Michael S. Diamond,
M.D., Ph.D.
Assistant Professor of Medicine, Molecular Microbiology, and Pathology & Immunology
Office: (314) 362-2842
Lab: (314) 362-2847
FAX: (314) 367-3214
E-mail:diamond@borcim.wustl.edu
Office: 520 McDonnell Sciences Building, Box 8051
The research in our laboratory focuses on the interface between viral pathogenesis and the host immune response. Two globally important mosquito-borne human pathogens are studied, the West Nile encephalitis and Dengue hemorrhagic fever viruses. They are single-stranded positive-polarity RNA viruses, and closely related to the viruses that cause yellow fever, St. Louis and Japanese encephalitis, and hepatitis C.
Studies with Dengue virus (DV) have focused on identifying the host and viral factors that modulate the severity of an infection. A methodology has been developed to monitor steps of the DV lifecycle in host cells including viral attachment and entry, nucleocapsid uncoating, translation and replication. We found that interferons (IFN) inhibit DV infection as they block the translation of viral RNA that occurs prior to RNA replication. Inhibition is by a novel, protein kinase R-independent mechanism that likely disrupts the elongation phase of translation or trafficking of the polysome-viral complex to the rough endoplasmic reticulum. Mutant DV strains have now been isolated that are resistant to IFN. Site specific substitutions into an infectious clone are underway to define the region(s) that confer resistance to IFN and the inhibitory molecules in the IFN antiviral pathway. Additional studies are underway to characterize novel classes of antiviral molecules with inhibitory activity against dengue and other flaviviruses.
We are beginning studies that investigate the pathogenesis of West Nile virus infection (WNV) and the immune system response that prevents dissemination in the central nervous system. An in vitro model of infection in neurons, astrocytes, and oligodendrocytes will determine the target of WNV infection in the brain, the molecular basis of cell injury, and the interaction of infected neuronal cells with immune cells. By infecting genetically and functionally immunodeficient mice with WNV, cells and molecules of the immune system will be identified that are essential to the resolution of viral infection.