Expanded evaluation of the role of antibody-dependent innate effector function in TB disease progression in HIV co-infected individuals - PROJECT SUMMARY/ABSTRACT HIV is the most important risk factor for progression to active tuberculosis (TB), but the immunologic mechanisms for this increased rate of progression are incompletely defined. Antibodies serve an important role coordinating the innate and adaptive immune compartments through the Fc-domain of the immunoglobulin molecule. Antibody production and Fc features are known to be broadly dysregulated in HIV infected individuals. This proposal will test the hypothesis that perturbations to antibody Fc-mediated functions contribute to increased risk in HIV infected individuals. This proposal presents a five-year research career development program to comprehensively investigate the roles of antibody-dependent effector functions in TB progression in the setting of HIV coinfection. Prior data indicate antibodies can predict TB progression in HIV-negative individuals and can confer protection against Mtb infection in vitro. Preliminary data presented here indicates that Ab functional features, and specifically neutrophil-activating functions, are altered in HIV co-infection. Published data suggest that neutrophils can play both pathogenic roles in TB (such as NETosis) and putatively protective roles (such as phagocytosis). In the studies proposed here, we aim to 1) apply expanded effector functional profiling to evaluate the impact of HIV on the breadth of Fc-mediated effector functions, and 2) define the antibody-dependent functional correlates that predict TB progression and Mtb antimicrobial control in the setting of HIV co-infection. We will leverage human plasma samples from two unique international cohorts: for Aim 1, we will use a Ugandan cohort of individuals with latent TB infection to investigate the impact of HIV on Mtb-specific antibody functionality; for Aim 2, we will use a multinational longitudinal cohort of HIV-coinfected TB progressors to evaluate both cross-sectional and temporal differences in Fc-mediated effector function. We will use innovative experimental and analytic methodologies including a high-throughput systems serology platform, in vitro functional assays measuring the ability of antibodies to drive NK cell activation, monocyte phagocytosis, complement deposition, and an expanded suite of neutrophil functions, and validated in vitro antimicrobial growth restriction assays. The candidate is currently an Instructor in Medicine at Brigham and Women’s Hospital with an ongoing research commitment of 75% time. The proposal is supported by an expert mentor in TB immunology and mycobacteriology, Dr. Sarah Fortune at the Harvard School of Public Health. The training plan unites the candidate’s postdoctoral training in humoral immunology with specific training in innate immunity, TB immunology, TB pathobiology, and bioinformatics, as well as ongoing professional development coursework. Completion of this comprehensive training plan will ensure the candidate’s successful development of a unique independent translational research program focused on Fc effector functions and systems immunology.
