ArticleLiterature Review

Mycobacterium tuberculosis, macrophages, and the innate immune response: Does common variation matter?

November 2007
Immunological Reviews 219(1):167-86

November 2007
219(1):167-86

DOI:10.1111/j.1600-065X.2007.00545.x

Source
PubMed

Authors:

William R Berrington

University of Washington Seattle

Despite the discovery of the tuberculosis (TB) bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis (MTb). Understanding the genetic and immunologic factors that influence human susceptibility could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease. Although a series of studies over the past 50 years suggests that host genetics influences resistance to TB, a comprehensive understanding of which genes and variants are associated with susceptibility is only partially understood. In this article, we review recent advances in our understanding of human variation of the immune system and its effects on macrophage function and influence on MTb susceptibility. We emphasize recent discoveries in human genetic studies and correlate these findings with efforts to understand how these variants alter the molecular and cellular functions that regulate the macrophage response to MTb.

Modulation of host pathways by Mycobacterium tuberculosis for survival

Chapter

Jan 2023

Mycobacterium tuberculosis (Mtb) is an extremely pathogenic bacterium which is responsible for causing tuberculosis. M. tuberculosis generally causes infection in lungs and other organs, can survive different physiological conditions inside the host and can also cause latent infection. Mtb, for its survival and pathogenesis, has to modulate various host pathways. The common pathways that are altered by Mtb include modulation of glycolytic flux, endoplasmic reticulum (EPR) stress, mitochondrial metabolism, apoptosis, and necrosis, inhibition of phagosome maturation and autophagy. Mtb harbors various mechanisms to evade host defense pathways for its survival. There are several types of antiinflammatory microRNA-21 which can help in cadence of glycolytic flux and also regulate the levels of phosphofructokinase by decreasing the biosynthetic precursors which are required for inflammatory responses. Further, the EPR stress pathway can be modulated by Mtb with the help of unfolded protein response–inducible transcription factor C/EBP homologous protein. The necrosis is regulated by inhibiting reactive oxygen species (ROS) production with the help of prostaglandin E2. With the help of extracellular regulated kinase 1/2, signal transducer and activator of transcription 3, and mitogen-activated protein kinase p38, interleukin -10 executes apoptosis pathway. Further, autophagy modulation synthesizes phenolic glycolipid with the help of polyketide synthase, encoded by intact pks 1–15 and by manipulating Ca²⁺ signaling.

Macrophage migration inhibitory factor − 794 CATT5−8 microsatellite polymorphism and susceptibility of tuberculosis

Article

Full-text available

Jun 2021
INFECTION

Purpose The establishment of candidate genetic determinants associated with tuberculosis (TB) is a challenge, considering the divergent frequencies among populations. The objective of this study was to evaluate the association between MIF − 794 CATT 5−8 polymorphism and susceptibility to TB. Methods Case–control study. Patients > 18 years, with pulmonary TB were included. The control group consisted of blood donors and household contacts, not relatives, healthy and > 18 years. MIF − 794 CATT 5−8 were genotyped using sequencing of PCR and capillary electrophoresis. Results 126 patients and 119 controls were included. The genotype 5/5 was more frequent among cases (15.1%) than in controls (5.9%) (p = 0.019). Cases had more frequently the allele 5 (29.4%) as compared with controls (19.3%) (p = 0.010). Prevalence of 7/X + 8/X genotypes was not different between cases and controls (p = 0.821). There was no difference between patients with alleles 7 and 8 and those with alleles 5 and 6 (p = 0.608). Conclusions The genotype 5/5 and the allele 5 of MIF − 794 CATT 5−8 were more frequent among TB patients than in controls.

Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis

Article

Full-text available

Oct 2019

The interleukin (IL)-12/interferon(IFN)γ axis plays an important role in the control of mycobacterial diseases as demonstrated by the increased susceptibility to mycobacterial species in patients with an inborn error of the IL-12-dependent IFNγ immunity. Here, we report a novel mutation in the IL-12Rβ1 gene in a female Pakistani patient who was born in a consanguineous marriage and developed severe bacille Calmette–Guérin (BCG) infection and recurrent tuberculosis. After reviewing the patient’s clinical records, she was investigated for IL-12/IFNγ defects using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and DNA genetic Sanger sequencing. Quantification of secretory cytokines from the patient’s peripheral blood mononuclear cells (PBMCs) revealed significantly reduced IFNγ production. Flow cytometric analysis revealed no surface expression of IL-12Rβ1 on PHA-activated T lymphocytes. In addition, IL-12-induced impaired STAT4 phosphorylation in the patient’s lymphocytes when compared with those from five healthy controls. The genetic analysis of IL-12Rβ1 gene identified a novel nonsense mutation c.199G>T/p.E67* within exon 3, which encodes part of the cytokine-binding region (CBR). In silico analysis indicates that this novel nonsense mutation generates a truncated protein with an apparent inactivating effect. Our data expand the genetic spectrum of IL-12Rβ1 deficiency. Moreover, our findings highlight the need for developing newborn screening for patients with primary immunodeficiency associated with mycobacterial infections in areas where BCG vaccination is mandatory in order to improve the treatment of patients, and consequently their quality of life.

Immunomodulatory Effects by Bifidobacterium longum KACC 91563 in Mouse Splenocytes and Macrophages

Article

Sep 2019
J Microbiol Biotechnol

The aim of the present study was to evaluate the immunomodulatory effect of Bifidobacterium longum KACC 91563 in murine primary splenocytes and macrophages. B. longum KACC 91563 regulated T and B-cell proliferation and inhibited the Th1 (IL-2, IFN-γ)/Th2 (IL-4, IL-10) cytokine imbalance and immune cytokine production. Moreover, immunoglobulin E (IgE) levels were significantly lower after treatment with B. longum KACC 91563. These findings suggest that B. longum KACC 91563 could modulate the systemic immune system toward both IgE production and regulation of the Th1/Th2 balance.

Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis

Article

Full-text available

May 2019

P P Aravindan

Background and objective: Tuberculosis (TB), the leading cause of morbidity and mortality by a single infectious agent, Mycobacterium tuberculosis, is still a major health problem in the world. To date, many studies have shown evidence of association between host genetic polymorphisms and TB susceptibility, including chemokine (C-C motif) ligand 2 (CCL-2)/monocyte chemoattractant protein1 (MCP-1), natural resistance-associated macrophage protein 1 (NRAMP-1)/solute carrier protein 11A1 (SLC11A1), Immunity-related GTPase family M protein (IRGMI), interleukin (IL)-8, toll-like receptor (TLR), and nucleotide-binding oligomerization domain containing protein-2 (NOD-2) genes. Most of these genes participate in immune response, and their polymorphism can alter immunity and lead to genetic susceptibility to TB. Materials and methods: This is a special article compiled with reference to various case-control studies, meta-analysis, and other research work on different genes and TB. The genes selected and a number of studies from different countries and ethnic groups for this article are shown below. The genes selected for the study are: NRAMP-1 (SLC11 A1), Vitamin D receptor, low molecular weight polypeptide/transporter with antigen processing, CCL-2/MCP-1, IRGM-1, IL-1, IL-8, IL-10, IL-12, TLR, NOD-2, human leukocyte antigen, mannose-binding lectin, major histocompatibility complex, tumor necrosis factor, P2X 7, epiregulin, SP110, and interferon gamma (IFN-gamma). Results: Genetic polymorphisms in different genes showed variable levels of significance in relation to TB. All these were proved by the researchers using appropriate statistical methods and tools. Conclusions: Based on different research works across the world, there is sufficient evidence to prove that TB is a genetically primed and determined infectious disease caused by M. tuberculosis and the genetic polymorphism is the mechanism that leads to progression from infection to TB disease. Why only 10-15% of the people infected with M. tuberculosis progress toward TB disease has continued to be an unresolved debate. Hence, for provoking thoughts and encouraging more research in the field of genetics and TB I formulated hypothesis and algorithms, and theory. Genetic susceptibility to TB has been substantiated based on the extensive literature review and the research findings that are well narrated.

Polymorphisms in Immune Genes and Their Association with Tuberculosis Susceptibility: An Analysis of the African Population

Article

Full-text available

Mar 2024

Tuberculosis remains a global health concern, with substantial mortality rates worldwide. Genetic factors play a significant role in influencing susceptibility to tuberculosis. This review examines the current progress in studying polymorphisms within immune genes associated with tuberculosis susceptibility, focusing on African populations. The roles of various proteins, including Toll-like receptors, Dendritic Cell-Specific Intercellular Adhesion Molecule-3 Grabbing Non-Integrin, vitamin D nuclear receptor, soluble C-type lectins such as surfactant proteins A and D, C-type Lectin Domain Family 4 Member E, and mannose-binding lectin, phagocyte cytokines such as Interleukin-1, Interleukin-6, Interleukin-10, Interleukin-12, and Interleukin-18, and chemokines such as Interleukin-8, monocyte chemoattractant protein 1, Regulated upon activation, normal T-cell expressed and secreted are explored in the context of tuberculosis susceptibility. We also address the potential impact of genetic variants on protein functions, as well as how these findings align with the genetic polymorphisms not associated with tuberculosis. Functional studies in model systems provide insights into the intricate host-pathogen interactions and susceptibility mechanisms. Despite progress, gaps in knowledge remain, highlighting the need for further investigations. This review emphasizes the association of Single Nucleotide Polymorphisms with diverse aspects of tuberculosis pathogenesis, including disease detection and Mycobacterium tuberculosis infection.

Mycobacterium tuberculosis-dependent monocyte expression quantitative trait loci, cytokine production, and TB pathogenesis

Article

Full-text available

Mar 2024

Introduction The heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis. Methods We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. Results cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in uninfected condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of BMP6, an Mtb-dependent eQTL gene, was associated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes. Discussion These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.

Toll-like receptor 2 (−196 to −174) del and TLR1 743 A > G gene polymorphism-a possible association with drug-resistant tuberculosis in the north Indian population-γ OPEN ACCESS EDITED BY

Article

Full-text available

Jan 2024

Objectives The objective of this study is to analyze the association between TLR2 deletion (−196 to −174) and TLR1 743 A > G gene polymorphism with drug resistant tuberculosis (PTB, MDR-TB, and XDR-TB) in a population from Agra, Uttar Pradesh. Methods The present case–control study included 101 pulmonary TB patients, 104 multidrug-resistant TB patients, 48 extremely drug-resistant TB patients, and 130 healthy and unrelated controls residing in the same locality. The genotyping method for TLR2 deletion (−196 to −174) was carried out by allele-specific polymerase chain reaction (PCR), and TLR1 743 A > G gene polymorphism was performed by hybridization probe chemistry in Roche Real-Time PCR. Genotype and allele frequencies were analyzed by the chi-square test. Cytokine levels were measured by ELISA and compared using Mann–Whitney and Kruskal–Wallis tests. Results The frequency of heterozygous ( Ins/del ) genotypes for TLR2 (−196 to −174) polymorphism was predominant in XDR-TB patients (0.57), whereas heterozygous A/G genotype for TLR1 743 A > G single nucleotide polymorphism (SNP) was predominant in healthy controls (0.57) for TLR1 743 A > G gene polymorphism. The heterozygous genotype of TLR2 deletion polymorphism was found to be significantly higher in XDR-TB ( p = 0.0001). TLR1 743 A > G SNP, AG genotypes were found to be significantly associated with healthy controls than PTB ( p = 0.047). The level of serum cytokines (IL-6, TNF-α, and IFN-γ) was also found to be significantly different among TB patients and healthy controls. Conclusion The findings suggested that in the present population, the heterozygous ( Ins/Del ) genotype and deletion allele of TLR2 deletion (−196 to −174) polymorphism are associated with the risk for the development of drug-resistant TB. Furthermore, for TLR1 743 A > G gene polymorphism, A/G genotype, and G allele are found associated with healthy controls, suggesting the protective role against TB.

Consanguineous marriages increase the incidence of recurrent tuberculosis: Evidence from whole exome sequencing

Article

Full-text available

Jan 2024

Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis

Preprint

Full-text available

Aug 2023

The heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis. We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in media condition [FDR ≥ 0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of BMP6, an Mtb-dependent eQTL gene, was associated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes. These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.

Vitamin D and estrogen steroid hormones and their immunogenetic roles in Infectious respiratory (TB and COVID-19) diseases

Article

Feb 2023
GENET MOL BIOL

The role of steroid hormones against infectious diseases has been extensively studied. From immunomodulatory action to direct inhibition of microorganism growth, hormones D 3 (VD 3) and 17β-estradiol (E 2), and the genetic pathways modulated by them, are key targets for a better understanding pathogenesis of infectious respiratory diseases (IRD) such as tuberculosis (TB) and the coronavirus disease-19 (COVID-19). Currently, the world faces two major public health problems, the outbreak of COVID-19, accounting for more than 6 million so far, and TB, more than 1 million deaths per year. Both, although resulting from different pathogens, the Mtb and the SARS-CoV-2, respectively, are considered serious and epidemic. TB and COVID-19 present similar infection rates between men and women, however the number of complications and deaths resulting from the two infections is higher in men when compared to women in childbearing age, which may indicate a role of the sex hormone E 2 in the context of these diseases. E 2 and VD 3 act upon key gene pathways as important immunomodulatory players and supporting molecules in IRDs. This review summarizes the main roles of these hormones (VD 3 and E 2) in modulating immune and inflammatory responses and their relationship with TB and COVID-19.

