highly effective and affordable.
Immunity to Plasmodium falciparum in African children has been correlated with antibodies to the P. falciparum erythrocyte membrane protein 1 (PfEMP1) variant gene family expressed on the surface of infected red cells. We immunized Aotus monkeys with a subregion of the Malayan Camp variant antigen (MCvar1) that mediates adhesion to the host receptor CD36 on the endothelial surface and present data that PfEMP1 is an important target for vaccine development. The immunization induced a high level of protection against the homologous strain. Protection correlated with the titer of agglutinating antibodies and occurred despite the expression of variant copies of the gene during recurrent waves of parasitemia. A second challenge with a different P. falciparum strain, to which there was no agglutinating activity, showed no protection but boosted the immune response to this region during the infection. The level of protection and the evidence of boosting during infection encourage further exploration of this concept for malaria vaccine development.
Malaria starts with Plasmodium sporozoites infection of the host's liver, where development into blood stage parasites occurs. It is not clear why natural infections do not induce protection against the initial liver stage and generate low CD8+ T cell responses. Using a rodent malaria model, we show that Plasmodium blood stage infection suppresses CD8+ T cell immune responses that were induced against the initial liver stage. Blood stage Plasmodium affects dendritic cell (DC) functions, inhibiting maturation and the capacity to initiate immune responses and inverting the interleukin (IL)-12/IL-10 secretion pattern. The interaction of blood stage parasites with DCs induces the secretion of soluble factors that inhibit the activation of CD8+ T cells in vitro and the suppression of protective CD8+ T cell responses against the liver stage in vivo. We propose that blood stage infection induces DCs to suppress CD8+ T cell responses in natural malaria infections. This evasion mechanism leaves the host unprotected against reinfection by inhibiting the immune response against the initial liver stage of the disease.
Much of the pathology of malaria is mediated by inflammatory cytokines (such as interleukin 12, interferon gamma, and tumor necrosis factor alpha), which are part of the immune response that kills the parasite. The antiinflammatory cytokine transforming growth factor (TGF)-beta plays a crucial role in preventing the severe pathology of malaria in mice and TGF-beta production is associated with reduced risk of clinical malaria in humans. Here we show that serum-free preparations of Plasmodium falciparum, Plasmodium yoelii 17XL, and Plasmodium berghei schizont-infected erythrocytes, but not equivalent preparations of uninfected erythrocytes, are directly able to activate latent TGF-beta (LatTGF-beta) in vitro. Antibodies to thrombospondin (TSP) and to a P. falciparum TSP-related adhesive protein (PfTRAP), and synthetic peptides from PfTRAP and P. berghei TRAP that represent homologues of TGF-beta binding motifs of TSP, all inhibit malaria-mediated TGF-beta activation. Importantly, TRAP-deficient P. berghei parasites are less able to activate LatTGF-beta than wild-type parasites and their replication is attenuated in vitro. We show that activation of TGF-beta by malaria parasites is a two step process involving TSP-like molecules and metalloproteinase activity. Activation of LatTGF-beta represents a novel mechanism for direct modulation of the host response by malaria parasites.
Infection with malaria parasites frequently induces total immune suppression, which makes it difficult for the host to maintain long-lasting immunity. Here we show that depletion of CD4(+)CD25(+) regulatory T cells (T(reg)) protects mice from death when infected with a lethal strain of Plasmodium yoelii, and that this protection is associated with an increased T-cell responsiveness against parasite-derived antigens. These results suggest that activation of T(reg) cells contributes to immune suppression during malaria infection, and helps malaria parasites to escape from host immune responses.
Much of the pathology of malaria is mediated by inflammatory cytokines (such as interleukin 12, interferon gamma, and tumor necrosis factor alpha), which are part of the immune response that kills the parasite. The antiinflammatory cytokine transforming growth factor (TGF)-beta plays a crucial role in preventing the severe pathology of malaria in mice and TGF-beta production is associated with reduced risk of clinical malaria in humans. Here we show that serum-free preparations of Plasmodium falciparum, Plasmodium yoelii 17XL, and Plasmodium berghei schizont-infected erythrocytes, but not equivalent preparations of uninfected erythrocytes, are directly able to activate latent TGF-beta (LatTGF-beta) in vitro. Antibodies to thrombospondin (TSP) and to a P. falciparum TSP-related adhesive protein (PfTRAP), and synthetic peptides from PfTRAP and P. berghei TRAP that represent homologues of TGF-beta binding motifis of TSP, all inhibit malaria-mediated TGF-beta activation. Importantly, TRAP-deficient P. berghei parasites are less able to activate LatTGF-beta than wild-type parasites and their replication is attenuated in vitro. We show that activation of TGF-beta by malaria parasites is a two step process involving TSP-like molecules and metalloproteinase activity. Activation of LatTGF-beta represents a novel mechanism for direct modulation of the host response by malaria parasites.
