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Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection.

ABSTRACT: D6 is a decoy and scavenger receptor for inflammatory CC chemokines. D6-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis. The death of D6(-/-) mice was associated with a dramatic local and systemic inflammatory response with levels of M. tuberculosis colony-forming units similar to control D6-proficient mice. D6-deficient mice showed an increased numbers of mononuclear cells (macrophages, dendritic cells, and CD4 and CD8 T lymphocytes) infiltrating inflamed tissues and lymph nodes, as well as abnormal increased concentrations of CC chemokines (CCL2, CCL3, CCL4, and CCL5) and proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1beta, and interferon gamma) in bronchoalveolar lavage and serum. High levels of inflammatory cytokines in D6(-/-) infected mice were associated with liver and kidney damage, resulting in both liver and renal failure. Blocking inflammatory CC chemokines with a cocktail of antibodies reversed the inflammatory phenotype of D6(-/-) mice but led to less controlled growth of M. tuberculosis. Thus, the D6 decoy receptor plays a key role in setting the balance between antimicrobial resistance, immune activation, and inflammation in M. tuberculosis infection.

SUBMITTER: Di Liberto D

PROVIDER: S-EPMC2526202 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection.

Di Liberto Diana D Locati Massimo M Caccamo Nadia N Vecchi Annunciata A Meraviglia Serena S Salerno Alfredo A Sireci Guido G Nebuloni Manuela M Caceres Neus N Cardona Pere-Joan PJ Dieli Francesco F Mantovani Alberto A

The Journal of experimental medicine 20080811 9

D6 is a decoy and scavenger receptor for inflammatory CC chemokines. D6-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis. The death of D6(-/-) mice was associated with a dramatic local and systemic inflammatory response with levels of M. tuberculosis colony-forming units similar to control D6-proficient mice. D6-deficient mice showed an increased numbers of mononuclear cells (macrophages, dendritic cells, and CD4 and CD8 T lymphocytes) in ...[more]

PMID: 18695004

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Project description:BackgroundAlthough immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized.MethodsWe conducted a nested case-control study using cryopreserved samples from persons who did and did not acquire HIV during the multinational Step clinical trial of the MRKAd5 HIV-1 vaccine. PBMCs from the last HIV-negative sample from incident HIV cases and controls were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining and scored with COMPASS. We measured inflammatory profiles with five Correlates of TB Risk (CoR) transcriptomic signatures. Our primary analysis examined the association of latent Mtb infection (LTBI; IFNγ+CD4+ T cell frequency) or RISK6 CoR signature with HIV acquisition. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether TB-associated immune markers were associated with HIV acquisition.ResultsAmong 465 participants, LTBI prevalence (21.5% controls vs 19.1% cases, p = 0.51) and the RISK6 signature were not higher in those who acquired HIV. In exploratory analyses, Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.78 (0.61, 0.98)), were associated with HIV acquisition. The transcriptomic pattern used to differentiate active vs latent TB (Sweeney3) was most strongly associated with acquiring HIV.ConclusionsLTBI, Mtb polyfunctional antigen-specific CD4+ T cell activation, and RISK6 were not identified as risks for HIV acquisition. In exploratory transcriptomic analyses, two CoR signatures were associated with HIV risk after adjustment for known behavioral and clinical risk factors. We identified host gene expression signatures associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.

Dataset Information

Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection.

Publications

Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection.

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