Vitamin D and estrogen steroid hormones and their immunogenetic roles in Infectious respiratory (TB and COVID-19) diseases

Article

Full-text available

Feb 2023

The role of steroid hormones against infectious diseases has been extensively studied. From immunomodulatory action to direct inhibition of microorganism growth, hormones D3 (VD3) and 17β-estradiol (E2), and the genetic pathways modulated by them, are key targets for a better understanding pathogenesis of infectious respiratory diseases (IRD) such as tuberculosis (TB) and the coronavirus disease-19 (COVID-19). Currently, the world faces two major public health problems, the outbreak of COVID-19, accounting for more than 6 million so far, and TB, more than 1 million deaths per year. Both, although resulting from different pathogens, the Mtb and the SARS-CoV-2, respectively, are considered serious and epidemic. TB and COVID-19 present similar infection rates between men and women, however the number of complications and deaths resulting from the two infections is higher in men when compared to women in childbearing age, which may indicate a role of the sex hormone E2 in the context of these diseases. E2 and VD3 act upon key gene pathways as important immunomodulatory players and supporting molecules in IRDs. This review summarizes the main roles of these hormones (VD3 and E2) in modulating immune and inflammatory responses and their relationship with TB and COVID-19.

Immunogenicity and protection against Mycobacterium avium with a heterologous RNA prime and protein boost vaccine regimen

Article

Full-text available

Dec 2022
TUBERCULOSIS

Prophylactic efficacy of two different delivery platforms for vaccination against Mycobacterium avium (M. avium) were tested in this study; a subunit and an RNA-based vaccine. The vaccine antigen, ID91, includes four mycobacterial antigens: Rv3619, Rv2389, Rv3478, and Rv1886. We have shown that ID91+GLA-SE is effective against a clinical NTM isolate, M. avium 2–151 smt. Here, we extend these results and show that a heterologous prime/boost strategy with a repRNA-ID91 (replicon RNA) followed by protein ID91+GLA-SE boost is superior to the subunit protein vaccine given as a homologous prime/boost regimen. The repRNA-ID91/ID91+GLA-SE heterologous regimen elicited a higher polyfunctional CD4+ TH1 immune response when compared to the homologous protein prime/boost regimen. More significantly, among all the vaccine regimens tested only repRNA-ID91/ID91+GLA-SE induced IFN-γ and TNF-secreting CD8+ T cells. Furthermore, the repRNA-ID91/ID91+GLA-SE vaccine strategy elicited high systemic proinflammatory cytokine responses and induced strong ID91 and an Ag85B-specific humoral antibody response a pre- and post-challenge with M. avium 2–151 smt. Finally, while all prophylactic prime/boost vaccine regimens elicited a degree of protection in beige mice, the heterologous repRNA-ID91/ID91+GLA-SE vaccine regimen provided greater pulmonary protection than the homologous protein prime/boost regimen. These data indicate that a prophylactic heterologous repRNA-ID91/ID91+GLA-SE vaccine regimen augments immunogenicity and confers protection against M. avium.

The association of cytokine gene polymorphisms with tuberculosis susceptibility in several regional populations

Article

Full-text available

Aug 2022
CYTOKINE

Purpose By collecting the data of all relevant articles, the goal of this study was to better understand the relationship between the IL-6/IL-18 polymorphism and susceptibility to tuberculosis in several regional populations. Methods Pubmed, Embase, WOS and CNKI were used to find relevant literature. The findings of separate research were merged using Review Manager. Results A total of 25 studies were included in this study. IL-6 rs1800795 (dominant. comparison: p-value < 0.0001, OR 1.43, 95 % CI 1.23–1.67; recessive comparison: p-value < 0.0001, OR 0.48, 95 % CI 0.35–0.65; allele comparison: p-value < 0.0001, OR 1.43, 95 % CI 1.27–1.62), IL-18 rs1946518 (dominant comparison: p-value = 0.01, OR 1.19, 95 % CI 1.04–1.35; recessive comparison: p-value = 0.01, OR 0.82, 95 % CI 0.71–0.96; allele comparison: p-value = 0.002, OR 1.14, 95 % CI 1.05–1.24), IL-18 rs187238 (dominant comparison: p-value = 0.0002, OR 1.35, 95 % CI 1.15–1.58; allele comparison: p-value < 0.0001, OR 1.31, 95 % CI 1.14–1.50). All gene polymorphisms were shown to be substantially linked to tuberculosis in the general population. Positive findings of rs187238 and rs1800795 polymorphisms were primarily driven by several regional populations, according to subgroup analyses. Conclusion This meta-analysis found that the the IL-6 rs1800795and IL-18 rs187238 polymorphisms may have a role in TB susceptibility

Human Macrophages Exhibit GM-CSF Dependent Restriction of Mycobacterium tuberculosis Infection via Regulating Their Self-Survival, Differentiation and Metabolism

Article

Full-text available

May 2022

GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of Mycobacterium tuberculosis bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage M. tuberculosis burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as BCL-2 and HSP27. Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against M. tuberculosis that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1β, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of M. tuberculosis and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against M. tuberculosis infection.

Systematic review and meta-analysis of human Toll-like receptors genetic polymorphisms for susceptibility to tuberculosis infection

Article

Full-text available

Apr 2022
CYTOKINE

Epidemiological data from the world health organization (WHO) show that Globally an estimated 10 million (range, 8.9–11.0 million) people around the world were infected with TB in 2019. M.tuberculosis (M.tb) is the major cause of tuberculosis. Infection with M.tb has varied host immune responses because of the host genetic factor and its response to the infection. Genetic polymorphism in TLRs imparts susceptibility or resistance to the host against several diseases. In the present study, a systematic review and meta-analysis were performed to describe the relationship among various TLRs and SNPs involved in M.tb infection and their association with susceptibility to pulmonary tuberculosis in various populations of the world. PubMed and Scihub databases from 2008 to 2019 were searched and 58 articles were shortlisted for the present study to explore the association between TLRs gene polymorphisms and susceptibility to tuberculosis infection. The combined analysis showed that the polymorphisms TLR1 (rs5743618), TLR1 (rs4833095), TLR2 (-196 to −174) del, TLR2 (rs3804099), TLR4 (rs4986790), TLR4 (rs4986791), TLR4 (rs7873784), TLR6 (rs5743810), TLR8 (rs3764880), TLR9 (rs5743836), TLR9 (rs352139) were significantly associated with TB disease in certain ethnic population. In our meta-analysis study, we have also found variations between studies in some polymorphism, for example. The TLR1 (rs 5743618), TLR2 (rs5743708), TLR4 Asp299Gly, TLR4 Thr399Ile, TLR4 (rs7873784), TLR6 (rs5743810), TLR9 (rs5743836) was associated with the protection against TB. Meta-analysis was performed between polymorphisms and pulmonary tuberculosis to define increase or decrease in susceptibility to tuberculosis in various populations, which indicated that a relationship exists between SNPs/host genetic factors and susceptibility or resistance in patients suffering from pulmonary tuberculosis our finding concludes that this gene polymorphism may be associated with susceptibility to TB. The present study adds value to the various researches and studies going on various populations of the world in better understanding the role of TLR polymorphism in TB.

PD-L1 Expression in Monocytes Correlates with Bacterial Burden and Treatment Outcomes in Active Pulmonary Tuberculosis

Article

Full-text available

Jan 2022
INT J MOL SCI

The PD-1/PD-L1 pathway is critical in T cell biology; however, the role of the PD-1/PD-L1 pathway in clinical characteristics and treatment outcomes in pulmonary tuberculosis (PTB) patients is unclear. We prospectively enrolled PTB, latent TB infection (LTBI), and non-TB, non-LTBI subjects. The expression of PD-1/PD-L1 on peripheral blood mononuclear cells (PBMCs) was measured and correlated with clinical characteristics and treatment outcomes in PTB patients. Immunohistochemistry and immunofluorescence were used to visualize PD-1/PD-L1-expressing cells in lung tissues from PTB patients and from murine with heat-killed MTB (HK-MTB) treatment. A total of 76 PTB, 40 LTBI, and 28 non-TB, non-LTBI subjects were enrolled. The expression of PD-1 on CD4+ T cells and PD-L1 on CD14+ monocytes was significantly higher in PTB cases than non-TB subjects. PTB patients with sputum smear/culture unconversion displayed higher PD-L1 expression on monocytes. PD-L1-expressing macrophages were identified in lung tissue from PTB patients, and co-localized with macrophages in murine lung tissues. Mycobacterium tuberculosis (MTB) whole cell lysate/EsxA stimulation of human and mouse macrophages demonstrated increased PD-L1 expression. In conclusion, increased expression of PD-L1 on monocytes in PTB patients correlated with higher bacterial burden and worse treatment outcomes. The findings suggest the involvement of the PD-1/PD-L1 pathway in MTB-related immune responses.

Association of TyG Index with CT Features in Patients with Tuberculosis and Diabetes Mellitus

Article

Full-text available

Jan 2022

Background: The purpose of this study was to investigate the association of the triglyceride glucose (TyG) index, a surrogate marker of insulin resistance (IR) with a high sensitivity of 96.5% and a specificity of 85.0% for the diagnosis of IR, with computed tomography (CT) features in patients with tuberculosis and diabetes mellitus. Methods: A total of 247 subjects were enrolled from July, 2020 to May, 2021. The basic clinical features and CT features were analyzed. In addition, multivariate logistic regression analysis models were employed to evaluate the association of the TyG indicator with CT features in participants. Results: In the quartile groups of TyG index, air bronchial sign detection rate was 11.7%, 14.5%, 23.2%, and 44.1%; large segmented leafy shadow detection rate was 27.9%, 40.6%, 46.4%, and 66.2%; thick-walled cavity was found in 38.2%, 43.4%, 57.9%, and 69.1%; the rate of multiple cavities was 17.6%, 27.5%, 36.2%, 52.9%; the rate of lymph node enlargement was 22.1%, 17.4%, 28.9%, and 38.2%, respectively. In addition, the positive relation with the TyG index and the prevalence of abnormal CT signs was observed in the fully adjusted model: TyG, per one-unit increase: air bronchial sign: adjusted odds ratio (AOR) 3.92, 95% CI 1-15.35, P = 0.049; multiple cavities: AOR 4.1, 95% CI 1.26-13.31, P = 0.019; thick-walled cavity: AOR 2.89, 95% CI 1.05-8.03, P = 0.041. In quartile of TyG index, compared with patients in quartile 1, the AOR (95% CI) values for air bronchial sign in quartile 4 was 8.1 (1.7-44), p = 0.011; multiple cavities was 7.1 (1.7-32), p = 0.008; thick-walled cavity was 7.8 (1.9-34.7), p = 0.005. Conclusion: The present study showed that an increased TyG index was positively related to the severity of patients with T2DM-PTB.

Acute Inflammation Confers Enhanced Protection against Mycobacterium tuberculosis Infection in Mice

Article

Full-text available

Jul 2021

Inflammation plays a crucial role in the control of Mycobacterium tuberculosis infection. In this study, we demonstrate that an inflammatory pulmonary environment at the time of infection mediated by lipopolysaccharide treatment in mice confers enhanced protection against M. tuberculosis for up to 6 months postinfection. This early and transient inflammatory environment was associated with a neutrophil and CD11b⁺ cell influx and increased inflammatory cytokines. In vitro infection demonstrated that neutrophils from lipopolysaccharide-treated mice exhibited increased association with M. tuberculosis and had a greater innate capacity for killing M. tuberculosis. Finally, partial depletion of neutrophils in lipopolysaccharide-treated mice showed an increase in M. tuberculosis burden, suggesting neutrophils played a part in the protection observed in lipopolysaccharide-treated mice. These results indicate a positive role for an inflammatory environment in the initial stages of M. tuberculosis infection and suggest that acute inflammation at the time of M. tuberculosis infection can positively alter disease outcome. IMPORTANCE Mycobacterium tuberculosis, the causative agent of tuberculosis disease, is estimated to infect one-fourth of the world’s population and is one of the leading causes of death due to an infectious disease worldwide. The high-level variability in tuberculosis disease responses in the human populace may be linked to immune processes related to inflammation. In many cases, inflammation appears to exasperate tuberculosis responses; however, some evidence suggests inflammatory processes improve control of M. tuberculosis infection. Here, we show an acute inflammatory stimulus in mice provides protection against M. tuberculosis for up to 6 months, suggesting acute inflammation can positively affect M. tuberculosis infection outcome.

