Skip to Content

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
VICC Member
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. The reovirus attachment protein, sigma 1, plays a key role in target cell selection in the infected host. We are conducting experiments to investigate the role of reovirus receptors, sialic acid and junctional adhesion molecule A (JAM-A), in reovirus dissemination and tropism. These studies employ polarized cells and mice lacking reovirus receptors. This work will be interpreted in the context of ongoing structural studies of sigma 1 in complex with its receptors with the goal of determining how sigma 1 structure relates to its function in receptor binding. Additional research focuses on the identification of receptors in host tissues that do not require JAM-A for productive infection.

(2) Reovirus entry into cells. Reovirus enters cells by clathrin-dependent endocytosis and undergoes proteolytic disassembly in endosomes. Studies are in progress to define mechanisms of reovirus uptake and transport within the endocytic pathway. Viral disassembly in most cell types is catalyzed by cathepsins B, L, or S. We are using molecular genetics, biochemical analyses, and electron cryomicroscopy to study domains in reovirus outer-capsid proteins that regulate proteolytic cleavage. A final series of experiments seeks to define mechanisms underlying the roles of individual cathepsins in reovirus disease. This research will reveal fundamental mechanisms by which viral and cellular factors cooperate to facilitate viral entry and illuminate new targets for therapy against viruses that use the endocytic pathway to enter cells.

(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 the viral mu 1 protein 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, and Southeast Asia. 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