Aaron Gregory Schmidt
Title: Using protein engineering, antibody evolution and small-molecule discovery to dissect host-pathogen interactions
Key words: Protein engineering, viral evolution, host-pathogen interactions, small-molecule discovery
Our research focuses on the development of adaptive immune responses, protein evolution and the interactions between host and pathogen using a combination of biophysical, biochemical and molecular virology techniques. We are structural biologists who bring mechanistic and quantitative approaches to address fundamental problems in virology and immunology. We primarily study orthomyxo- and flaviviruses but our interests extend to emerging viruses (e.g. alpha-, arena-, bunya- and filoviruses) and other pathogens. We are strong believers in collaboration and are always open to pursuing new directions and pathogens.
Can novel small-molecules and antibodies be identified to inhibit viral entry?
Antibodies as therapeutics: broadly neutralizing antibodies (bnAbs) against viruses like influenza and HIV are possible therapeutic interventions in the absence of successful vaccines. We use directed evolution to understand bnAb development and to artificially affinity mature bnAbs to optimize specificity and breadth to inhibit viral entry.
Small-molecules as therapeutics: viruses that fuse from internal compartments present a significant hurdle for small-molecule inhibition. Targeting intermediates in the viral fusion pathway requires that the small-molecule be present in the same internal compartment as the fusing virus. We are developing strategies to deliver small-molecules in order to inhibit conformational rearrangements of viral glycoproteins and to target host proteins required for entry. We are also using our understanding of the viral fusion pathway to develop assays to identify small-molecule inhibitors of viral entry.
Can viral antigens be manipulated using structure-guided protein engineering to produce a desired immune response?
Traditional vaccination approaches have failed for many viral and parasitic diseases such as dengue, HIV and malaria. New approaches to rational vaccine design are necessary. We use a structure-guided approach for immunogen design in order to direct B-cell populations. We test these immunogens in animal models and analyze resulting B-cell repertoires in order to understand potential “rules” that may govern antigenicity and immunogenicity.
Can the evolutionary arms race between host and pathogen be recapitulated in vitro?
Pathogens use antigenic variation of their surface-exposed proteins as an evasion strategy to subvert and avoid host immune surveillance. We are broadly interested in understanding the evolution and co-evolution of pathogens with their hosts. In particular, how the adaptive immune system exerts pressure on viral proteins and how viruses evolve to escape such selective pressures. Understanding these interactions on a structural level may guide therapeutic intervention and vaccine development. We aim to reconstitute the evolutionary arms race between by using directed evolution platforms to evolve both antibodies and viruses.
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