In Vitro Profiling of Anti-tubercular Compounds by Rapid, Efficient, and Non-Destructive Assays Using Auto-luminescent Mycobacterium tuberculosis

Article

Full-text available

Jul 2021
ANTIMICROB AGENTS CH

Anti-infective drug discovery is greatly facilitated by the availability of in vitro assays that are more proficient at predicting the preclinical success of screening hits. TB drug-discovery is hindered by the relatively slow growth rate of Mycobacterium, and the use of whole cell-based in vitro assays that are inherently time consuming and for these reasons, rapid, non-invasive bioluminescence-based assays have been widely used in anti-TB drug discovery and development. In this study, in vitro assays that employ auto-luminescent M. tuberculosis (Mtb) were optimized to determine MIC, minimum bactericidal concentration (MBC), time-kill curves, activity against macrophage internalized Mtb (EC90), and post-antibiotic effect (PAE), to provide rapid and dynamic biological information. Standardization of the luminescence-based MIC, MBC, time-kill, EC90, and PAE assays was accomplished by comparing results of established TB drugs and two ClpC1-targeting TB leads, ecumicin and rufomycin, to those obtained from conventional assays and/or to previous studies. Cumulatively, the use of the various streamlined luminescence based in vitro assays has reduced the time for comprehensive in vitro profiling (MIC, MBC, time-kill, EC90, and PAE) by 2 months. The luminescence-based in vitro MBC and EC90 assays yield time and concentration-dependent kill information that can be used for PK/PD modelling. The MBC and EC90 time kill graphs revealed a significantly more rapid bactericidal activity for ecumicin than rufomycin. The PAEs of both ecumicin and rufomycin were comparable to that of the first line TB drug rifampin. The optimization of several non-destructive, luminescence-based TB assays facilitates the in vitro profiling of TB drug leads in an efficient manner.

Accessing BCG in infected macrophages by antibody-mediated drug delivery system and tracking by surface-enhanced Raman scattering spectroscopy

Article

Mar 2021
SPECTROCHIM ACTA A

Gold nanoparticles (AuNP) modified with antibody and rifampicin (RP) were tested against Mycobacterium bovis Bacillus Calmette-Guérin (BCG), which previously generated in vitro infection of macrophages from mice. Such a drug delivery system works as nanocarrier for RP and presented lower toxicity for macrophages cells than each separated component. Surface-enhanced Raman scattering (SERS) spectroscopy and fluorescence microscopy were used as analytical tools for the characterization of the internalization of gold nanocarriers into macrophage cells. The effective antibiotic action of RP, when combined with gold nanocarrier, was confirmed by dead-live assay of BCG bacteria lysed from macrophages after incubation. Such results indicate the delivery of RP to BCG bacteria, which were infecting macrophages, occurred with remarkable efficiency. It was rationalized based on the strategy used for the adsorption of antibody molecules on gold surface.

Investigation of genetic susceptibility to Mycobacterium tuberculosis (VDR and IL10 genes) in a population with a high level of substructure in the Brazilian Amazon region

Article

Full-text available

Jun 2020
INT J INFECT DIS

Objectives Tuberculosis (TB) is an infectious and contagious disease that is very influential in human history and presents high rates of mortality. The objective of this study was to investigate the association ofVDR, IL10 and SLC11A1 gene polymorphisms with susceptibility to presence of tuberculosis infection. Methods A total of 135 patients with confirmed tuberculosis and 141 healthy individuals were analyzed. Blood samples were collected for DNA extraction. Genotyping of the polymorphisms in VDR and IL10 genes was performed with real-time PCR and, in SLC11A1 gene, with conventional PCR followed by visualization in polyacrylamide gel. Genomic ancestry was obtained by an autosomal panel with 48 insertion/deletion ancestry informative markers. Results Polymorphisms TaqI (TT, p = 0.004), FokI (CC and CC + CT, p = 0.012 and p = 0.003, respectively), and BsmI (GG, p = 0.008) in VDR gene, as well as A-592C ( GC + AG, p = 0.001) in IL10 gene, were significantly associated to TB susceptibility. In addition, high production of VDR combined with low production of IL10 showed protection for TB group (p = 0.035). Conclusions The VDR polymorphisms may confer an increased risk and the IL10 haplotype may be a protection factor to presence of tuberculosis infection in the Brazilian population.

Interconnection of Mycobacterium tuberculosis with host immune system

Article

Full-text available

Jun 2020

Precise estimation of development of active tuberculosis (TB) infection from a latent Mycobacterium tuberculosis H 37 Rv (MTB) infection within host body signifies an indefinable and serious objective. Most of the infected individuals with excellent immune system are also at risk due to diverse local environmental and systemic factors. Therefore, it becomes mandatory to have a balance between pro and anti-immune regulators to work efficiently in optimized manner. This study thus signifies some essential factors involved in maintaining this balance and rescue host cellular environment from MTB infection. Inside host, MTB develops effective survival strategies, such as hampering of lysosome-phagosome fusion, hampering of phagosome acidification by a secretary protein phosphatase PtpA that binds to H subunit of V-ATPase to block V-ATPase transportation towards phagosome membrane, recruitment of TACO protein on phagosomal membrane to escape their transportation to lysosome. Bacterial infected cell undergoing apoptosis release ATP, UTP, LPC, S1P and several chemokines that intervene signaling of "find me" signal. Eventually, a balance between all these immunological factors must be set for optimized functioning of immune system against MTB. In this review we have elaborated various balancing mechanisms among pro and anti-inflammatory immune components that raise this disease from latent to active form. Through a brief and complete evaluation of different types of immune components that take part in host defense, we aimed to highlight the review with recent documented literatures to have a better and precise understanding of this disease. In conclusion, this review abridges various defensive strategies that moderate the distinct capability to fight MTB infection.

Interconnection of Mycobacterium tuberculosis with host immune system

Article

Full-text available

Jun 2020

Shivangi ..

TLR9 Polymorphisms Might Contribute to the Ethnicity Bias for EBV-Infected Nasopharyngeal Carcinoma

Article

Full-text available

Feb 2020

Nasopharyngeal carcinoma (NPC) is a rare malignancy in most part of the world, but is endemic in some ethnic groups. The association of NPC with the Epstein-Barr virus (EBV) is firmly established; however the mechanism is still unclear. TLR9 is well known for its essential role in viral pathogen recognition and activation of innate immunity. Here, we report a set of TLR9 polymorphisms in the TIR-2 domain of the TLR9 protein collected from the EBV infected NPC samples from North-East Indian populations sharing the aforesaid ethnicity. The occurrence of mutations is significantly high in these samples as we found a p-value of <0.0001 at a significance level of 0.05. These might play an important role for the lack of function of TLR9 and thus for the higher occurrence of EBV-mediated NPC in such ethnic groups.

Capsular glycan recognition provides antibody-mediated immunity against tuberculosis

Article

Jan 2020
J CLIN INVEST

A better understanding of all immune components involved in protecting against M. tuberculosis infection is urgently needed to inform strategies for novel immunotherapy and tuberculosis (TB) vaccine development. While cell-mediated immunity is critical, increasing evidence supports that antibodies also have a protective role against TB. Yet, knowledge of protective antigens is limited. Analyzing sera from 97 US immigrants at various states of M. tuberculosis infection, we showed protective in vitro and in vivo efficacy of polyclonal IgG to the M. tuberculosis capsular polysaccharide arabinomannan (AM). Using recently developed glycan arrays, we established that anti-AM IgG induced in natural infection is highly heterogeneous in its binding specificity and differs in both its reactivity to oligosaccharide motifs within AM and its functions between BCG vaccination and/or controlled (latent) versus uncontrolled (TB) M. tuberculosis infection. We showed that anti-AM IgG from asymptomatic but not diseased individuals was protective, and provided data suggesting a potential role of IgG2 and specific AM oligosaccharides. Filling a gap in the current knowledge of protective antigens in humans, our data support the key role of the M. tuberculosis surface glycan AM and suggest the importance of targeting specific glycan epitopes within AM in antibody-mediated immunity against TB.

Functional variations of the TLR4 gene in association with chronic obstructive pulmonary disease and pulmonary tuberculosis

Article

Full-text available

Oct 2019
BMC Pulm Med

Objective: Chronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis (PTB) share a number of common risk factors, including innate immunity-related genetic factors. In the present study, we compared the role of genetic variations of the TLR4 gene in susceptibility to COPD and PTB and illuminated the underlying molecular mechanism of functional single-nucleotide polymorphisms (SNPs). Methods: A population-based case control study was performed in a Chinese Han population and included 152 COPD cases, 1601 PTB cases and 1727 controls. Five SNPs in the TLR4 gene (rs10759932, rs2737190, rs7873784, rs11536889, and rs10983755) were genotyped using TaqMan allelic discrimination technology. We estimated the effects of SNPs using the odds ratio (OR) together with 95% confidence interval (CI). Dual-luciferase reporter vectors expressing different genotypes of SNPs were constructed and transfected into the human HEK 293 T cell line to explore their effects on potential transcription activity. Results: After Bonferroni correction, the genetic polymorphisms of all five SNPs remained significantly associated with COPD, while rs10759932 and rs2737190 were also associated with PTB. Compared with rs10759932-TT, individuals carrying TC (OR: 0.42, 95% CI: 0.28-0.64) or CC (OR: 0.24, 95% CI: 0.09-0.63) had a significantly reduced risk of COPD. However, individuals carrying TC (OR: 1.28, 95% CI: 1.11-1.49) or CC (OR: 1.26, 95% CI: 0.98-1.62) had an increased risk of PTB. The OR (95% CI) for allele rs10759932-C was 0.45 (0.32-0.62) for COPD and 1.18 (1.07-1.32) for PTB. For rs2737190, heterozygous AG was related to a decreased risk of COPD (OR: 0.32, 95% CI: 0.21-0.49) and an increased risk of PTB (OR: 1.30, 95% CI: 1.11-1.52). The dual-luciferase reporter assay showed decreased transcription activity caused by rs10759932-C and rs2737190-G. Conclusion: Genetic polymorphisms of rs10759932 and rs2737190 in TLR4 are significantly related to both COPD and PTB but with inverse effects. The altered transcription activity caused by mutations in these two loci may partly explain the observed relationship.

Immunity to the Dual Threat of Silica Exposure and Mycobacterium tuberculosis

Article

Full-text available

Jan 2019

Exposure to silica and the consequent development of silicosis are well-known health problems in countries with mining and other dust producing industries. Apart from its direct fibrotic effect on lung tissue, chronic and immunomodulatory character of silica causes susceptibility to tuberculosis (TB) leading to a significantly higher TB incidence in silica-exposed populations. The presence of silica particles in the lung and silicosis may facilitate initiation of tuberculous infection and progression to active TB, and exacerbate the course and outcome of TB, including prognosis and survival. However, the exact mechanisms of the involvement of silica in the pathological processes during mycobacterial infection are not yet fully understood. In this review, we focus on the host's immunological response to both silica and Mycobacterium tuberculosis, on agents of innate and adaptive immunity, and particularly on silica-induced immunological modifications in co-exposure that influence disease pathogenesis. We review what is known about the impact of silica and Mycobacterium tuberculosis or their co-exposure on the host's immune system, especially an impact that goes beyond an exclusive focus on macrophages as the first line of the defense. In both silicosis and TB, acquired immunity plays a major role in the restriction and/or elimination of pathogenic agents. Further research is needed to determine the effects of silica in adaptive immunity and in the pathogenesis of TB.

Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response

Article

Full-text available

Nov 2018

It is uncertain whether differences in Mycobacterium tuberculosis (Mtb) virulence defined in vitro influence clinical tuberculosis pathogenesis, transmission, and mortality. We primarily used a macrophage lysis model to characterize the virulence of Mtb isolates collected from 153 Vietnamese adults with pulmonary tuberculosis. The virulence phenotypes were then investigated for their relationship with sputum bacterial load, bacterial lineages, bacterial growth, and cytokine responses in macrophages. Over 6 days of infection, 34 isolates (22.2%) showed low virulence (< 5% macrophages lysed), 46 isolates (30.1%) showed high virulence (≥90% lysis of macrophages), and 73 isolates (47.7%) were of intermediate virulence (5–90% macrophages lysed). Highly virulent isolates were associated with an increased bacterial load in patients' sputum before anti-tuberculosis therapy (P = 0.02). Isolate-dependent virulence phenotype was consistent in both THP-1 and human monocyte-derived macrophages. High virulence isolates survived better and replicated in macrophages one hundred fold faster than those with low virulence. Macrophages infected with high virulence isolates produced lower concentrations of TNF-α and IL-6 (P = 0.002 and 0.0005, respectively), but higher concentration of IL-1β (P = 5.1 × 10−5) compared to those infected with low virulence isolates. High virulence was strongly associated with East Asian/Beijing lineage [P = 0.002, Odd ratio (OR) = 4.32, 95% confident intervals (CI) 1.68–11.13]. The association between virulence phenotypes, bacterial growth, and proinflammatory cytokines in macrophages suggest the suppression of certain proinflammatory cytokines (TNF-α and IL-6) but not IL-1β allows better intracellular survival of highly virulent Mtb. This could result in rapid macrophage lysis and higher bacterial load in sputum of patients infected with high virulence isolates, which may contribute to the pathogenesis and success of the Beijing lineage.

