Terence S. Dermody, MD
- MD, Columbia University
- BS, Cornell University
Vira I. Heinz Professor and Chair, Department of Pediatrics
Professor, Department of Microbiology & Molecular Genetics
Member, Graduate Program in Microbiology and Immunology (PMI)
Member, Integrative Systems Biology (ISB) Graduate Program
Our lab studies the molecular pathogenesis of mammalian reovirus infection. Reovirus is an enteric, neurotropic virus that infects many mammalian species, including humans, but disease is restricted to the very young. Research in my laboratory encompasses several interrelated themes to better understand viral and cellular mediators of disease. These include the structural basis of viral attachment and entry into cells, mechanisms of genome replication and packaging, patterns of cell signaling and gene expression occurring in response to viral infection, mechanisms of virus-induced apoptosis and its significance in the viral life cycle, and roles of viral receptor distribution and utilization in disease pathology. We also are developing viral vectors for oncolytic and vaccine applications.
(1) Reovirus receptors and pathogenesis. Following peroral inoculation of newborn mice, reovirus disseminates systemically to target the heart, liver, and central nervous system. We are conducting experiments to investigate the role of reovirus receptors, sialic acid, junctional adhesion molecule A (JAM-A), and Nogo receptor-1 (NgR1) in reovirus dissemination and tropism. These studies employ primary cells and mice lacking reovirus receptors. This work will be interpreted in the context of ongoing studies to determine the structure of reovirus in complex with its receptors. Since not all of the reovirus receptors are known, we are working to identify additional reovirus receptors engaged in the intestine and the brain.
(2) Reovirus cell entry and replication. Reovirus enters cells by clathrin-dependent endocytosis in an integrin-dependent process and undergoes proteolytic disassembly in endosomes. Studies are in progress to define mechanisms of reovirus uptake and transport within the endocytic pathway within transformed cells and primary neuronal cells. We also are working to define how the viral gene products reorganize cellular architecture to form the viral replication organelles that serve as sites for genome replication and particle assembly. This research will reveal mechanisms by which viral and cellular factors cooperate to facilitate viral replication and illuminate new targets for therapeutic intervention.
(3) Reovirus assortment, packaging, and egress. The reovirus genome is composed of ten dsRNA gene segments that must interact, condense, and be packaged into newly synthesized capsid components to complete the infectious life cycle. We are investigating the specific viral and host interactions that dictate efficient genome packaging. Studies are in progress to understand the elusive, but critical, functions of reovirus non-structural proteins in dsRNA synthesis. We are also working to understand the cellular processes that catalyze folding of viral capsid components and contribute to non-cytolytic egress of nascent virus particles from cells. These studies will inform how viruses efficiently package and encapsidate genome and elucidate mechanisms underlying non-enveloped virus exit from infected cells.
Konopka-Anstadt JL, Mainou BA, Sutherland DM, Sekine Y, Strittmatter SM and Dermody TS. 2014. The Nogo receptor NgR1 mediates infection by mammalian reovirus. Cell Host Microbe. 15: 681-691.
Doyle JD, Setencel-Baerenwald JE, Copeland CA, Rhoads JP, Brown JJ, Boyd KL, Atkinson JB and Dermody TS. 2015. Diminished reovirus capsid stability alters disease pathogenesis and littermate transmission. PLoS Pathog. 1: e1004693.
Bouziat R, Hinterleitner R, Brown JJ [...] Dermody TS and Jabri B. 2017. Reovirus infection breaks tolerance to dietary antigens and promotes development of celiac disease. Science. 356: 44-50.
Knowlton JJ, Fernández de Castro I, Ashbrook AW, Gestaut DR, Zamora PF, Bauer JA, Forrest JC, Frydman J, Risco C and Dermody TS. The TRiC chaperonin controls reovirus replication through outer-capsid folding. Nat Micrbiol. 3: 481-493.