Harvard Catalyst Profiles

My research interests focus on the immune responses to fungal pathogens. Charged with the responsibility to protect a host from pathogenic microorganisms, the immune system detects, neutralizes, and eliminates these invaders using many different specialized cells. One arm of the immune system deploys sentinels throughout the body. Their purpose is two-fold. First, professional antigen presenting cells (APCs) capture invading pathogens by phagocytosis and degrade them before they cause additional harm to the host. Second, APCs must “deliver the message” about the presence of pathogens in the periphery to T cells located in regional lymph nodes in order to amplify the immune response. How does an APC talk to the T cell? Both cells come together and form a cell-cell synapse whereby the T cell interrogates the surface of the APC for the presence of a pathogen-specific signal that, when present, activates the T cell. Specialized immune proteins, termed class II MHC molecules, are heterodimeric protein complexes that present this signal. Dendritic cells (DCs) are potent professional APCs that express abundant class II MHC molecules and possess the unique capacity to activate naïve T cells. In order to serve as an effective APC, newly-captured pathogens must be shuttled to the endolysosomes for degradation. To accomplish this task, APCs place pathogens into membrane-delimited compartments termed phagosomes. These compartments undergo a series of membrane modifications, drop their pH and activate proteases which facilitate degradation of the cargo. The biomolecular mechanism of phagosome maturation is incompletely understood including the identity and kinetics of association and dissociation of most proteins on phagosomal membranes. When properly folded, class II MHC molecules form a pocket for pathogen-derived peptides (protein fragments). In the endolysosome, a specialized compartment within the APC, class II MHC molecules associate with pathogen-derived peptides and traffic from intracellular compartments to the cell surface. Antigen presentation requires the coordinated efforts of multiple host proteins including members of the tetraspanin superfamily, though their exact function in this process remains poorly understood.
When the process of antigen processing and presentation works well, the host is protected from a number of virulent microorganisms. Failure of an effective immune response, however, can lead to overwhelming infection and possibly death. This failure is caused typically by specific cellular defects in the immune system as seen in HIV infection, older age, or administration of immunosuppressive medications. My major goal is to understand the rules that govern the fate of fungal pathogens including Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans upon phagocytosis by real-time visualization of professional APCs expressing fluorescently-tagged proteins relevant to antigen processing and presentation using spinning-disk confocal microscopy.

I also serve as the tenth Program Director for the Massachusetts General Hospital Department of Medicine. I oversee the educational activities for the interns and residents. The MGH Internal Medicine Residency program has a long and world-renowned tradition of training leaders in academic medicine and biomedical science. The foundation of our program is rigorous clinical training that emphasizes clinical excellence, teamwork, leadership and career development. Our dedicated teaching faculty, resident research opportunities and experiences in international health and the local community ensure that our residents become outstanding physicians.

We enjoy strong house staff camaraderie and a supportive community in which diversity is celebrated. We take pride in training leaders in clinical and basic research, clinical practice, education, health policy, global health, administration and others. The outstanding achievements of our graduates remain the strongest affirmation of the goals of the training program