Polysaccharide rich extract (PRE) from Tinospora cordifolia inhibits the intracellular survival of drug resistant strains of Mycobacterium tuberculosis in macrophages by Nitric oxide induction

Article

Sep 2018
TUBERCULOSIS

Rv3033, as an Emerging Anti-apoptosis Factor, Facilitates Mycobacteria Survival via Inhibiting Macrophage Intrinsic Apoptosis

Article

Full-text available

Sep 2018

Apoptosis inhibition is a critical strategy of mycobacteria facilitating its survival in macrophages, but the underlying mechanism is not completely understood. In this study, we found that Rv3033, a secreted virulence factor of mycobacteria, played an important role in bacillary survival within macrophages. Forced over-expressed of Rv3033 in macrophages could efficiently resist mycobacteria-induced early and late apoptosis, accompanied with the obvious increased cellular bacterial burden. By exploring the underlying mechanism, we found that Rv3033 efficiently repressed the intrinsic (caspase-9 meditated), but not the extrinsic (caspase-8 mediated) apoptotic pathway in mycobacteria-infected macrophages. And this repression relied on the orchestrating blockade of both mitochondrial cytochrome c release and endoplasmic reticulum (ER) stress PERK branch activation. Our study uncovered a novel function of mycobacterial virulence factor Rv3033 as an anti-apoptotic protein, which may provide a new target for tuberculosis (TB) treatment.

AmpliSeq transcriptome analysis of human alveolar and monocyte-derived macrophages over time in response to Mycobacterium tuberculosis infection

Article

Full-text available

May 2018
PLOS ONE

Human alveolar macrophages (HAM) are primary bacterial niche and immune response cells during Mycobacterium tuberculosis (M.tb) infection, and human blood monocyte-derived macrophages (MDM) are a model for investigating M.tb-macrophage interactions. Here, we use a targeted RNA-Seq method to measure transcriptome-wide changes in RNA expression patterns of freshly obtained HAM (used within 6 h) and 6 day cultured MDM upon M.tb infection over time (2, 24 and 72 h), in both uninfected and infected cells from three donors each. The Ion AmpliSeq™ Transcriptome Human Gene Expression Kit (AmpliSeq) uses primers targeting 18,574 mRNAs and 2,228 non-coding RNAs (ncRNAs) for a total of 20,802 transcripts. AmpliSeqTM yields highly precise and reproducible gene expression profiles (R² >0.99). Taking advantage of AmpliSeq’s reproducibility, we establish well-defined quantitative RNA expression patterns of HAM versus MDM, including significant M.tb-inducible genes, in networks and pathways that differ in part between MDM and HAM. A similar number of expressed genes are detected at all time-points between uninfected MDM and HAM, in common pathways including inflammatory and immune functions, but canonical pathway differences also exist. In particular, at 2 h, multiple genes relevant to the immune response are preferentially expressed in either uninfected HAM or MDM, while the HAM RNA profiles approximate MDM profiles over time in culture, highlighting the unique RNA expression profile of freshly obtained HAM. MDM demonstrate a greater transcriptional response than HAM upon M.tb infection, with 2 to >10 times more genes up- or down-regulated. The results identify key genes involved in cellular responses to M.tb in two different human macrophage types. Follow-up bioinformatics analysis indicates that approximately 30% of response genes have expression quantitative trait loci (eQTLs in GTEx), common DNA variants that can influence host gene expression susceptibility or resistance to M.tb, illustrated with the TREM1 gene cluster and IL-10.

Epigenetic programming of host lipid metabolism associates with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis

Preprint

Full-text available

Mar 2024

Mycobacterium tuberculosis (Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon gamma release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. In contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid and cholesterol associated pathways including in the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived HDL from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFNγ-independent mechanisms. IMPORTANCE Tuberculosis (TB) remains an enduring global health challenge with millions of deaths and new cases each year. Despite recent advances in TB treatment, we lack an effective vaccine or a durable cure. While heavy exposure to Mycobacterium tuberculosis often results in latent TB latent infection (LTBI), subpopulations exist who are either resistant to infection or contain Mtb with IFNγ-independent mechanisms not indicative of LTBI. These resisters provide an opportunity to investigate mechanisms of TB disease and discover novel therapeutic targets. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. We identify methylation signatures in host lipid and cholesterol pathways with potential relevance to early TB clearance before the sustained IFN responses indicative of LTBI. This adds to a growing body of literature linking TB disease outcomes to host lipids.

Immune-endocrine network in diabetes-tuberculosis nexus: does latent tuberculosis infection confer protection against meta-inflammation and insulin resistance?

Article

Full-text available

Jan 2024

Tuberculosis patients with diabetes, have higher sputum bacillary load, delayed sputum conversion, higher rates of drug resistance, higher lung cavitary involvement and extra-pulmonary TB infection, which is called as “Diabetes-Tuberculosis Nexus”. However, recently we have shown a reciprocal relationship between latent tuberculosis infection and insulin resistance, which has not been reported before. In this review, we would first discuss about the immune-endocrine network, which operates during pre-diabetes and incipient diabetes and how it confers protection against LTBI. The ability of IR to augment anti-TB immunity and the immunomodulatory effect of LTBI to quench IR were discussed, under IR-LTB antagonism. The ability of diabetes to impair anti-TB immunity and ability of active TB to worsen glycemic control, were discussed under “Diabetes-Tuberculosis Synergy”. The concept of “Fighter Genes” and how they confer protection against TB but susceptibility to IR was elaborated. Finally, we conclude with an evolutionary perspective about how IR and LTBI co-evolved in endemic zones, and have explained the molecular basis of “IR-LTB” Antagonism” and “DM-TB Synergy”, from an evolutionary perspective.

Tuberculosis Vaccines

Chapter

Jan 2023

Cell wall and immune modulation by Rv1800 (PPE28) helps M. smegmatis to evade intracellular killing

Article

Jul 2023
INT J BIOL MACROMOL

Rv1800 is predicted as PPE family protein found in pathogenic mycobacteria only. Under acidic stress, the rv1800 gene was expressed in M. tuberculosis H37Ra. In-silico study showed lipase/esterase activity in C-terminus PE-PPE domain having pentapeptide motif with catalytic Ser-Asp-His residue. Full-length Rv1800 and C-terminus PE-PPE domain proteins showed esterase activity with pNP-C4 at the optimum temperature of 40 °C and pH 8.0. However, the N-terminus PPE domain showed no esterase activity, but involved in thermostability of Rv1800 full-length protein. M. smegmatis expressing rv1800 (MS_Rv1800) showed altered colony morphology and a significant resistance to numerous environmental stresses, antibiotics and higher lipid content. In extracellular and membrane fraction, Rv1800 protein was detected, while C terminus PE-PPE was present in cytoplasm, suggesting the role of N-terminus PPE domain in transportation of protein. MS_Rv1800 infected macrophage showed higher intracellular survival and low production of ROS, NO and expression levels of iNOS and pro-inflammatory cytokines, while induced expression of the anti-inflammatory cytokines. The Rv1800, PPE and PE-PPE showed antibody-mediated immunity in MDR-TB and PTB patients. Overall, these results confirmed the esterase activity in the C-terminus and function of N-terminus in thermostabilization and transportation; predicting the role of Rv1800 in immune/lipid modulation to support intracellular mycobacterium survival.

Dynamics of Clinical, Radiological and Laboratory Parameters in Patients with an Infiltrative Form of Firstly Diagnosed Pulmonary Tuberculosis

Article

Full-text available

Dec 2021

According to the World Health Organization, each year 10 million people are diagnosed with tuberculosis for the first time and 1.5 million people die from it. The death rate from this disease has increased in the world for the first time in more than ten years. Unfortunately, Ukraine is in the TOP-10 countries with the largest number of tuberculosis cases among population. Only in December 2021, 1,229 cases of tuberculosis were registered in Ukraine. To date, the course of the tuberculosis process has undergone significant changes. The infiltrative form (IF) of pulmonary tuberculosis accounts for the majority of new cases. Standardized treatment (60 doses in the intensive phase and 120 doses in the continuation phase) is not always sufficient for effective recovery and requires prolongation. That is why it is necessary to study the predictors that maximally reflect the need in therapy prolongation. The objective: to analyze the dynamics of clinical, laboratory and radiological parameters in patients with IF of newly diagnosed pulmonary tuberculosis (NDPT) under conditions of varying treatment effectiveness. Materials and methods. 120 men of working age with IF NDPT were examined in KNP of the Kharkiv Regional Council “Regional TB Dispancer N1” during 2019–2021. Patients were divided into two groups: Group 1 (n=89) included patients with positive clinical and radiological dynamics of the tuberculosis process, and as a result of treatment clearing of Mycobacterium tuberculosis (MBT) from the sputum; Group 2 included patients (n=31) with weak positive dynamics, as a result of which IF was extended to 90 doses. Comparison of clinical, laboratory and radiological data at the beginning and end of IF treatment in patients with different therapy efficiency was performed. The study was conducted in accordance with the requirements of good clinical practice, the Declaration of Helsinki of the World Medical Association, and was approved by the local ethic committee of the Kharkiv Medical Academy of Postgraduate Education. Results. An analysis of the dynamics of clinical, radiological and laboratory data showed that the decrease of immuno-inflammatory indicators levels (C-reactive protein, IL-4, IL-10, circulating immune complexes; CD4/CD8 ratio) was more pronounced in the group of patients who did not need treatment prolongation. At the same time this group was also characterized by significant increase in the level of IFN-γ by the end of the IF treatment, which could indicate activation of cellular immunity together with decrease in the levels of IL-4 and IL-10 which indicated the suppression of humoral immunity. Due to the predominance of cellular immunity over humoral, macrophage activation and their phagocytic activity were accelerated, as a result of which the process of MBT elimination was much faster and more efficient in Group 1 patients. Changes in cytokine levels were observed in patients of Group 1, who showed positive dynamics after IF treatment, but not in patients of Group 2, who demonstrated signs of cytokine dysregulation due to continuing specific inflammatory process. Conclusions. Tuberculosis remains one of the global health problems. The general trend in the spread of tuberculosis and mortality from it throughout the world requires urgent efforts to the detection and treatment of this disease. In patients with IF pulmonary TB standard treatment was less effective in case of slow insufficient decrease in the levels of CRP, IL-10, γ-INF, and the CD4/CD8 ratio which was associated with slow cavities healing, continuing spreading of the infiltrative process. These patients needed prolonged treatment regimen.

The Innate Immune Response to Mycobacterium Tuberculosis is Dependent on Strain Lineage and on Host Population

Experiment Findings

Full-text available

Mar 2021

Dr Rajesh Sarkar

The Innate Immune Response to Mycobacterium Tuberculosis is Dependent on Strain Lineage and on Host Population publication description. Google Book : The Innate Immune Response to Mycobacterium Tuberculosis is Dependent on Strain Lineage and on Host Population. https://books.google.com.et/books/about/The_Innate_Immune_Response_to_Mycobacter.html?id=LsdUnQAACAAJ&redir_esc=y publication description : The genome structure of Mycobacterium tuberculosis is strongly clonal, in the absence of horizontal gene transfer. Thus it is feasible that clonal lineages may exhibit particular phenotypic characteristics, which may, in turn, result in differences in virulence or influence their association with particular host populations. Indeed, the global distribution of M. tuberculosis strains is not uniform and certain strain lineages predominate in particular geographical areas. Further, there is evidence that some strain lineages are emerging, suggesting differences in virulence. Firstly, we investigated the association between strain genotype of M. tuberculosis and in vitro correlates of virulence such as growth phenotype and cytokine induction in the monocyte-derived macrophage (MDM) model. Secondly, in order to study the interaction between host genetic background and the innate immune response to different strains of M. tuberculosis we conducted a cross sectional study comparing cytokine responses to in vitro infection of healthy donor monocyte derived macrophages (MDM) from individuals from different population groups with strains from different M. tuberculosis lineages. The inflammatory cytokines TNF, IL-12p40, IL-6, IL-1b and GMCSF were secreted at higher levels in response to infection with lineage 4 and lineage 3 strains as compared to lineage 2 and lineage 1 strains. Principal component analysis and linear modeling identified three inflammatory cytokines (IL-6, IL-12p40, and GM-CSF) to be differentially secreted in all four-population groups. All research datas' are analyzed by Rajesh Sarkar, myself as per guidance of UCT statistic department and expert acknowledged in the thesis and dissertation sections. One postgraduate student from statistic department got postgraduate degree from these data analysis. In this regard, any misleading information will not be acceptable.

Recent advances in non-specific immune memory against bovine tuberculosis

Article

Jan 2021

Bovine tuberculosis is an important worldwide disease mainly related to cattle, although it also affects other mammals, including humans. In recent years, there have been considerable advances in the knowledge of the immune response mechanisms underlying the interaction of Mycobacterium bovis, the main agent of bovine tuberculosis, with its hosts. In this review we describe the most recent findings on the cattle immune response to M. bovis, particularly regarding trained innate immune responses and γδ T cells, that could support the development of vaccines and diagnostic tools to control this disease.

Acute inflammation, mediated by lung neutrophils, confers enhanced protection against Mycobacterium tuberculosis infection in mice

Preprint

Full-text available

Jan 2021

Inflammation plays a crucial role in the control of Mycobacterium tuberculosis ( M.tb ) infection. In this study, we demonstrate that an inflammatory pulmonary environment at the time of infection mediated by liposaccharide (LPS) treatment in mice confers enhanced protection against M.tb for up to 6 months post infection. This transient protective inflammatory environment was associated with a neutrophil and monocyte/macrophage influx as well as increased inflammatory cytokines. In vitro infection of neutrophils from LPS treated mice demonstrated that LPS neutrophils exhibited increased recognition of M.tb , and had a greater innate capacity for killing M.tb . Finally, partial depletion of neutrophils in LPS treated mice showed an increase in M.tb burden, suggesting neutrophils conferred the enhanced protection observed in LPS treated mice. These results indicate a positive role of an inflammatory environment during initial M.tb infection, and suggests that acute inflammation at the time of M.tb infection can positively alter disease outcome.

