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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

 

Terence S. Dermody, M.D.

Dorothy Overall Wells Professor of Pediatrics (Pediatric Infectious Disease)
Professor of Pathology, Microbiology and Immunology
Director, Medical Scientist Training Program
Director, Pediatric Infectious Diseases
Researcher

Contact Information:

Vanderbilt University Medical Center
D-7235 Medical Center North
Nashville, TN 37232-2581
615-343-9943

Research Specialty

Viral pathogenesis and vaccine development

Research Description

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. 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.

Publications