Dynamics of tuberculosis immune response in peripartum HIV-infected and HIV-uninfected women

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ABSTRACT Tuberculosis (TB) is the leading infectious cause of death worldwide, and contributes to substantial morbidity and mortality among HIV-infected peripartum women and their children. Risk of active TB appears to be higher during pregnancy/postpartum, but it is not known whether pregnancy-associated immunologic changes contribute to this increased susceptibility. Improved understanding of the host factors that influence M. tuberculosis (Mtb) infection and TB disease severity is needed to improve TB treatments and vaccines. Multiple lines of evidence indicate pregnancy diminishes T cell immunity to pathogens and may impair innate immune recognition of Mtb. After Mtb infection, macrophages and dendritic cells initiate the immune response, leading to mycobacterial killing, granuloma formation, and T cell activation. Our long-term goal is to determine the molecular and cellular mechanisms that influence susceptibility to TB. Discovery of the immune changes that influence Mtb pathogenesis in pregnancy may lead to improved public health efforts to reduce Mtb morbidity and transmission in at-risk populations. The objective of this grant is to characterize the effect of pregnancy on innate and adaptive immune responses to Mtb using stored samples that permit the study of immune responses pre-, during, and post-pregnancy. The central hypothesis is that pregnancy dampens the innate immune response to Mtb in a deleterious fashion, weakening Mtb-specific T cell responses and increasing TB susceptibility. The rationale is that identification of factors that influence Mtb-specific innate and T cell immunity in a nuanced fashion provides a novel path toward rational vaccine design and provides better understanding of high-risk populations. Our specific aims will test the following hypotheses: 1) pregnancy diminishes the proportion of CD4+IFN+ T cells and polyfunctional TH1 and CD8+T cells in pregnant women with latent Mtb infection; and 2) pregnancy impairs the capacity of peripheral blood monocytes to induce proinflammatory cytokines to Mtb and permits increased intracellular replication. This contribution is significant because it will establish the immune mechanisms that are influenced by pregnancy in the context of HIV, using samples from pre- and post-pregnancy and from HIV- uninfected women as a comparison; this proposal will lead to better understanding of the effects of pregnancy on macrophage and T cell biology. The proposed work is innovative because we assembled a new collaborative team with extensive experience in epidemiology and immunology to analyze banked samples with innovative controls, in an understudied population (HIV-infected, pregnant women), utilizing cutting-edge statistical tools, to measure innate immune and T cell responses. Insight into pregnancy as an immunomodulatory condition is impactful because this approach may offer new targets for novel therapeutics and vaccines, and will provide clinically relevant epidemiologic and immunologic data to inform future TB screening and prevention in maternal child health settings.