Innate Immune Pattern Recognition Receptors of Mycobacterium tuberculosis: Nature and Consequences for Pathogenesis of Tuberculosis

Chapter

Oct 2021
ADV EXP MED BIOL

Innate immunity against Mycobacterium tuberculosis is a critical early response to prevent the establishment of the infection. Despite recent advances in understanding the host-pathogen dialogue in the early stages of tuberculosis (TB), much has yet to be learnt. The nature and consequences of this dialogue ultimately determine the path of infection: namely, either early clearance of M. tuberculosis, or establishment of M. tuberculosis infection leading to active TB disease and/or latent TB infection. On the frontline in innate immunity are pattern recognition receptors (PRRs), with soluble factors (e.g. collectins and complement) and cell surface factors (e.g. Toll-like receptors and other C-type lectins receptors (Dectin 1/2, Nod-like receptors, DC-SIGN, Mincle, mannose receptor, and MCL) playing a central role in recognising M. tuberculosis and supporting its clearance. However, in a ‘double-edged sword’ scenario, these factors can also be involved in enhancement of pathogenesis as well. Furthermore, innate immunity is also a critical bridge in establishing the subsequent adaptive immune response, which is also responsible for granuloma formation that cordons off M. tuberculosis infection, establishing latency and acting as a reservoir for bacterial persistence and dissemination of future disease. This chapter discusses the current understanding of pattern recognition of M. tuberculosis by innate immunity and the role this plays in the pathogenesis and protection against TB.

Variations in Antimicrobial Activities of Human Monocyte-Derived Macrophage and Their Associations With Tuberculosis Clinical Manifestations

Article

Full-text available

Oct 2020

Macrophages play a significant role in preventing infection through antimicrobial activities, particularly acidification, and proteolysis. Mycobacterium tuberculosis (Mtb) infection can lead to diverse outcomes, from latent asymptomatic infection to active disease involving multiple organs. Monocyte-derived macrophage is one of the main cell types accumulating in lungs following Mtb infection. The variation of intracellular activities of monocyte-derived macrophages in humans and the influence of these activities on the tuberculosis (TB) spectrum are not well understood. By exploiting ligand-specific bead-based assays, we investigated macrophage antimicrobial activities real-time in healthy volunteers (n = 53) with 35 cases of latent TB (LTB), and those with active TB (ATB), and either pulmonary TB (PTB, n = 70) or TB meningitis (TBM, n = 77). We found wide person-to-person variations in acidification and proteolytic activities in response to both non-immunogenic IgG and pathogenic ligands comprising trehalose 6,6'−dimycolate (TDM) from Mtb or β-glucan from Saccharamyces cerevisiase. The variation in the macrophage activities remained similar regardless of stimuli; however, IgG induced stronger acidification activity than immunogenic ligands TDM (P = 10⁻⁵, 3 × 10⁻⁵ and 0.01 at 30, 60, and 90 min) and β-glucan (P = 10⁻⁴, 3 × 10⁻⁴ and 0.04 at 30, 60, and 90 min). Variation in proteolysis activity was slightly higher in LTB than in ATB (CV = 40% in LTB vs. 29% in ATB, P = 0.03). There was no difference in measured antimicrobial activities in response to TDM and bacterial killing in macrophages from LTB and ATB, or from PTB and TBM. Our results indicate that antimicrobial activities of monocyte-derived macrophages vary among individuals and show immunological dependence, but suggest these activities cannot be solely responsible for the control of bacterial replication or dissemination in TB.

The Innate Immune Response to Mycobacterium Tuberculosis is Dependent on Strain Lineage and on Host Population https://books.google.com.et/books/about/The_Innate_Immune_Response_to_Mycobacter.html?id=LsdUnQAACAAJ&redir_esc=y

Book

Full-text available

Aug 2013

Dr Rajesh Sarkar

The genome structure of Mycobacterium tuberculosis is strongly clonal, in the absence of horizontal gene transfer. Thus it is feasible that clonal lineages may exhibit particular phenotypic characteristics, which may, in turn, result in differences in virulence or influence their association with particular host populations. Indeed, the global distribution of M. tuberculosis strains is not uniform and certain strain lineages predominate in particular geographical areas. Further, there is evidence that some strain lineages are emerging, suggesting differences in virulence. Firstly, we investigated the association between strain genotype of M. tuberculosis and in vitro correlates of virulence such as growth phenotype and cytokine induction in the monocyte-derived macrophage (MDM) model. We report that ‘modern’ clinical M. tuberculosis isolates from Cape Town (Lineage 2 and Lineage 4 strains) exhibit both lineage-specific patterns of growth in vitro (in broth and MDM) as well as cytokine responses in MDM. Secondly, in order to study the interaction between host genetic background and the innate immune response to different strains of M. tuberculosis we conducted a cross sectional study comparing cytokine responses to in vitro infection of healthy donor MDM from individuals from different population groups with strains from different M. tuberculosis lineages. The inflammatory cytokines TNF, IL-12p40, IL-6, IL-1b and GMCSF were secreted at higher levels in response to infection with lineage 4 and lineage 3 strains as compared to lineage 2 and lineage 1 strains. Principal component analysis and linear modeling identified three inflammatory cytokines (IL-6, IL-12p40, and GM-CSF) to be differentially secreted in all four-population groups. In addition, we noted evidence of possible strain lineage-host ethnicity interactions for several cytokines. Together, these studies suggests that genetic diversity of M. tuberculosis might influence the early innate immune response during tuberculosis infection, and that lineage-specific responses may be modulated by host genetic background.

Immune Response and Tissue Damage

Chapter

Jan 2020

Jürgen Arnhold

Associations of polymorphisms in IL-6 and IL-18 with tuberculosis: Evidence from a meta-analysis

Article

Oct 2019

Background: Associations between polymorphisms in interleukin-6 (IL-6)/interleukin-18 (IL-18) and tuberculosis (TB) were already reported by many publications. The aim of this meta-analysis was to better clarify associations between polymorphisms in IL-6/IL-18 and TB by combing the results of all relevant publications. Methods: Eligible publications were searched from Pubmed, Embase, WOS and CNKI. We used Review Manager to combine the results of individual studies. Results: Twenty-five studies were included in this study. IL-6 rs1800795 (dominant comparison: OR 1.43, 95% CI 1.23-1.67; recessive comparison: OR 0.48, 95% CI 0.35-0.65; allele comparison: OR 1.43, 95% CI 1.27-1.62), IL-18 rs1946518 (dominant comparison: OR 1.19, 95% CI 1.04-1.35; recessive comparison: OR 0.82, 95% CI 0.71-0.96; allele comparison: OR 1.14, 95% CI 1.05-1.24) and IL-18 rs187238 (dominant comparison: OR 1.35, 95% CI 1.15-1.58; allele comparison: OR 1.31, 95% CI 1.14-1.50) polymorphisms were all significantly associated with TB in the total population. Subgroup analyses showed that positive findings for rs1946518, rs187238 and rs1800795 polymorphisms were mainly driven by the Asians. Conclusions: Collectively, this meta-analysis proved that IL-6 rs1800795, IL-18 rs1946518 and IL-18 rs187238 polymorphisms may confer susceptibility to TB, especially for Asians.

Transferrin conjugates of antitubercular drug isoniazid: Synthesis and in vitro efficacy

Article

Sep 2019

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become the world's leading killer disease due to a single infectious agent which survives in the host macrophage for the indefinite period. Hence, it is necessary to enhance the efficacy of the clinically existing antitubercular agents or to discover new anti antitubercular agents. Here, we report the synthesis, characterization and antimycobacterial evaluation of protein-drug conjugates. A carrier protein, Transferrin (Tf) was covalently conjugated to isoniazid (INH) utilizing hydrazone and amide linkers. The purity of the reactions was confirmed by SDS-PAGE while conjugation was confirmed by UV-visible spectrophotometry, MALDI-TOF analysis, and FTIR spectrophotometry. The in vitro antitubercular assay result showed that the inhibitory activity of the parent drug was conserved in both the conjugates. The conjugates were effective against intracellular Mtb H37Rv and were devoid of cytotoxic effect at therapeutic concentration.

Effect of dehydroepiandrosterone on the immune function of mice in vivo and in vitro

Article

Aug 2019

Dehydroepiandrosterone (DHEA) has anti-inflammatory, anti-oxidant and immune-regulating properties, while the mechanism of DHEA actions remains unclear. The present study aims to investigate the effect and possible mechanism of DHEA on immune function of mice in vivo and in vitro. In vivo, a lipopolysaccharide (LPS)-induced experimental inflammation model was constructed to analyze the regulation of DHEA on anti-oxidative and immune function in ICR mice; In vitro, the effects of DHEA on the biological functions of lymphocytes and macrophages were studied. The results showed that DHEA increased the activity of total antioxidant capacity and superoxide dismutase, while it decreased the level of reactive oxygen species in LPS-induced mice. Meanwhile, DHEA increased the proportion of T lymphocytes and decreased that of B lymphocytes in primary cultured spleen lymphocytes, and markedly enhanced the Th1/Th2 ratio in spleen T lymphocytes. Furthermore, DHEA significantly increased the Th1 type cytokine (IL-2 and IFN-α) and decreased the Th2 type cytokine (IL-4 and IL-10) levels in LPS-induced mice or in primary cultured spleen T lymphocytes. In addition, DHEA improved the phagocytic ability, enhanced the NO production and increased the iNOS activity in peritoneal macrophages. Our data indicates that DHEA increases the macrophages function via improving NO content and up-regulating TNF-α expression levels; and it evoked a Th1 immuno-response and repressed a Th2 immuno-response through promoting a shift in Th1/Th2 balance toward Th1-dominant immunity in vivo and in vitro. These results provide substantial evidence on the mechanism of DHEA-mediated immune function and the efficient protection against infectious and inflammatory response in animals and humans.

ANTHOCYANINS: POWERFUL NATURAL ANTIOXIDANT PIGMENTS WITH SIGNIFICANT BIOMEDICAL AND TECHNOLOGICAL APPLICATIONS

Book

Full-text available

Apr 2018

Teleost contributions to the understanding of mycobacterial diseases

Article

Feb 2019
DEV COMP IMMUNOL

Few pathogens have shaped human medicine as the mycobacteria. From understanding biological phenomena driving disease spread, to mechanisms of host-pathogen interactions and antibiotic resistance, the Mycobacterium genus continues to challenge and offer insights into the basis of health and disease. Teleost fish models of mycobacterial infections have progressed significantly over the past three decades, now supplying a range of unique tools and new opportunities to define the strategies employed by these Gram-positive bacteria to overcome host defenses, as well as those host antimicrobial pathways that can be used to limit its growth and spread. Herein, we take a comparative perspective and provide an update on the contributions of teleost models to our understanding of mycobacterial diseases.

Significance of Serum Vitamin D Level in Tuberculosis Patients

Article

Full-text available

Jul 2018

Introduction: The role of vitamin D in bone homeostasis is well known but nowadays, its role in various essential body processes including prevention of various infective and chronic illnesses like Tuberculosis (TB), by facilitating adaptive and innate immunity in lungs and peripheral blood, is being a matter of debate. Low levels have been associated with respiratory tract infections like TB. Present study aimed to evaluate the level of vitamin D in tubercular patients. Aim: To determine serum vitamin D level in patients with TB and compare it with controls. To compare serum vitamin D level among different types of TB, including Pulmonary TB (PTB), tubercular lymphadenitis and tubercular pleural effusion. Materials and Methods: The present study was a single centre cross-sectional study done during the study period from September 2013 to September 2016 at a tertiary care centre of Uttar Pradesh, India. Total 216 subjects aged between 21 and 60 years were included randomly out of which 113 patients were cases and 103 were controls. Cases of TB were confirmed by sputum Acid Fast Bacilli (AFB) staining, sputum and pleural fluid cytology, Adenosine Deaminase (ADA) of pleural fluid and Fine Needle Aspiration Cytology (FNAC) of lymph nodes. Controls were healthy subjects. Total serum vitamin D levels were measured by Diasorin competitive Radioimmunoassay (RIA) (Autoimmune Diagnostika, GmbH, Strasburg, Germany). Results: The mean serum vitamin D level for patients with TB was 22.4±8.5 ng/mL. Among controls, it was 30.5±8.6 ng/mL (p

Autoimmunity and tuberculosis. Opposite association with TNF polymorphism

Article

Full-text available

Feb 2005

To examine the influence of the -308 and -238 single nucleotide polymorphisms (SNP) of tumor necrosis factor-a gene (TNF) on patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjogren's syndrome (SS), and tuberculosis (TB). Genomic DNA from patients with RA (n = 165), SLE (n = 100), primary SS (n = 67), and TB (n = 135) and ethnically matched controls (n = 430) was genotyped for TNF -308 and -238 SNP by PCR-RFLP. TNF -308A allele was associated with RA (odds ratio, OR 1.8, p = 0.002), SLE (OR 2.6, p < 0.0001), and primary SS (OR 2.9, p < 0.0001). TNF -308G was associated with TB (OR 1.8, p = 0.02). The -308 GG genotype was protective for autoimmunity (p < 0.003). TNF -238A allele was protective for autoimmunity but represented a susceptibility factor for TB (OR 2.2, p < 0.0001). Haplotype -308A-238G was a protective factor against TB, whereas it carried susceptibility for RA, SLE, and primary SS (p < 0.0001). The results show an opposite association of TNF polymorphism with autoimmunity and TB, and suggest the existence of heterozygote advantage, sustaining the hypothesis that autoimmune diseases are a consequence of natural selection for enhanced TB resistance. Data also provide genetic evidence supporting the common variants/multiple disease hypothesis, which emphasizes that many disease genes may not be disease-specific, and that similar immunogenetic mechanisms underlie autoimmune diseases.

