Building an atlas of B cell mediated protective immunity to alphaviruses

Abstract This proposal outlines a five-year career development program for Dr. Saravanan Raju M.D., Ph.D. with the goal of preparing him for an independent research career as an academic physician-scientist. Dr. Raju completed his M.D. and Ph.D. in Immunology at Washington University in St. Louis and his medical residency in Clinical Pathology at Barnes-Jewish Hospital/Washington University. With the goal of dissecting the basis of broad and durable immunity to pathogens, Dr. Raju sought the mentorship of Dr. Michael Diamond, who is a Professor of Medicine and Co-Director of the Center for Vaccines and Immunity to Microbial Pathogens. Dr. Diamond is an expert in the field of viral immunology and has previously served as a mentor to physician- scientists who have transitioned to independent positions in academic medicine. Washington University provides an outstanding environment for Dr. Raju to develop his independent research career. First, Dr. Raju’s Advisory Committee comprised of Drs. Ellebedy, Fremont, Amarasinghe, and Murphy has diverse and extensive scientific expertise relevant to all aspects of this proposal and highly successful track records as scientific mentors. Second, Dr. Raju will acquire additional scientific, grant-writing, and laboratory management skills through resources available within the School of Medicine and Office of Postdoctoral Affairs. Third, the research infrastructure within the Diamond laboratory and on-site core facilities will enable Dr. Raju to efficiently perform the scientific aims described in this proposal. The goal of the proposed research is to study the basis by which cross-reactive B cells are induced to arthritogenic alphaviruses in mice. As the genus of alphaviruses includes several related but antigenically distinct species with established epidemic potential (e.g., Chikungunya virus and Mayaro virus), knowledge gained from this proposal may inform the development of pan-alphavirus vaccines. Dr. Raju will engage in formal coursework, workshop attendance, and mentored practical training in both B cell repertoire analysis and structure determination by cryo-electron microscopy to accomplish the aims in the proposal. Upon completion, the studies outlined in this proposal will yield insight into germinal center dynamics in a relevant infection model that can be expanded to other virus families and serves as a launching point for Dr. Raju’s independent research career.