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An eQTL variant of ZXDC is associated with IFN-? production following Mycobacterium tuberculosis antigen-specific stimulation.

ABSTRACT: There is a large inter-individual variability in the response to Mycobacterium tuberculosis infection. In previous linkage analyses, we identified a major locus on chromosome region 8q controlling IFN-? production after stimulation with live BCG (Bacillus Calmette-Guérin), and a second locus on chromosome region 3q affecting IFN-? production triggered by the 6-kDa early secretory antigen target (ESAT-6), taking into account the IFN-? production induced by BCG (IFN?-ESAT6BCG). High-density genotyping and imputation identified ~100,000 variants within each linkage region, which we tested for association with the corresponding IFN-? phenotype in families from a tuberculosis household contact study in France. Significant associations were replicated in a South African familial sample. The most convincing association observed was that between the IFN?-ESAT6BCG phenotype and rs9828868 on chromosome 3q (p?=?9.8?×?10-6 in the French sample). This variant made a significant contribution to the linkage signal (p?

SUBMITTER: Jabot-Hanin F

PROVIDER: S-EPMC5634485 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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An eQTL variant of ZXDC is associated with IFN-γ production following Mycobacterium tuberculosis antigen-specific stimulation.

Jabot-Hanin Fabienne F Cobat Aurélie A Feinberg Jacqueline J Orlova Marianna M Niay Jonathan J Deswarte Caroline C Poirier Christine C Theodorou Ioannis I Bustamante Jacinta J Boisson-Dupuis Stéphanie S Casanova Jean-Laurent JL Alcaïs Alexandre A Hoal Eileen G EG Delacourt Christophe C Schurr Erwin E Abel Laurent L

Scientific reports 20171009 1

There is a large inter-individual variability in the response to Mycobacterium tuberculosis infection. In previous linkage analyses, we identified a major locus on chromosome region 8q controlling IFN-γ production after stimulation with live BCG (Bacillus Calmette-Guérin), and a second locus on chromosome region 3q affecting IFN-γ production triggered by the 6-kDa early secretory antigen target (ESAT-6), taking into account the IFN-γ production induced by BCG (IFNγ-ESAT6<sub>BCG</sub>). High-den ...[more]

PMID: 28993696

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Project description:BackgroundIFN-? is presently the only soluble immunological marker used to help diagnose latent Mycobacterium tuberculosis (M.tb) infection. However, IFN-? is not available to distinguish latent from active TB infection. Moreover, extrapulmonary tuberculosis, such as tuberculous pleurisy, cannot be properly diagnosed by IFN-? release assay. As a result, other disease- or infection-related immunological biomarkers that would be more effective need to be screened and identified.MethodologyA panel of 41 soluble immunological molecules (17 cytokines and 24 chemokines) was tested using Luminex liquid array-based multiplexed immunoassays. Samples, including plasma and pleural effusions, from healthy donors (HD, n?=?12) or patients with latent tuberculosis infection (LTBI, n?=?20), pulmonary tuberculosis (TB, n?=?12), tuberculous pleurisy (TP, n?=?15) or lung cancer (LC, n?=?15) were collected and screened for soluble markers. Peripheral blood mononuclear cells (PBMCs) and pleural fluid mononuclear cells (PFMCs) were also isolated to investigate antigen-specific immune factors.Principal findingsFor the 41 examined factors, our results indicated that three patterns were closely associated with infection and disease. (1) Significantly elevated plasma levels of IL-2, IP-10, CXCL11 and CXCL12 were present in both patients with tuberculosis and in a sub-group participant with latent tuberculosis infection who showed a higher level of IFN-? producing cells by ELISPOT assay compared with other latently infected individuals. (2) IL-6 and IL-9 were only significantly increased in plasma from active TB patients, and the two factors were consistently highly secreted after M.tb antigen stimulation. (3) When patients developed tuberculous pleurisy, CCL1, CCL21 and IL-6 were specifically increased in the pleural effusions. In particular, these three factors were consistently highly secreted by pleural fluid mononuclear cells following M.tb-specific antigen stimulation. In conclusion, our data imply that the specific secretion of soluble immunological factors, in addition to IFN-?, may be used to evaluate M.tb infection and tuberculosis disease.

Project description:Despite significant advances, asthma remains a cause of premature death, and current treatments are suboptimal. Antigen-specific Th2 cells and their cytokines are primary mediators of the pathophysiological changes seen in asthma. Studies in animal models have shown that mycobacteria can suppress the asthma phenotype by alteration of the Th1/Th2 cytokines ratio. In this study, utilizing a Th1 delivery system to modulate the allergic airway inflammation in a Th2-driven model of asthma, we evaluated the efficacy of immunization with Mycobacterium tuberculosis-specific antigen Rv3619c, either alone or in combination with low dose dexamethasone. The rv3619c gene was cloned in an expression plasmid pGES-TH-1, expressed in Escherichia coli, and the recombinant protein Rv3619c was purified to homogeneity using affinity chromatography. Mice were immunized with the recombinant protein emulsified in Freund's Incomplete Adjuvant (IFA) alone and in combination with low dose dexamethasone, and then challenged with ovalbumin (OVA). Airway inflammation was assessed by quantifying airway cytology, histological changes and Th2 cytokine (IL-5) secretion from splenocytes. OVA-specific IgE, IgG and IgG1 from sera was assessed, as well as pERK1/2 expression in the lung tissue. Immunization with recombinant Rv3619c alone inhibited the OVA-induced increase in total cell counts, eosinophil airway cell infiltration in BAL fluid, perivascular and peribronchial inflammation and fibrosis, and goblet cell hyper/metaplasia. In addition, Rv3619c/IFA inhibited the OVA-induced IL-5 in spleen cells, OVA-specific IgE, IgG, and IgG1 levels in sera, and pERK1/2 expression in lung tissue. Immunization with Rv3619c/IFA in combination with low dose dexamethasone resulted in an enhanced effect on some but not all the asthma features. Taken together, this study demonstrates that immunization with Rv3619c/IFA, alone or in combination with dexamethasone, may be an effective treatment strategy for the prevention of asthma.

Dataset Information

An eQTL variant of ZXDC is associated with IFN-? production following Mycobacterium tuberculosis antigen-specific stimulation.

Publications

An eQTL variant of ZXDC is associated with IFN-γ production following Mycobacterium tuberculosis antigen-specific stimulation.

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