SLC11A1 (formerly NRAMP1) and disease resistance

Article

Full-text available

Dec 2001

A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis

Article

Full-text available

May 2007

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Protective Role of Interleukin-1 in Mycobacterial Infection in IL-1 / Double-Knockout Mice

Article

Full-text available

May 2000

To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in mycobacterial inflammation, IL-1 α/β double-knockout (KO) mice were produced. These mice were infected with either Mycobacterium tuberculosis H37Rv by the airborne route using an airborne infection apparatus, and their capacities to control mycobacterial growth, granuloma formation, cytokine, and nitric oxide (NO) production were examined. The IL-1 α/β mice developed significantly larger (p < 0.01) granulomatous, but not necrotic, lesions in their lungs than wild-type (WT) mice after infection with H37Rv. Inflammatory lesions, but not granulomas, were observed in spleen and liver tissues from both IL-1 α/β KO and wild-type mice. Granulomatous lesion development in IL-1 α/β KO mice was not significantly inhibited by treatment with exogenous recombinant IL-1α/β. Compared with wild-type mice, splenic IFN-γ and IL-12 levels were within the normal range. NO production by cultured alveolar macrophages from IL-1 α/β KO mice was lower than in wild-type mice but were increased by the addition of recombinant IL-1 α/β. Our data clearly indicate that IL-1 is important for the generation of early-phase protective immunity against mycobacterial infection.

Disseminated Tuberculosis in Interferon 7 Gene-disrupted Mice

Article

Full-text available

Dec 1993

Summary The expressionofprotective immunity toMycobacterium tuberculosisinmice ismediatedby T lymphocytesthatsecretecytokines .Thesemoleculesthenmediateavarietyofroles,including theactivation ofparasitized hostmacrophages,andtherecruitment ofothermononuclearphagocytes tothesiteoftheinfectioninordertoinitiate granulomaformation.Among thesecytokines, interferon y (IFN-y)isbelieved toplayakeyroleistheseevents .Inconfirmation ofthishypothesis, we show inthisstudythatmiceinwhich theIFN-y genehasbeendisruptedwereunableto containor controla normallysublethaldoseof M. tuberculosis,deliveredeitherintravenously oraerogenically .Insuchmice,aprogressive andwidespreadtissue destruction andnecrosis, associated withveryhighnumbersofacid-fast bacilli, wasobserved.Incontrast, despitethelackofprotective immunity,some DTH-like reactivity couldstill beelicited .Thesedata,therefore, indicatethat althoughIFN-y may notbe neededforDTH expression, itplaysapivotaland essential role inprotective cellular immunity totuberculosis infection .

Efficacy of BCG Vaccine in the Prevention of TuberculosisMeta-analysis of the Published Literature

Article

Full-text available

Mar 1994

Objective. —To quantify the efficacy of BCG vaccine against tuberculosis (TB).

Influence of Polymorphism in the Genes for the Interleukin (IL)-1 Receptor Antagonist and IL-1 on Tuberculosis

Article

Full-text available

Jun 1999
J EXP MED

Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The proinflammatory cytokine interleukin (IL)-1β and its antagonist, IL-1Ra (IL-1 receptor agonist), are strongly induced by M. tuberculosis and are encoded by polymorphic genes. The induction of both IL-1Ra mRNA and secreted protein by M. tuberculosis in IL-1Ra allele A2–positive (IL-1Ra A2+) healthy subjects was 1.9-fold higher than in IL-1Ra A2− subjects. The M. tuberculosis–induced expression of mRNA for IL-1β was higher in subjects of the IL-1β (+3953) A1+ haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1β induced by M. tuberculosis was markedly higher in IL-1Ra A2+ individuals (P < 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1β (+3953) A2 alleles. In M. tuberculosis–stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon γ increased and IL-10 decreased IL-1β production, indicative of a differential influence on the IL-1Ra/IL-1β ratio by cytokines. In a study of 114 healthy purified protein derivative–reactive subjects and 89 patients with tuberculosis, the frequency of allelic variants at two positions (−511 and +3953) in the IL-1β and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2−/IL-1β (+3953) A1+ haplotype was unevenly distributed, being more common in patients with tuberculous pleurisy (92%) in comparison with healthy M. tuberculosis–sensitized control subjects or patients with other disease forms (57%, P = 0.028 and 56%, P = 0.024, respectively). Furthermore, the IL-1Ra A2+ haplotype was associated with a reduced Mantoux response to purified protein derivative of M. tuberculosis: 60% of tuberculin-nonreactive patients were of this type. Thus, the polymorphism at the IL-1 locus influences the cytokine response and may be a determinant of delayed-type hypersensitivity and disease expression in human tuberculosis.

A Vitamin D Receptor Gene Polymorphism in the Translation Initiation Codon: Effect on Protein Activity and Relation to Bone Mineral Density in Japanese Women

Article

Full-text available

Jun 1997
J BONE MINER RES

The effect of a T-C transition polymorphism at the translation initiation codon of the human vitamin D receptor (VDR) gene on the biological function of the encoded protein was investigated. Of 239 Japanese women volunteers subjected to genotype analysis for this polymorphism, 32 (13%) were genotype MM (the M allele is ATG at the putative translation start site), 75 (31%) were genotype mm (the m allele is ACG at the putative translation start site), and 132 (55%) were genotype Mm. The bone mineral density (BMD) in the lumbar spine (L2–L4) was determined for 110 healthy premenopausal women from the volunteers and was shown to be 12.0% greater (p < 0.05) for mm homozygotes than for MM homozygotes. Synthesis of the proteins by the M and m alleles from the cloned cDNAs in vitro and in transfected COS-7 cells revealed them to have a size of 50 and 49.5 kD, respectively, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is consistent with initiation of translation of the M allele-encoded protein from an ATG codon located at nucleotides +10 to +12 in the conventional open reading frame. The extent of vitamin D–dependent transcriptional activation of a reporter construct under the control of a vitamin D response element in transfected HeLa cells was ∼1.7-fold greater for the m type VDR than for the M type protein. These results suggest that the polymorphism at the translation start site of the VDR gene may modulate BMD in premenopausal Japanese women.

Release of reactive nitrogen intermediates and reactive oxygen intermediate from mouse peritoneal macrophages: Comparison of activating cytokines and evidence for independent production

Article

Full-text available

Nov 1988

The capacity of 12 cytokines to induce NO2- or H2O2 release from murine peritoneal macrophages was tested by using resident macrophages, or macrophages elicited with periodate, casein, or thioglycollate broth. Elevated H2O2 release in response to PMA was observed in resident macrophages after a 48-h incubation with IFN-gamma, TNF-alpha, TNF-beta, or CSF-GM. Of these, only IFN-gamma induced substantial NO2- secretion during the culture period. The cytokines inactive in both assays under the conditions tested were IL-1 beta, IL-2, IL-3, IL-4, IFN-alpha, IFN-beta, CSF-M, and transforming growth factor-beta 1. Incubation of macrophages with IFN-gamma for 48 h in the presence of LPS inhibited H2O2 production but augmented NO2- release, whereas incubation in the presence of the arginine analog NG-monomethylarginine inhibited NO2- release but not H2O2 production. Although neither TNF-alpha nor TNF-beta induced NO2- synthesis on its own, addition of either cytokine together with IFN-gamma increased macrophage NO2- production up to six-fold over that in macrophages treated with IFN-gamma alone. Moreover, IFN-alpha or IFN-beta in combination with LPS could also induce NO2- production in macrophages, as was previously reported for IFN-gamma plus LPS. These data suggest that: 1) tested as a sole agent, IFN-gamma was the only one of the 12 cytokines capable of inducing both NO2- and H2O2 release; 2) the pathways leading to secretion of H2O2 and NO2- are independent; 3) either IFN-gamma and TNF-alpha/beta or IFN-alpha/beta/gamma and LPS can interact synergistically to induce NO2- release.

Serum concentrations of vitamin D metabolites in untreated tuberculosis

Article

Full-text available

Apr 1985

A prospective study of 50 consecutive patients presenting with tuberculosis has shown that patients have on average lower serum concentrations of 25-hydroxycholecalciferol (25-OHD) than healthy matched controls. No difference was shown in serum 1,25-(OH)2D, 24,25-(OH)2D, or parathyroid hormone. Uncorrected serum calcium was lower in the patient group but identical when correction concentrations were made for albumin. Serum liver enzyme concentrations were significantly higher in the patient population. Low serum vitamin D concentrations may be a consequence of disease. The possibility that low serum 25-OHD concentrations may predispose to tuberculosis infection cannot, however, be excluded. Prolonged treatment with isoniazid or rifampicin, both of which have been shown to reduce serum 25-OHD, may increase the risk of vitamin D deficiency and consequent osteomalacia in groups of patients most at risk, such as those of Indian subcontinental ethnic origin.

An essential role for interferon ?? in resistance to Mycobacterium tuberculosis infection

Article

Full-text available

Jan 1994

Tuberculosis, a major health problem in developing countries, has reemerged in recent years in many industrialized countries. The increased susceptibility of immunocompromised individuals to tuberculosis, and many experimental studies indicate that T cell-mediated immunity plays an important role in resistance. The lymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophage activation and resistance to intracellular pathogens. Mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection with Mycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactive nitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma.

Tumor necrosis factor-?? is required in the protective immune response against Mycobacterium tuberculosis in mice

Article

Full-text available

Jul 1995
IMMUNITY

Understanding the immunological mechanisms of protection and pathogenesis in tuberculosis remains problematic. We have examined the extent to which tumor necrosis factor-alpha (TNF alpha) contributes to this disease using murine models in which the action of TNF alpha is inhibited. TNF alpha was neutralized in vivo by monoclonal antibody; in addition, a mouse strain with a disruption in the gene for the 55 kDa TNF receptor was used. The data from both models established that TNF alpha and the 55 kDa TNF receptor are essential for protection against tuberculosis in mice, and for reactive nitrogen production by macrophages early in infection. Granulomas were formed in equal numbers in control and experimental mice, but necrosis was observed only in mice deficient in TNF alpha or TNF receptor. TNF alpha and the 55 kDa TNF receptor are necessary conditions for protection against murine M. tuberculosis infection, but are not solely responsible for the tissue damage observed.

Pulmonary surfactant protein A mediates enhanced phagocytosis of Mycobacterium tuberculosis by a direct interaction with human macrophages

Article

Full-text available

Jan 1996

During initial infection with Mycobacterium tuberculosis, bacteria that reach the distal airspaces of the lung are phagocytosed by alveolar macrophages in the presence of pulmonary surfactant. Here we have examined the role of surfactant-associated protein A (SP-A) in phagocytosis of the virulent Erdman strain of M. tuberculosis by human monocyte-derived macrophages (MDMs) and human alveolar macrophages (HAMs). Macrophage monolayers incubated with soluble SP-A from alveolar proteinosis patients (APP SP-A4) and recombinant rat SP-A (SP-Ahyp) demonstrated enhanced adherence of M. tuberculosis, 82 +/- 17% and 49 +/- 18%, respectively. Removal of SP-A from monolayers by washing before adding bacteria did not diminish the enhanced adherence. Fluorescence microscopy demonstrated that washed monolayers contained intracellular rather than surface-bound SP-A. These studies indicated a direct interaction between SP-A and the macrophage in mediating enhanced adherence of M. tuberculosis. Consistent with this interpretation, macrophage monolayers formed on human or rat SP-A (substrate SP-A) demonstrated enhanced adherence of M. tuberculosis to their apical surface (APP SP-A and native rat SP-A increased M. tuberculosis adherence by 102 +/- 16% and 102 +/- 25%, respectively). Electron microscopy demonstrated increased numbers of phagocytosed bacteria in APP SP-A-treated MDM cross-sections. SP-A proteins devoid of carbohydrate failed to enhance M. tuberculosis adherence to macrophages. In contrast, heat-denatured APP SP-A enhanced adherence of bacteria equivalent to that of intact glycoprotein. Thus, the carbohydrate moieties of SP-A appear to be critical in the SP-A-macrophage interaction. Finally, mannan and anti-mannose receptor Ab completely inhibited the enhanced phagocytosis of M. tuberculosis observed with APP SP-A, providing evidence for up-regulation of macrophage mannose receptor activity. These studies implicate SP-A as an important modulator of alveolar macrophage function that results in an enhanced potential for M. tuberculosis to gain access to its intracellular niche.

