Project Summary/Abstract This proposal presents a five year research career development program focused on the study of antibody mediated immune modulation in tuberculosis to expand the breadth and depth of understanding the role of humoral immunity in this disease. The candidate is currently an Instructor of Medicine at Harvard Medical School in the Division of Infectious Diseases at the Massachusetts General Hospital. The outlined proposal builds on the candidate's previous research and clinical experience in host pathogen interactions by integrating two new domains of expertise represented by her mentor team of Drs Sarah Fortune and Galit Alter at the Harvard School of Public Health and the Ragon Institute of MGH, MIT and Harvard: tuberculosis and antibody mediated mechanisms of innate immune effector functions. The proposed experiments and didactic work will position the candidate with a unique set of cross disciplinary skills that will enable her transition to independence as a physician scientist in antibody mediated host pathogen interactions in tuberculosis. One third of the world's population carries the burden of tuberculosis (TB). Efforts to reduce this burden 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 antibody (Ab) or humoral landscape is poorly understood. Ab function is determined by the combination of antigen specificity via the Fab and ability to recruit functional responses via the Fc domain. Ab Fc mediated recruitment of cellular responses is a promising underexplored potential for immune control. The foundation for this proposal is based on preliminary studies evaluating differences in antibody profiles from a systems serological approach in a cohort of individuals with latent and active TB that suggest a potential protective role for antibodies in TB disease. How exactly antibodies might function in this context and its physiological relevance are questions that this proposal begins to address. More specifically, the aims of this proposal are 1: Define the antigen specificity of functional M. tuberculosis (Mtb) specific antibodies, 2: Dissect the role for Fc/FcR mediated intracellular Mtb restriction and 3: Identify the macrophage effector mechanisms through which Ab restrict intracellular Mtb. The scientific objective of this proposal is to begin to define the Ab Fab and Fc features with the capacity to mediate effector function against intracellular Mtb with the vision of targeted transition into an appropriate animal model to generate hypotheses that inform the direction and design of subsequent human studies to expand the repertoire for immune correlates/diagnostics and rational vaccine design.