MD, Columbia University
BS, Cornell University
Vira I. Heinz Professor and Chair, Department of Pediatrics
Professor, Department of Microbiology & Molecular Genetics
Member, Molecular Virology & Microbiology Graduate Program
Our lab studies the molecular pathogenesis of mammalian reovirus and chikungunya virus infections. Reovirus is an enteric, neurotropic virus that infects many mammalian species, including humans, but disease is restricted to the very young. Chikungunya virus is an emerging arthropod-borne alphavirus that causes epidemics of febrile arthritis in humans. 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.
(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. 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-induced apoptosis. Reovirus induces apoptosis in cultured cells and in the murine central nervous system and heart. Our studies indicate that apoptosis is triggered by innate immune response signal transducers initiated by viral components following reovirus disassembly and penetration of endosomal membranes. Experiments are in progress to identify components of the cell-signaling apparatus required for apoptosis induction by reovirus and to determine the relationship between apoptosis and virulence. These studies will establish new ideas about how RNA-containing viruses interact with innate immune response signaling circuits and lead to a better understanding of how viruses injure their host cells.
(4) Chikungunya virus (CHIKV) attachment and cell entry. CHIKV has produced explosive outbreaks in East Africa, several islands in the Indian Ocean, India, Southeast Asia, and most recently the Caribbean. We have found that attenuated CHIKV vaccine strain 181/25 engages heparan sulfate proteoglycans to initiate infection. Ongoing work is focused on identification of host cell proteins that contribute to CHIKV attachment and internalization and definition of CHIKV virulence determinants. This research will fill major gaps in an understanding of CHIKV pathogenesis and illuminate new targets for antiviral therapies and vaccines.
Nitin Arora, Postdoctoral Fellow
Pavithra Aravamudhan, Postdoctoral Fellow
Judy Brown, Graduate Student
Anthony Lentscher, Graduate Student
Jon Knowlton, Graduate Student
Nicole Mcallister, Graduate Student
Laurie Silva, Research Assistant Professor
Danica Sutherland, Graduate Student
Gwen Taylor, Research Instructor and Laboratory Manager
Kelly Urbanek, Research Assistant
Paula Zamora, Graduate Student
Areas of Interest
Viral pathogenesis and vaccine development
Ashbrook AW, Lentscher AJ, Zamora PF, Silva LA, May NA, Bauer JA, Morrison TE and Dermody TS. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio. 7: e00693-00716. | View Abstract
Doyle JD, Stencel-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. 11: e1004693. | View Abstract
Silva LA, Khomandiak S, Ashbrook AW, Weller R, Heise MT, Morrison TE, Dermody TS. (2014) A single-amino-acid polymorphism in Chikungunya virus E2 glycoprotein influences glycosaminoglycan utilization. J Virol. 88: 2385-2397. | View Abstract
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. | View Abstract
Kirchner E, Guglielmi KM, Strauss HM, Dermody TS and Stehle T. (2008) Structure of reovirus sigma1 in complex with its receptor junctional adhesion molecule-A. PLoS Pathog. 4: e1000235. | View Abstract
O'Donnell SM, Hansberger MW, Connolly JL, Chappell JD, Watson MJ, Pierce JM, Wetzel JD, Han W, Barton ES, Forrest JC, Valyi-Nagy T, Yull FE, Blackwell TS, Rottman JN, Sherry B and Dermody TS. (2005) Organ-specific roles for transcription factor NF-kappaB in reovirus-induced apoptosis and disease. J Clin Invest. 115: 2341-2350. | View Abstract
Barton ES, Forrest JC, Connolly JL, Chappell JD, Liu Y, Schnell FJ, Nusrat A, Parkos CA and Dermody TS. (2001) Junction adhesion molecule is a receptor for reovirus. Cell. 104: 441-451. | View Abstract