The Efficacy of Bacillus Calmette-Guérin Vaccination of Newborns and Infants in the Prevention of Tuberculosis: Meta-Analyses of the Published Literature

Article

Full-text available

Aug 1995

To quantify the efficacy of vaccination of infants with bacillus Calmette-Guérin (BCG) against tuberculosis. MEDLINE with index terms BCG vaccine, tuberculosis, and human; lists of all known studies provided by experts at the Centers for Disease Control and Prevention, the World Health Organization, and other organizations. A total of 1264 articles and abstracts were reviewed for details on BCG vaccination, the availability of concurrent vaccinated and unvaccinated groups, and a tuberculosis outcome. Seventy articles were reviewed in depth for method of vaccine allocation used to create comparable groups, age at vaccination of study participants, comparability of surveillance and follow-up of recipient and concurrent control groups in trials, an appropriately defined control group in case-control studies, and outcome measures (tuberculosis cases and/or deaths). Five prospective trials and eleven case-control studies of vaccination during infancy were included in the present analyses. We recorded study design, age range of study population, number of patients enrolled, efficacy of vaccine, location of the study, and a series of items to assess the potential for bias in study design, follow-up, and diagnosis. We extracted or computed vaccine efficacy by years since vaccination wherever possible. At least two readers independently extracted data and evaluated data validity. The relative risk (RR) or odds ratio (OR) for tuberculosis in vaccinated versus unvaccinated infants was the measure of vaccine efficacy analyzed. A random-effects method estimated a weighted average RR or OR from data extracted from the trials and case-control studies. The protective effect was then computed by 1-RR or 1-OR. Overall, the protective effect of vaccination against cases of tuberculosis was 0.74 (95% confidence interval [95% CI], 0.62 to 0.83) when estimated from four randomized controlled trials, and 0.52 (95% CI, 0.38 to 0.64) when estimated from nine case-control studies. Five trials reporting deaths from tuberculosis showed a BCG protective effect of 0.65 (95% CI, 0.12 to 0.86), five studies reporting on meningitis showed a protective effect of 0.64 (95% CI, 0.30 to 0.82), and three studies of disseminated tuberculosis showed a protective effect of 0.78 (95% CI, 0.58 to 0.88). Three case-control studies included separate results for laboratory-confirmed cases of tuberculosis. These studies documented a protective effect of 0.83 (95% CI, 0.58 to 0.93). In a random-effects regression model of the nine case-control studies, study validity score explained 15% of the heterogeneity among study-estimated protective effects, suggesting that better studies reported greater efficacy. Three trials and six case-control studies provided some age-specific information that allowed us to examine the duration of BCG efficacy. Most of this evidence suggested that BCG efficacy may persist through 10 years after infant vaccination. BCG vaccination of newborns and infants significantly reduces the risk of tuberculosis--by over 50%, on average. Protection has been observed across many populations, study designs, and forms of tuberculosis. Rates of protection against cases that are confirmed by laboratory tests, reflecting reduced error in disease classification and consequently more accurate estimates of BCG efficacy, are highest at 83%.

IL-12 increases resistance of BALB/c mice to

Article

Full-text available

Oct 1995

IL-12, a cytokine produced by macrophages and B cells, has recently been found to exert pleiotropic effects on the immune system. When BALB/c mice, a strain highly susceptible to virulent Mycobacterium tuberculosis infection, were given IL-12 at the initiation of infection with M. tuberculosis, their mean survival time doubled from 58 to 112 days. IL-12-treated mice had diminished bacterial burdens, whereas treatment with exogenous IFN-gamma had no effect on survival or bacterial burden. IL-12 treatment also delayed lung pathology in BALB/c mice. In contrast with the findings in the BALB/c model, IL-12 did not increase survival of M. tuberculosis-infected gko mice, transgenic mice in which the IFN-gamma gene has been disrupted, indicating that IL-12 does not induce protection against tuberculosis in mice in the absence of IFN-gamma.

Enhanced interleukin-8 release and gene expression in macrophages after exposure to Mycobacterium tuberculosis and its components

Article

Full-text available

Mar 1995

Mycobacterium tuberculosis infection is accompanied by acute and chronic inflammatory infiltrates associated with necrotizing granulomas in lung tissue. The cellular infiltrate is characterized by inflammatory cells which include neutrophils, lymphocytes, and macrophages. In animal and in vitro models of mycobacterial infection, cytokines including tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and interleukin-1 beta (IL-1 beta) participate in granulomatous inflammation. We hypothesized that interleukin-3, a potent chemoattractant for neutrophils and lymphocytes, could be released by activated alveolar macrophages after exposure to M. tuberculosis or its components and contribute to granulomatous lung inflammation. A quantitative immunoassay revealed that IL-8 protein release was significantly elevated in supernatants of macrophages and in lavage fluid obtained from patients with pulmonary tuberculosis compared to normal controls. In addition, Northern blots demonstrated striking up-regulation of IL-8 mRNA in macrophages from these patients. M. tuberculosis and its cell wall components lipoarabinomannan (LAM), lipomannan (LM), and phosphoinositolmannoside (PIM) stimulated IL-8 protein release and mRNA expression in vitro from alveolar macrophages, but deacylated LAM did not. Neutralizing antibodies to TNF-alpha and/or IL-1-alpha and beta blocked 83% of the stimulation. IL-8 synthesis and release is an early response of macrophages after phagocytosis of M. tuberculosis. Its production serves to attract both acute and chronic inflammatory cells of active infection and thus participates in the process of containment of the pathogen.

Prediction of bone density from Vitamin D receptor

Article

Full-text available

Feb 1994

Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.

Disseminated tuberculosis in IFN-?? gene disrupted mice

Article

Full-text available

Jan 1994

The expression of protective immunity to Mycobacterium tuberculosis in mice is mediated by T lymphocytes that secrete cytokines. These molecules then mediate a variety of roles, including the activation of parasitized host macrophages, and the recruitment of other mononuclear phagocytes to the site of the infection in order to initiate granuloma formation. Among these cytokines, interferon gamma (IFN-gamma) is believed to play a key role is these events. In confirmation of this hypothesis, we show in this study that mice in which the IFN-gamma gene has been disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis, delivered either intravenously or aerogenically. In such mice, a progressive and widespread tissue destruction and necrosis, associated with very high numbers of acid-fast bacilli, was observed. In contrast, despite the lack of protective immunity, some DTH-like reactivity could still be elicited. These data, therefore, indicate that although IFN-gamma may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection.

IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection.

Article

Sep 1995

Prediction of Bone Density from Vitamin D Receptor Alleles

Article

Jul 1994
ENDOCRINOLOGIST

Toll-Like Receptor Triggering of a Vitamin-DMediated Human Antimbacterial Response

Article

Jan 2006

Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation

Article

Jan 1995

Effects of polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation

Article

Apr 1997

Common interleukin 10 polymorphism associated with decreased risk of tuberculosis

Article

Apr 2005

Interleukin 10 (IL10) is a powerful TH2-cell cytokine that inhibits lymphocyte replication and secretion of inflammatory cytokines. The genetic associations of polymorphisms in IL10 with clinical manifestations of tuberculosis (TB) were examined in a large number of patients with clinical TB infection (n = 459) and normal controls (n = 871). One common promoter SNP (IL10 -592 A > C) was found to be significantly associated with decreased risk of TB manifestation. The frequency of the "C"-bearing genotype was higher in normal controls than in patients with clinical TB infection (P = 0.005, OR = 0.69). A summary of the genetic effect of IL10 -1082 A > G, the other nearby promoter SNP, in other ethnic groups is also presented.

Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae (vol 32, pg 97, 2002)

Article

Oct 2002

Erratum: Interleukin-10, polymorphism in SLC11A1 (formerly NRAMP1), and susceptibility to tuberculosis (Journal of Infections Diseases (2002) 186 (1808-1814))

Article

Dec 2003

Human toll-like receptors mediate cellular activation by M. tuberculosis

Article

Jan 1999

Natural resistance to infection with intracellular parasites: Isolation of a candidate gene for Bcg

Article

Jan 1993
CELL

Dectin-1: A signalling non-TLR pattern-recognition receptor

Article

Jan 2006
NAT REV IMMUNOL

G.D. Brown

Cooper, A.M., Dalton, D.K., Stewart, T.A., Griffin, J.P., Russell, D.G. & Orme, I.M. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J. Exp. Med. 178, 2243-2247

Article

Dec 1993

Andrea M Cooper

Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BRAn essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 178:2249-2254

Article

Dec 1993

Joanne L Flynn

Tuberculosis in Household Contacts of Infectious Cases in Kampala, Uganda

Article

Nov 2003
AM J EPIDEMIOL

David Guwatudde

Tuberculosis remains a serious threat to public health, especially in sub-Saharan Africa. To determine the host and environmental factors responsible for tuberculosis in African households, the authors performed a prospective cohort study of 1,206 household contacts of 302 index cases with tuberculosis enrolled in Uganda between 1995 and 1999. All contacts were systematically evaluated for active tuberculosis and risk factors for active disease. Among the 1,206 household contacts, 76 secondary cases (6%) of tuberculosis were identified. Of these cases, 51 were identified in the baseline evaluation, and 25 developed during follow-up. Compared with index cases, secondary cases presented more often with minimal disease. The risk for secondary tuberculosis was greater among young children than adults (10% vs. 1.9%) and among human immunodeficiency virus-seropositive than -seronegative contacts (23% vs. 3.3%). Host risk factors could not be completely separated from the effects of environmental risk factors, suggesting that a household may represent a complex system of interacting risks for tuberculosis.

Natural Resistance to Intracellular Infections

Article

Nov 2000

Mutations at the natural resistance–associated macrophage protein 1 (Nramp1) locus cause susceptibility to infection with antigenically unrelated intracellular pathogens. Nramp1 codes for an integral membrane protein expressed in the lysosomal compartment of macrophages, and is recruited to the membrane of phagosomes soon after the completion of phagocytosis. To define whether Nramp1 functions as a transporter at the phagosomal membrane, a divalent cation-sensitive fluorescent probe was designed and covalently attached to a porous particle. The resulting conjugate, zymosan–FF6, was ingested by macrophages and its fluorescence emission was recorded in situ after phagocytosis, using digital imaging. Quenching of the probe by Mn2+ was used to monitor the flux of divalent cations across the phagosomal membrane in peritoneal macrophages obtained from Nramp1-expressing (+/+) and Nramp1-deficient (−/−) macrophages. Phagosomes from Nramp1+/+ mice extrude Mn2+ faster than their Nramp−/− counterparts. The difference in the rate of transport is eliminated when acidification of the phagosomal lumen is dissipated, suggesting that divalent metal transport through Nramp1 is H+ dependent. These studies suggest that Nramp1 contributes to defense against infection by extrusion of divalent cations from the phagosomal space. Such cations are likely essential for microbial function and their removal from the phagosomal microenvironment impairs pathogenesis, resulting in enhanced bacteriostasis or bactericidal activity.

Triacyl-lipopentapeptide adjuvants: TLR2-dependent activation of macrophages and modulation of receptor-mediated cell activation by altering acyl-moieties

Article

May 2004
INT IMMUNOPHARMACOL

Muller SD

Synthetic lipopeptides derived from bacterial lipoprotein are efficient immunoadjuvants. In vitro they activate antigen presenting cells (APCs) to induce the translocation of nuclear factor kappa B (NF-κB) and the activation of further transcription factors. This results in the expression of genes encoding cytokines such as IL-1, IL-6, TNF-α and in the release of reactive oxygen/nitrogen intermediates. The molecular structure of microbial products determines TLR specificity and thus their activatory potential and immunoadjuvanticity. In the present study, we investigated the lipopeptide-induced activation of leukocytes at different cellular levels by applying derivatives of a synthetic lipopentapeptide-fatty acid library. Our results show that TLR2 plays a key role for the activation of bone marrow-derived macrophages (BMDMs) by lipopentapeptide derivatives and that the fatty acid composition of the lipopeptides determines their activation potential and TLR specificity.

Immune recognition: A new receptor for β-glucans

Article

Sep 2001

The carbohydrate polymers known as β-1,3-D-glucans exert potent effects on the immune system - stimulating antitumour and antimicrobial activity, for example - by binding to receptors on macrophages and other white blood cells and activating them. Although β-glucans are known to bind to receptors, such as complement receptor 3 (ref. 1), there is evidence that another β-glucan receptor is present on macrophages. Here we identify this unknown receptor as dectin-1 (ref. 2), a finding that provides new insights into the innate immune recognition of β-glucans.

