PROJECT SUMMARY/ABSTRACT Reducing progression to active TB disease in individuals infected with Mycobacterium tuberculosis (Mtb) is a key component of eradicating TB worldwide, yet it is hampered by poor predictive value of existing diagnostics, cumbersome antibiotic regimens, lack of understanding of immune mechanisms of control, and absence of an effective vaccine. A growing field of research implicates antigen-specific antibodies as critical biomarkers and mediators of control of Mtb infection, implicating antibodies as the potential basis of novel diagnostic or therapeutic strategies for TB. This proposal describes a five-year research plan to comprehensively investigate the roles of antibodies targeting the mycobacterial glycolipid lipoarabinomannan (LAM) in TB progression in the setting of HIV coinfection. Preliminary data presented indicate that LAM-specific antibodies can predict TB progression in HIV- negative individuals, that they can confer protection against Mtb infection in vitro, and that their recognition of Mtb varies across clinical strains. The LAM epitopes most relevant to immune correlates of TB progression and control of infection, their prevalence across Mtb clinical isolates, and the functional mechanisms of LAM antibody- mediated remain unclear. The studies proposed here aim to 1) define the humoral signatures that predict TB progression in the setting of HIV coinfection, 2) define the breadth and specificity of LAM antibody responses against global Mtb isolates, and 3) define LAM antibody-mediated effector functions that confer antimicrobial control against global Mtb strains. These aims will be approached using an international cohort of HIV-coinfected TB progressors, and make use of innovative methodologies including a powerful systems immunology platform, a panel of synthetic oligosaccharides, a barcoded library of clinical Mtb isolates, and validated in vitro antimicrobial functional assays. The candidate is currently an Instructor in Medicine at Harvard Medical School and an Associate Physician in the Division of Infectious Diseases at Brigham and Women’s Hospital, with an ongoing research commitment of 80% time. The proposal is supported by an expert mentor in humoral immunology, Dr. Galit Alter at the Ragon Institute of MGH, MIT, and Harvard, and an expert co-mentor in mycobacterial diversity, Dr. Sarah Fortune at the Harvard School of Public Health. The training plan unites the candidate’s prior graduate work in glycobiology with specific training in humoral immunology, microbiology, and bioinformatics, as well as ongoing professional development and responsible conduct of research coursework. Completion of this comprehensive training plan will ensure the candidate’s successful development of a unique independent translational research program focused on humoral responses to Mtb glycans.

PROJECT NARRATIVE Tuberculosis (TB) is the leading cause of death among people living with HIV, yet strategies for preventing the progression of infected individuals to active TB disease are lacking. The proposed studies dissect the role of antibodies against the mycobacterial surface molecule lipoarabinomannan (LAM) in both the prediction and control of TB disease progression in HIV coinfection. The overarching vision is to define specific responses that can be leveraged to develop new diagnostic tests, therapeutic strategies, or vaccines against TB.