One approach towards the development of a vaccine against malaria is to immunize against the parasite sexual stages that mediate transmission of the parasite from man to mosquito. Antibodies against these stages, ingested with the blood meal, inhibit the parasite development in the mosquito vector, constituting "transmission blocking immunity." Most epitopes involved in transmission-blocking immunity depend on the tertiary conformational structure of surface antigens. However, one of the transmission-blocking monoclonal antibodies we have raised against Plasmodium vivax reacts with a linear epitope on both asexual stages and gametes. This monoclonal antibody (A12) is capable of totally blocking development of the parasite in the mosquito host when tested in membrane feeding assays with gametocytes from P. vivax-infected patients. Immune screening of a P. vivax lambda gt11 genomic expression library with A12 led to the isolation of a clone to which was mapped the six-amino acid epitope recognized by A12. Antisera raised in mice against a 12-mer synthetic peptide containing this epitope coupled to bovine serum albumin not only had high titers of antipeptide antibodies as measured by enzyme-linked immunosorbent assay, but in addition recognized the same 24- and 57-kD parasite components as A12 on Western blots and reacted with the parasite by immunofluorescence. When tested in membrane feeding assays, these antibodies have significant suppressive effects on parasite development in the mosquito.
Children with acute malaria were vaccinated with Salmonella typhi and meningococcal vaccines at varying times after the onset of their illness. The immune response to both vaccines was depressed when they were given on the day of presentation at hospital. Immune responsiveness to S. typhi vaccine was rapidly regained after treatment, but a month after the attack the immune response to meningococcal vaccine was still impaired.
The precursor of the major merozoite surface Ag (PMMSA) represents one of the principal molecules of the erythrocytic stages of malarial parasites. Previously we reported that mAb 302 recognizing the 230-kDa PMMSA of Plasmodium yoelii provided passive protection to mice challenged with this parasite. We now report that the protective capacity of mAb 302 is variant specific, affording protection against infection with only three of five P. yoelii lines. Immunoprecipitation analyses of their PMMSA revealed that the expression of the epitope recognized by mAb 302 also varied and correlated completely with the results of the passive protection studies. Although this specific determinant was not present on the merozoite Ag of all P. yoelii lines, the common expression of other B cell epitopes was noted by the demonstration of serologic cross-reactivity between these molecules. Furthermore, the relatedness of the genes encoding the PMMSA of several murine plasmodial strains and species was clearly shown in nucleic acid hybridization studies. Although strain-common and strain-variable epitopes have been observed in the PMMSA of the human parasite, Plasmodium falciparum, little is known concerning the variability of its biologically relevant epitopes. The current studies using the P. yoelii model system demonstrate that the epitope recognized by a protective mAb is strain variable. Because of the similarities between these antigens of P. falciparum and P. yoelii, this information may impact on the construction of an effective blood-stage malarial vaccine.
In Aotus trivirgatus, the night monkey, schizonts and mature trophozoites of Plasmodium falciparum are concentrated in myocardium, adipose tissue, and skeletal muscle where parasitized red cells line the veins and block some capillaries. Electronmicroscopy reveals gross distortion of host red cells with numerous ultramicroscopic abnormalities of the red cell surface. Ultrastructural lesions of the red cell membrane have been demonstrated in cells infected with Plasmodium coatneyi and, as we have shown, in A. trivirgatus infected with P. falciparum. In infections with these parasites deep vascular schizogony is a prominent feature. The superficial alterations of the parasitized cells appear to be sites of attachment to venous endothelium and to other parasitized erythrocytes, thus explaining the paucity of circulating cells with maturing parasites in falciparum malaria.
