Major Loci on Chromosomes 8q and 3q Control Interferon γ Production Triggered by Bacillus Calmette-Guerin and 6-kDa Early Secretory Antigen Target, Respectively, in Various Populations

Jabot–Hanin, Fabienne; Cobat, Aurélie; Feinberg, Jacqueline; Grangé, G.; Remus, Natascha; Poirier, C.; Boland‐Augé, Anne; Besse, Céline; Bustamante, Jacinta; Boisson–Dupuis, Stéphanie; Casanova, Jean‐Laurent; Schurr, Erwin; Alcaïs, Alexandre; Hoal, Eileen G.; Delacourt, Christophe; Abel, Laurent

doi:10.1093/infdis/jiv757

Cited by 15 publications

(33 citation statements)

References 41 publications

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“…Many of these heritable variations affect mediators that are likely to be relevant to Mtb immunity, such as the number of central memory T cells or abundance of cytokines such as IL-12p40, GM-CSF, IFNa, and IL-6 (31). Indeed, numerous studies suggest that the immunological response to mycobacterial infection (32-35) and BCG vaccination (36, 37) is heritable. However, the relationship between these immunological markers and vaccine efficacy is unknown and very difficult to address in natural populations.…”

Section: Introductionmentioning

confidence: 99%

Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

Smith

Proulx

Olive

et al. 2016

Preprint

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The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus CalmetteGuerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the "Collaborative Cross" project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines.IMPORTANCE Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition in BCG efficacy. We found that the ability of BCG to protect mice with different genotypes was remarkably variable. The efficacy of BCG did not depend on the intrinsic susceptibility of the animal but, instead, correlated with qualitative differences in the immune responses to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provide a model system to develop interventions that will be useful in genetically diverse populations.

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Section: Introductionmentioning

confidence: 99%

Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

Smith

Proulx

Olive

et al. 2016

Preprint

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“…The TST1 locus is associated with a TST positivity per se (TST1 on 11p14), and the TST2 locus is associated with the intensity of TST reactivity (TST2 on 5p15) [3]. On the other hand, the production of INF-γ has been associated with genetic factors such as the locus located in chromosomal regions 8q12-22n and 3q13-22 [2]. The ethnicity must be considered when performing the immunological analysis in further research.…”

Section: Discussionmentioning

confidence: 99%

“…Latent tuberculosis (LTBI) is defined as the presence of a positive tuberculin skin test (TST) or interferon-γ (IFNγ) release assays (IGRAs) in the absence of clinical or radiographic signs of disease. These accepted tests are imperfect for LTBI diagnosis for several reasons: (1) the sensitivity and specificity are between 71 and 82% for TST and 81 and 86% for IGRAs [1], (2) the sensitivity is reduced in immunocompromised patients, (3) there is inability to differentiate between LTBI and active tuberculosis (TB), (4) a positive TST or IGRA result does not automatically imply LTBI, as individuals who eliminate the infection successfully might still be TST-or IGRA-positive because of memory T cell responses, which partly explains the low predictive value of TST and IGRAs [1], and (5) genetic factors may impact test sensitivity as well as the susceptibility for acquisition of mycobacterial infection [2][3][4]. To date, there is no available diagnostic tool that allows diagnosis of LTBI and differentiates clearly between LTBI and active TB.…”

Section: Introductionmentioning

confidence: 99%

“…Despite advances in the study of immune parameters, there are pervasive limitations in the analysis and conclusions of many of these studies. Cytokine/chemokine expression is affected by ethnicity [2,10], cell simulation protocols (or no stimulation) [11][12][13], time of LTBI (which in most cases is impossible to quantify), and if the comparison group is people with TB, the clinical manifestations of disease (pulmonary vs. extrapulmonary TB) [14].…”

Section: Introductionmentioning

confidence: 99%

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Gaps in Study Design for Immune Parameter Research for Latent Tuberculosis Infection: A Systematic Review

