Exploiting Fc-engineering to dissect mechanisms of anti-microbial action of M. tuberculosis-specific antibodies

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Project Summary Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading cause of death from a single infectious agent globally. While TB is curable, the intensive chemotherapeutic regimen coupled with the emergence of antibiotic resistance, has highlighted the need for an efficacious tuberculosis vaccine, as well as for the development of therapeutics robust to drug resistance. Bacillus Calmette-Guérin (BCG), developed in 1921, remains the only licensed TB vaccine to date, and does not effectively protect against the development of pulmonary TB. Consequently, innovative approaches to therapeutic and vaccine design are needed to curb the ongoing tuberculosis epidemic. Remarkably, despite the critical nature of the humoral immune response to protection by a majority of approved vaccines, humoral immunity to Mtb remains understudied. However, emerging evidence supports a role for antibodies in Mtb restriction. Antibodies can block the progression of infection and prevent spread. Moreover, mice unable to signal through activating Fc- gamma receptors have increased bacterial burden in the lung following Mtb infection, as well as decreased survival compared to wild-type mice. These data strongly implicate a role for antibodies, and more critically for the antibody constant domain (Fc), in protection; however, the Fc-mediated functions able to drive protection remain extensively unclear. Thus, this work aims explore antibody Fc-mediated mechanisms of Mtb control. We hypothesize that antibodies targeting surface exposed Mtb antigens direct the innate immune system to restrict Mtb growth in an Fc-dependent manner, and we plan to test this hypothesis using rationally designed Fc-engineered libraries of monoclonal antibodies, which allow the probing of individual Fc-enhancements and modifications for their impact on antibody anti-microbial activity. These antibody Fc-libraries will be tested in a systematic and rigorous set of in vitro assays, designed to capture potentially disparate mechanisms of antibody action. Aim 1 will identify the functions of antibodies able to drive Mtb growth restriction in whole- blood when present at the time of infection; Aim 2 will explore the intracellular mechanisms of antibody action in limiting Mtb survival within its host macrophage, the primary niche of the bacterium during infection. Overall, if successful, this work will contribute to our understanding of how antibodies may contribute to Mtb disease control, and thus help guide the next generation of vaccines and/or therapeutics against this global killer. This work will primarily be carried out at the Ragon Institute of MGH, MIT, and Harvard, a world leader in immunology research. Moreover, in parallel with the described research project, this fellowship will provide abundant teaching and science communication opportunities, to collectively encompass a comprehensive, systematic graduate training plan.