.eukotrienes are significantly involved in immunoregulation and in a variety of diseases, including asthma, inflammation and various allergic conditions. They are initially biosynthesized by 5-lipoxygenase from arachidonic acid, which can also be metabolized to prostaglandin endoperoxide by cyclooxygenase. The specific inhibitors for 5-lipoxygenase would be useful not only as tools for investigating the regulation mechanism of leukotriene biosynthesis, but also as drugs for clinical use. Although recently a few selective inhibitors have been reported, most of them are difficult to obtain, since they are new compounds. We found that caffeic acid, which is one of the most common reagents, is a selective inhibitor for 5-lipoxygenase and therefore for leukotriene biosynthesis. The inhibitory effect of its methyl ester on 5-lipoxygenase (ID50 = 4.8 X 10(-7) M) was stronger than that of caffeic acid itself (ID50 = 3.7 X 10(-6) M). Caffeic acid inhibited 5-lipoxygenase in a non-competitive manner. Caffeic acid and its methyl ester did not inhibit prostaglandin synthase activity at all, at least up to 5 X 10(-4) M, but rather stimulate at higher doses. The biosynthesis of leukotriene C4 and D4 in mouse mast tumor cells was also inhibited completely with 10(-4) caffeic acid. Besides, caffeic acid had little effect on arachidonic acid metabolism in platelet at less than 1 X 10(-5) M, but at higher doses it showed a definite inhibitory effect, i.e., thromboxane B2, HHT (12(S)-hydroxy-5,8,10-heptadecatetraenoic acid) and 12-HETE (12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid) syntheses were inhibited 33, 40 and 80% at 1 X 10(-4) M, respectively. Platelet aggregation induced by arachidonic acid was also inhibited by caffeic acid at high dose, while platelet aggregation induced by ADP is not influenced by caffeic acid at all. The observations on caffeic acid and its derivatives may contribute to leukotriene research.
Women are particularly susceptible to malaria during first and second pregnancies, even though they may have developed immunity over years of residence in endemic areas. Plasmodium falciparum-infected red blood cells (IRBCs) were obtained from human placentas. These IRBCs bound to purified chondroitin sulfate A (CSA) but not to other extracellular matrix proteins or to other known IRBC receptors. IRBCs from nonpregnant donors did not bind to CSA. Placental IRBCs adhered to sections of fresh-frozen human placenta with an anatomic distribution similar to that of naturally infected placentas, and this adhesion was competitively inhibited by purified CSA. Thus, adhesion to CSA appears to select for a subpopulation of parasites that causes maternal malaria.
In the past 10 years, our knowledge of the malaria parasite has increased enormously: identification and analysis of parasite antigens, demonstration of protection of monkeys and mice following immunization with these antigens, and better understanding of the mechanisms of immunity to malaria and the pathogenesis of disease in malaria. Powerful new adjuvants have been developed, some of which--it is hoped--will be suitable for human use. Recently, a successful human trial of a vaccine aimed at sporozoites (the stage inoculated by mosquitoes) was completed. However, it is the red blood cell stage of the parasite that causes disease, and it is against this stage--in which the parasite grows at an exponential rate--that it has proven very difficult to induce a protective immune response by vaccination. This review focuses on recent exciting developments toward a blood-stage vaccine. We analyze the major obstacles to vaccine development and outline a strategy involving public- and industry-funded research that should result in development of a vaccine.
The 19-kDa antigenic domain of Plasmodium falciparum merozoite surface protein (MSP)-1 is a potential malaria vaccine candidate. Based on the amino acid substitution, four known alleles, E-TSR (PNG-MAD20 type), E-KNG (Uganda-PA type), Q-KNG (Wellcome type), and Q-TSR (Indo type) of this domain have been identified. Using single or double crossover recombinational events, we predicted the existence of additional alleles of this antigen. The presence of the predicted alleles was determined in parasite isolates from western Kenya, by undertaking a cross-sectional and a longitudinal study. Of the ten predicted alleles, we have revealed the presence of three new alleles: E-KSG-L (Kenya-1 type); E-KSR-L (Kenya-2 type); and E-KNG-F (Kenya-3 type). The results of this study suggest that it may be possible to predict the complexity of the genetic makeup of natural parasite populations.
The immunodominant CD4 T cell epitope region, Th2R, of the circumsporozoite protein of Plasmodium falciparum is highly polymorphic. Such variation might be utilized by the parasite to escape from or interfere with CD4 T cell effector functions. Here, we show that costimulation with naturally occurring altered peptide ligands (APL) can induce a rapid change from IFNgamma production to the immunosuppressive mediator interleukin 10 (IL-10). This mechanism may contribute to the low levels of T cell responses observed to this pathogen in malaria-endemic areas.