Influence of interleukin-12 receptor ß1 polymorphisms on tuberculosis

Article

Mar 2003

Host genetic factors may be important determinants of susceptibility to tuberculosis, and several candidate gene polymorphisms have been shown to date. A series of recent reports concerning rare human deficiencies in the type-1 cytokine pathway suggest that more subtle variants of relevant genes may also contribute to susceptibility to tuberculosis at the general population level. To investigate whether polymorphisms in the interleukin-12 receptor (IL-12R) gene predispose individuals to tuberculosis, we studied these genes by single-strand conformational polymorphism analysis and direct sequencing. Although no common polymorphisms could be identified in the IL-12RЈ gene ( IL-12RB2), we confirmed four single nucleotide polymorphisms (SNPs; 641A&#77G, 684C&#77T, 1094T&#77C, and 1132G&#77C) causing three missense variants (Q214R, M365T, G378R) and one synonymous substitution in the extracellular domain of the IL-12RЇ gene ( IL12RB1). All SNPs were in almost perfect linkage disequilibrium (D'=0.98), and two common haplotypes of IL12RB1 (allele 1: Q214-M365-G378; allele 2: R214-T365-R378) were revealed. Polymerase chain reaction/restriction fragment length polymorphism and sequence analyses were used to type IL12RB1polymorphisms in 98 patients with tuberculosis and 197 healthy controls in Japanese populations. In our case-control association study of tuberculosis, the R214-T365-R378 allele (allele 2) was over-represented in patients with tuberculosis, and homozygosity for R214-T365-R378 (the 2/2 genotype) was significantly associated with tuberculosis (odds ratio: 2.45; 95% CI: 1.20-4.99; P =0.013). In healthy subjects, homozygotes for R214-T365-R378 had lower levels of IL-12-induced signaling, according to differences in cellular responses to IL-12 between two haplotypes. These data suggest that the R214-T365-R378 allele, i.e., variation in IL12RB1, contribute to tuberculosis susceptibility in the Japanese population. This genetic variation may predispose individuals to tuberculosis infection by diminishing receptor responsiveness to IL-12 and to IL-23, leading to partial dysfunction of interferon-&#110-mediated immunity.

Polymorphism in IL1B: IL1B--511 association with tuberculosis and decreased lipopolysaccharide-induced IL-1 in IFN- primed ex-vivo whole blood assay

Article

Oct 2005

To determine whether variation in two interleukin 1 family genes (IL1B and interleukin 1 receptor antagonist, IL1RN) is associated with pulmonary tuberculosis (TB), two published polymorphisms at nucleotide positions —511 and +3953 in IL1B and one in the IL1RN 86 bp VNTR were genotyped in 335 smear positive Gambian TB patients, and 298 ethnically matched controls. All individuals were HIV negative. Decreased risk of pulmonary TB was associated with both heterozygosity and homozygosity for the IL1B—511-C allele (OR 0.66, P = 0.027, and OR 0.58, P = 0.015, respectively). Nonetheless, the C allele was present at a frequency of 0.66 in TB cases suggesting that whilst IL-1β contributes to disease susceptibility, it is not the major factor. There was no association between the IL1B+3953-T/C polymorphism or the 86 bp IL1RN pentallelic repeat and TB in this population. Using an ex-vivo whole blood assay, healthy Gambian individuals who are homozygous for the IL1B—511-T allele failed to exhibit a significant increase in IL-1β production in response to LPS after IFN-ypriming.

SLC11A1 (formerly NRAMP1) and disease resistance. Microreview

Article

Dec 2001
CELL MICROBIOL

Genetic variants of NRAMP1 and active tuberculosis in Japanese populations

Article

Dec 2001
CLIN GENET

Macrophage Receptors for Mycobacterium tuberculosis

Article

Apr 1998

Joel D Ernst

Production of Monocyte Chemoattractant Protein 1 in Tuberculosis Patients

Article

May 1998

To investigate the role of monocyte chemoattractant protein 1 (MCP-1) in the immune response to Mycobacterium tuberculosis, we studied MCP-1 production in tuberculosis patients. CD14+ blood monocytes from tuberculosis patients spontaneously expressed higher levels of MCP-1 mRNA and protein than CD14+ monocytes from healthy tuberculin reactors. MCP-1 production in lymph nodes from tuberculosis patients was also markedly increased. These findings suggest that MCP-1 can contribute to the antimycobacterial inflammatory response by attracting monocytes and T lymphocytes.

Tuberculosis in twins: A re-analysis of the Prophit survey

Article

May 1978
Am J Respir Crit Care Med

G W Comstock

Data on tuberculosis in twins collected by Dr. Barbara Simonds for the Prophit Committee of the Royal College of Physicians of London were re-analyzed using multiple regression to control for the effects of variables other than zygosity. Concordance for tuberculosis was significantly higher among monozygotic than dizygotic twin pairs. This finding indicates that inherited susceptibility is an important risk factor for tuberculosis among humans.

Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes

Article

Feb 1986

Previous studies have shown that recombinant interferon gamma (IFN-gamma), crude T cell supernatants, or appropriate T-cell lines can cause total inhibition of the growth of M. tuberculosis inside murine peritoneal macrophages. In similar experiments with human monocytes much smaller effects are seen. This could be due to the relative immaturity of these cells. Because dihydroxy vitamin D3 (1,25-(OH)2 D3) can cause phenotypic differentiation of immature leukemic lines into macrophage-like cells, we have explored the possibility that exposure to cholecalciferol metabolites in vitro might increase the ability of monocytes to control proliferation of M. tuberculosis, or cause monocytes to mature into cells able to respond appropriately to IFN-gamma. Incubation of monocytes with three cholecalciferol metabolites induced anti-tuberculosis activity to an extent that correlated with their binding affinities to the intracellular receptor protein for the derivatives. 1,25-(OH)2 D3 also primed monocytes for phorbol myristate acetate-triggered reduction of nitroblue tetrazolium. The effects were additive rather than synergistic with those of IFN-gamma. Monocytes incubated with IFN-gamma developed 25-OH D3 1-hydroxylase activity, detected by conversion of tritiated 25-(OH) D3 to a more polar metabolite which coeluted with 1,25-(OH)2 D3 on straight and reverse-phase HPLC. The latter is a more active form in vivo. These findings help to explain claims for the efficacy of vitamin D in the treatment of some forms of tuberculosis, and also the occasional finding of raised serum calcium, and disturbed vitamin D metabolism in these patients.

Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages

Article

Jan 1988

Historically, sunlight has seemed to fortify antituberculosis resistance. Evidence is presented here suggesting a role for vitamin D in this effect. The active metabolite of this photosynthesized vitamin, 1,25-dihydroxy-vitamin D3 (1,25D), promotes maturation and activation of human monocytes and macrophages (MPs). Therefore, it was tested for ability to protect MPs against virulent tubercle bacilli. MPs were derived by 7-day culture from blood monocytes, infected with the bacilli, and exposed to 1,25D in several regimens. Their inhibition of bacilli was measured by lysing samples of the cultures at 0, 4, and 7 days after infection and making bacillary CFU counts from serial dilutions of the lysates. 1,25D enabled MPs to slow or stop bacillary replication. Autologous serum supported the 1,25D-induced protection because the vitamin was not effective in medium supplemented with a serum substitute and was less effective in a heterologous AB serum than in autologous serum. The protection developed rapidly and could be induced even when 1,25D was added 3 days after infection. A concentration on the order of 4 micrograms/ml was needed for protection by the regimens used in these experiments. That is considerably higher than normal circulating concentrations of 1,25D but could be reached in infectious granulomas, because MPs can make 1,25D from precursor 25-hydroxyvitamin D3. The precursor circulates at levels 10(3) higher than those of 1,25D and is directly influenced by dietary intake or photosynthetic production of vitamin D. These results identify 1,25D as an immunomodulator which can reproducibly activate human MPs to express tuberculoimmunity. They connect vitamin D, sunlight, and tuberculoimmunity and suggest that vitamin D should be considered a vital factor in the practical control of tuberculosis.

A possible link between vitamin D deficiency and impaired host defence to Mycobacterium tuberculosis

Article

Jan 1986
Tubercle

P.D.O. Davies

High level monocyte chemoattractant protein-1 expression in transgenic mice increases their susceptibility to intracellular pathogens

Article

Dec 1995

We have constructed transgenic mice in which the mouse mammary tumor virus long terminal repeat controls the expression of murine monocyte chemoattractant protein-1 (MCP-1). Several independently derived lines of transgenic mice constitutively expressed MCP-1 protein in a variety of organs. Protein extracts from these organs had substantial in vitro monocyte chemoattractant activity that was neutralized by an anti-MCP-1 Ab, indicating that transgenic MCP-1 protein is biologically active. However, no transgenic mouse at any age displayed monocyte infiltrates in MCP-1-expressing organs. Two transgenic lines had circulating MCP-1 levels of 13 to 26 ng/ml, which is a concentration sufficient to induce maximal monocyte chemotaxis in vitro. These transgenic lines showed a 1 to 1.5 log greater sensitivity to infection with Listeria monocytogenes and Mycobacterium tuberculosis. A third transgenic line had lower serum levels of MCP-1 and was resistant to L. monocytogenes. The results suggest that this transgenic model is one of monocyte nonresponsiveness to locally produced MCP-1 due to either receptor desensitization or neutralization of a chemoattractant gradient by high systemic concentrations of MCP-1. Regardless of the mechanism, the data indicate that constitutively high levels of MCP-1 expression do not induce monocytic infiltrates, and that MCP-1 is involved in the host response to intracellular pathogens.

Nitric Oxide Synthase Is Not a Constituent of the Antimicrobial Armature of Human Mononuclear Phagocytes

Article

Jun 1993

Nitric oxide synthase (NOS) has received immense interest as an antimicrobial and antitumoral effector system of mononuclear phagocytes from rodents. Because there is increasing doubt that an analogous system exists in human macrophages, NOS was reexamined in these cells. Under tightly controlled conditions, with murine macrophages as positive controls, human macrophages failed to secrete nitric oxide <0.1µmol/106 cells/24 h), even after activation with endotoxin, intcrferon-γ, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor- a, bacteria, or proliferating lymphocytes. The discrepancy between murine and human macrophages depended on neither the anatomic source (blood, peritoneum), the agent used for activation, nor the duration of activation. NOS activity was paralleled by metabolization of L-arginine to L-citrulline. Exogenous tetrahydrobiopterin, an essential cofactor of NOS not synthesized by human macrophages, did not support NOS activity in human macrophages. Also, no NOS activity was found in cellular subfractions of human macrophages. It appears that in humans, the inducible high-output NOS is not conserved as an antimicrobial system of macrophages.

Inhibition of ex vivo proinflammatory cytokine secretion in fatal Mycobacterium tuberculosis infection

Article

May 1995

Tuberculosis is characterized by fever, weight loss, a prolonged acute-phase protein response and granuloma formation. These characteristics may partly be due to action of proinflammatory cytokines tumour necrosis factor (TNF), IL-6 and IL-8. We investigated plasma concentrations of these cytokines before and after ex vivo lipopolysaccharide stimulation of whole blood leucocytes from 41 Zambian patients with tuberculosis, 32 of whom were also HIV+. Although patients had a reduced weight, were more anaemic and had higher erythrocyte sedimentation rate compared with controls (all P < 0.0005), clinical and laboratory measurements of disease state were similar in those who died and survivors. In contrast, plasma IL-6 and IL-8 concentrations were higher in patients who died (P < 0.05). There was no detectable cytokine mRNA in unstimulated leucocytes. There was reduced secretion of TNF (P < 0.005 at 2 h), IL-6 (P < 0.005 at 8 h) and IL-8 (P < 0.005 at 24 h) after ex vivo stimulation of whole blood leucocytes from patients who died compared with survivors. This was partly due to a soluble inhibitory factor present in plasma. The only additional effect of concurrent infection by HIV with Myco. tuberculosis was decreased IL-6 secretion following ex vivo stimulation of leucocytes. Reduced proinflammatory cytokine release may represent a critical impairment of host immune defences important in determining outcome in tuberculosis.

Variation in the TNF-?? promoter region associated with cerebral malaria

Article

Nov 1994

Tumour-necrosis factor-alpha (TNF-alpha) is believed to have an important role in the pathogenesis of severe infectious disease and fatal cerebral malaria is associated with high circulating levels of this cytokine. In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-alpha gene promoter region, have a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighbouring HLA alleles, we show that this disease association is independent of HLA class I and class II variation. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biological advantage.

Growth inhibition of Mycobacterium bovis by IFN-?? stimulated macrophages: Regulation by endogenous tumor necrosis factor-?? and by IL-10

Article

Jun 1994

Murine bone marrow-derived macrophages (BMM) are able to inhibit the intracellular growth of Mycobacterium bovis and Mycobacterium tuberculosis H37Rv after activation with recombinant (r) IFN and growth inhibition is mediated by reactive nitrogen intermediates (RNI) derived from L-arginine. We now demonstrate that tumor necrosis factor (TNF)-alpha acts as an endogenous cofactor in the induction of mycobacterial growth inhibition. TNF-alpha was produced by BMM stimulated with rIFN-gamma and infected with mycobacteria, and a specific antiserum to TNF-alpha inhibited rIFN-gamma-induced production of RNI as well as growth inhibition of M. bovis. IL-10, a cytokine which suppresses antimycobacterial macrophage functions, was also produced by BMM activated with rIFN-gamma and infected with M. bovis. IFN-gamma-induced production of TNF-alpha and of reactive nitrogen intermediates as well as mycobacterial growth inhibition were inhibited by exogenous IL-10, but only when given prior to IFN-gamma stimulation. We conclude that the outcome of mycobacterial infection is regulated by a coordinate interplay between IFN-gamma, TNF-alpha and IL-10.

Mycobacterium tuberculosis, macrophages, and the innate immune response: Does common variation matter?

Abstract

No full-text available

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