Defining the antibody interface between Mycobacterium tuberculosis and host immunity

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Project Summary/Abstract: Tuberculosis (TB) kills 1.5 million people per year. Efforts to reduce this number have been hindered by the lack effective diagnostics and a protective vaccine underpinned by gaps in the understanding of the immune response in TB disease. While cellular immunity is important, the humoral immune response to infection by Mycobacterium tuberculosis (Mtb) is poorly understood. Antibodies, specifically IgG, are critical components of the adaptive immune response which have been indispensable in our understanding of infectious diseases and vaccine development. Antibodies function through the combination of recognizing antigens by the Fab domain and the recruitment of immune effector responses via the Fc domain. Variability in the Fc domain by isotype, subclass, and post translational glycosylation impact engagement with Fc receptors on immune cells that alter function in clinically significant manners. We have published that the antibody Fc domain diverges between individuals with latent infection who appear healthy and able to restrict bacteria compared to active TB disease which is permissive to Mtb replication. These distinctions are linked to differential Mtb burden in an in vitro primary human monocyte derived macrophage model of infection. How exactly antibodies might function in this context and its physiological relevance are questions that this proposal begins to address. The specific aims are 1: Determine how the Mtb antigenic repertoire impacts polyclonal IgG functions, 2: Identify the macrophage pathways by which the IgG Fc modulates Mtb survival, 3: Examine the in vivo effect of polyclonal IgG on chronic Mtb infection. The scientific objective of this proposal is to determine how polyclonal IgG contributes to restrictive and permissive host states for Mtb. The central hypothesis is that polyclonal IgG from individuals with active TB disease induces a host state permissive to bacterial growth. The overall goal is to understand fundamental mechanisms of humoral immunity in TB through antibodies to inform diagnostic, therapeutic and vaccine design.