Research Interest Summary
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) 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.
Barton, E. S., Forrest, J. C., Connolly, J. L., Chappell, J. D., Liu, Y., Schnell, F. J., Nusrat, A., Parkos, C. A., and T. S. Dermody. Junction adhesion molecule is a receptor for reovirus. Cell 104:441-451, 2001. PMID: 11239401
Ebert, D. H., Deussing, J., Peters, C., and T. S. Dermody. Cathepsin L and cathepsin B mediate reovirus disassembly in murine fibroblasts. J. Biol. Chem. 277:24609-24617, 2002. PMID: 11986312
O'Donnell, S. M., Connolly, J. L., Hansberger, M. W., Chappell, J. D., Watson, M. J., Han, W., Barton, E. S., Forrest, J. C., Valyi-Nagy, T., Pierce, J. M., Yull, F. E., Blackwell, T. S., Rottman, J. N., Sherry, B. J., and T. S. Dermody. Organ-specific roles for transcription factor NF-kappaB in reovirus-induced apoptosis and disease. J. Clin. Invest. 115:2341-2350, 2005. PMCID: PMC1184036
Kirchner, E., Guglielmi, K. M., Strauss, H., Dermody, T. S., and T. Stehle. Structure of reovirus sigma 1 in complex with its receptor junctional adhesion molecule-A. PLoS Pathog. 4:e1000235, 2008. PMCID: PMC2588538
Antar, A. A. R., Konopka, J. L., Campbell, J. A., Henry, R. A., Perdigoto, A. L., Carter, B. D., Pozzi, A., Abel, T. W., and T. S. Dermody. Junctional adhesion molecule-A is required for hematogenous dissemination of reovirus. Cell Host Microbe. 5:59-71, 2009. PMCID: PMC2642927
Danthi, P., Pruijssers, A. J., Berger, A. K., Holm, G. H., Zinkel, S. S., and T. S. Dermody. Bid regulates the pathogenesis of neurotropic reovirus. PLoS Pathog. 6:e1000980, 2010. PMCID: PMC2895667
Konopka-Anstadt, J. L., Mainou, B. A., Sutherland, D. M., Sekine, Y., Strittmatter, S. M., and T. S. Dermody. The Nogo receptor NgR1 mediates infection by mammalian reovirus. Cell Host Microbe. 15:681-691, 2014. PMCID: PMC4100558
Doyle, J. D., Stencel-Baerenwald, J. E., Copeland, C. A., Rhoads, J. P., Brown, J. J., Boyd, K. L., Atkinson, J. B., and T. S. Dermody. Diminished reovirus capsid stability alters disease pathogenesis and littermate transmission. PLoS Pathog. 11:e1004693, 2015. PMCID: PMC4349883
Ashbrook, A. W., Lentscher, A. J., Zamora, P. F., Silva, L. A., May, N. A., Bauer, J. A., Morrison, T. E., and T. S. Dermody. Antagonism of the sodium-potassium ATPase impairs chikungunya virus infection. mBio 7:e00693-16, 2016. PMCID: PMC4895112
Bouziat, R., Hinterleitner, R., Brown, J. J., […], Dermody, T. S., and B. Jabri. Reovirus infection breaks tolerance to dietary antigens and promotes development of celiac disease. Science. 356:44-50, 2017. PMCID: In progress