Viral pathogenesis:

Viruses successfully negotiate a gauntlet of cellular restrictions which serve to limit their entry, replication, emergence and dispersal. Viral entry is a key determinant of host, tissue and cellular tropism and often delimits the intrinsic characteristics of viral disease. Endothelial cells form a fluid barrier within capillaries and ß3 integrin receptors play prominent roles in platelet and endothelial cell functions which regulate vascular integrity. Pathogenic hantaviruses primarily infect endothelial cells, and bind and dysregulate the function of ß3 integrin receptors. Pathogenic hantaviruses cause two vascular leak syndromes, hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) with acute thrombocytopenia and endothelial cell permeability as hallmarks of disease. Our research investigates the role of hantavirus ß3 interactions in regulating endothelial cell permeability, platelet recruitment and the role of altered receptor functions as a mechanism of hantavirus pathogenesis.

Pathogenic viruses manipulate innate cellular responses in order to replicate within cells. Pathogenic hantaviruses regulate the early induction of interferon through interactions with cellular TRAF-TBK1 complexes that block IRF-3 activation. Our studies address the mechanism by which the hantavirus Gn-tail protein functions to regulate interferon and NF-κB pathway activation through protein interactions with cellular TRAFs and cellular ubiquitination and degradation machinery.

Additional projects include the genetic manipulation of hantaviruses and rotaviruses, defining rotavirus, hantavirus and influenza virus protein functions, analyzing dengue virus interactions with endothelial cell ß3 integrin receptors and defining mechanisms of aberrant fluid regulation induced by viral infection.