Herrera

Vera

Keynan

et al. 2020

Journal of Immunology Research

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Background. Immune parameters (IP) have been extensively studied to distinguish between latent tuberculosis (LTBI) and active tuberculosis (TB). Objective. To determine the IP associated with LTBI, compared to active TB and individuals not infected by M. tuberculosis published in literature. Methods. We conducted a systematic search using Google Scholar and PubMed databases, combining the MeSH terms latent tuberculosis, Mycobacterium tuberculosis, cytokines, and biological markers, with the free terms, biomarkers and cytokines. Spanish, English, and Portuguese articles comparing the concentration of IP associated with LTBI, either in plasma/serum or in vitro, in adults and nonimmunocompromised versus individuals with TB or without M. tuberculosis infection between 2006 July and 2018 July were included. Two blinded reviewers carried out the searches, read the abstracts, and selected the articles for analysis. Participants’ information, diagnostic criteria, IP, detection methods, and biases were collected. Results. We analyzed 36 articles (of 637 abstracts) with 93 different biomarkers in different samples. We found 24 parameters that were increased only in active TB (TGF-α, CSF3, CSF2, CCL1 [I-309], IL-7, TGF-β1, CCL3 [MIP-1α], sIL-2R, TNF-β, CCL7 [MCP-3], IFN-α, fractalkine, I-TAG, CCL8 [MCP-2], CCL21 [6Ckine], PDGF, IL-22, VEGF-A, LXA4, PGE2, PGF2α, sCD163, sCD14, and 15-Epi-LXA4), five were elevated in LTBI (IL-5, IL-17F, IL-1, CCL20 [MIP-3α], and ICAM-1), and two substances were increased among uninfected individuals (IL-23 and basic FGF). We found high heterogeneity between studies including failure to account for the time/illness of the individuals studied; varied samples and protocols; different clinical classification of TB; different laboratory methods for IP detection, which in turn leads to variable units of measurement and assay sensitivities; and selection bias regarding TST and booster effect. None of the studies adjusted the analysis for the effect of ethnicity. Conclusions. It is mandatory to harmonize the study of immune parameters for LTBI diagnosis. This systematic review is registered with PROSPERO CRD42017073289.

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“…It appears that TST reactivity and INFγ responses are under distinct genetic control. Two loci that control BCG and ESAT-6 triggered IFNγ production were mapped to chromosomes 8q and 3q, respectively (37). Different genetic control of TST and IFNγ release are consistent with the low correlation between both read-outs of anti- mycobacterial immunity.…”

Section: Infection With Mtbmentioning

confidence: 99%

Human Genomics of Mycobacterium tuberculosis Infection and Disease

Orlova

Schurr

2017

Curr Genet Med Rep

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Purpose of review The study of the genetic basis of tuberculosis pathogenesis has benefited from powerful technological innovations, a more structured definition of latent and clinical manifestations of the disease, and the application of functional genomics approaches. This short review aims to summarize recent advances and to provide a link with results of previous human genetic studies of tuberculosis susceptibility. Recent findings Transcriptomics has been shown to be a useful tool to predict progression from latency to clinical disease while functional genomics has traced the molecular events that link pathogen-triggered gene expression and host genetics. Resistance to infection with Mycobacterium tuberculosis has been revealed to be strongly impacted by host genetics. Host genomics of clinical disease has been shown to be most powerful when focusing on carefully selected clinical entities and possibly by considering host pathogen combinations. Summary Future studies need to build on the latest molecular findings to define disease subtypes to successfully elucidate the human genetic component in tuberculosis pathogenesis.

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Major Loci on Chromosomes 8q and 3q Control Interferon γ Production Triggered by Bacillus Calmette-Guerin and 6-kDa Early Secretory Antigen Target, Respectively, in Various Populations

Cited by 15 publications

References 41 publications

Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

Gaps in Study Design for Immune Parameter Research for Latent Tuberculosis Infection: A Systematic Review

Human Genomics of Mycobacterium tuberculosis Infection and Disease

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