In areas of unstable transmission malaria affects all age groups, but the malaria incidence is lower in adults compared to children and teenagers. Under such conditions subclinical Plasmodium falciparum infections are common and some infections are controlled, because blood parasitaemia is maintained at low densities. Here, we test the hypothesis that the presence or absence of antibodies against variant antigens on the surface of P. falciparum-infected erythrocytes protect individuals against some infectious challenges and render them susceptible to others. Plasma collected in Daraweesh, eastern Sudan, before and after the malaria season from individuals who had (susceptible) or did not have malaria (protected) during the season, were tested for reactivity against variant antigens on the surface of nine parasite isolates by flow cytometry. Both protected and susceptible individuals acquired antibodies to variant antigens during the malaria season. The presence of antibody to a Ghanaian isolate before the season was statistically significantly associated with protection against malaria. When considering all nine isolates, the patterns of antibody acquisition differed between susceptible and protected individuals. Together, the results indicate that pre-existing anti-PfEMP1 antibodies can reduce the risk of contracting clinical malaria when challenged by novel parasite clones expressing homologous, but not heterologous variable surface antigens. The results also confirm that antibodies to variant antigens are induced by both clinical and subclinical infections, and that antibodies against several var sero-types are induced during an infection.
Several mechanisms control discrimination between self and non-self, including the thymic deletion of autoreactive T cells and the induction of anergy in the periphery. In addition to these passive mechanisms, evidence has accumulated for the active suppression of autoreactivity by a population of regulatory or suppressor T cells that co-express CD4 and CD25 (the interleukin-2 receptor alpha-chain). CD4+ CD25+ T cells are powerful inhibitors of T-cell activation both in vivo and in vitro. The enhancement of suppressor-cell function might prove useful for the treatment of immune-mediated diseases, whereas the downregulation of these cells might be beneficial for the enhancement of the immunogenicity of vaccines that are specific for tumour antigens.
The malaria parasite Plasmodium falciparum infects 5-10% of the world's population and kills two million people annually. Fatalities are thought to result in part from pathological reactions initiated by a malarial toxin. Glycosylphosphatidylinositol (GPI) originating from the parasite has the properties predicted of a toxin; however, a requirement for toxins in general and GPI in particular in malarial pathogenesis and fatality remains unproven. As anti-toxic vaccines can be highly effective public health tools, we sought to determine whether anti-GPI vaccination could prevent pathology and fatalities in the Plasmodium berghei/rodent model of severe malaria. The P. falciparum GPI glycan of the sequence NH(2)-CH(2)-CH(2)-PO(4)-(Man alpha 1-2)6Man alpha 1-2Man alpha 1-6Man alpha 1-4GlcNH(2)alpha 1-6myo-inositol-1,2-cyclic-phosphate was chemically synthesized, conjugated to carriers, and used to immunize mice. Recipients were substantially protected against malarial acidosis, pulmonary oedema, cerebral syndrome and fatality. Anti-GPI antibodies neutralized pro-inflammatory activity by P. falciparum in vitro. Thus, we show that GPI is a significant pro-inflammatory endotoxin of parasitic origin, and that several disease parameters in malarious mice are toxin-dependent. GPI may contribute to pathogenesis and fatalities in humans. Synthetic GPI is therefore a prototype carbohydrate anti-toxic vaccine against malaria.
The long-term persistence of pathogens in a host that is also able to maintain strong resistance to reinfection, referred to as concomitant immunity, is a hallmark of certain infectious diseases, including tuberculosis and leishmaniasis. The ability of pathogens to establish latency in immune individuals often has severe consequences for disease reactivation. Here we show that the persistence of Leishmania major in the skin after healing in resistant C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T cells. These cells constitute 5-10% of peripheral CD4+ T cells in naive mice and humans, and suppress several potentially pathogenic responses in vivo, particularly T-cell responses directed against self-antigens. During infection by L. major, CD4+CD25+ T cells accumulate in the dermis, where they suppress-by both interleukin-10-dependent and interleukin-10-independent mechanisms-the ability of CD4+CD25- effector T cells to eliminate the parasite from the site. The sterilizing immunity achieved in mice with impaired IL-10 activity is followed by the loss of immunity to reinfection, indicating that the equilibrium established between effector and regulatory T cells in sites of chronic infection might reflect both parasite and host survival strategies.
The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.
Toll-like receptors. An-nual Review of Immunology
- K Takeda
- T Kaisho
- S Akira
Takeda, K., Kaisho, T., & Akira, S. (2003). Toll-like receptors. An-nual Review of Immunology, 21, 335–376.
CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity
- Belkaid
CD4+CD25+ suppressor T cells: More questions than answers
- Shevach