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Principal Investigator: David Margulies
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $370,759
Funding agency: National Institute of Allergy and Infectious Diseases
The focus of this work has been to understand the molecular details that control initial steps in the recognition of cells infected with pathogens such as viruses by cells of the innate and adaptive immune systems. Understanding the function, mechanism, structure, and evolution of the interaction of virus-encoded molecules recognized by the immune system can lead not only to a deeper understanding of molecular interactions in general and of cell-cell interactions in the immune system, but also may lead to rational approaches to intervention in virus infection and neoplasia. In particular, we study representative members of the large family of major histocompatibility complex (MHC)-encoded molecules from a biophysical and structural perspective. We are interested in how MHC-I molecules interact with receptors on natural killer (NK) cells and on T lymphocytes through their NK and T cell receptors, respectively. Large DNA viruses of the herpesvirus family produce proteins that mimic host MHC-I molecules as part of their immunoevasive strategy, and we have directed our efforts to understand the function, cellular expression, and structure of a set of these MHC-I (referred to as MHC-Iv) molecules encoded by the mouse cytomegalovirus (mCMV). In the past we studied expression and binding of several members of the MHC-Iv family, in particular the molecules, m144, m152, and m153. Recent experiments have identified a novel immunoevasin encoded by the Molluscum contagiosum virus, MC80, that impedes antigen presentation by interacting with tapasin in the protein loading complex, and directs tapasin to an endoplasmic reticulum degradative pathway. We have expressed and purified a recombinant form of the MC80 protein for structural and binding studies, and we expect that the basic knowledge gained will enhance our understanding of the MHC peptide loading pathway. These studies not only address the function of MC80 as an immunoevasin, but they also complement our studies of the role of tapasin in peptide loading in the peptide loading complex (PLC). MC80 competes for MHC-I binding to tapasin, and thus blocks the function of the PLC.
With respect to our studies of SARS-CoV-2 epitopic sites, we have computationally analyzed structures of over 400 antibodies or nanobodies to the major receptor Binding Domain, and identified 23 distinct regions on the surface of the RBD that evoke antibodies. These results offer insight into strategies for vaccine design.
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