Jay Nelson

The long-term goal of his laboratory is to understand the molecular basis of disease mediated by pathogenic human viruses. A major focus in the laboratory has been the identification of mechanisms involved in the pathogenesis of cytomegalovirus (CMV). CMV is a ubiquitous opportunistic infection that is usually asymptomatic following infection in the host. However, in immunocompromised individuals CMV can cause significant disease. The topics that we are currently pursuing in the laboratory are as follows: 1) molecular mechanisms of CMV latency, persistence, and reactivation in macrophages and endothelial cells; 2) establishment of a mouse model to examine mechanisms of HCMV latency and reactivation 3) characterization of the function of CMV-encoded miRNAs in the replication cycle of the virus; 4) analysis an function of CMV induced secreted extracellular proteins (secretome) in the induction of wound healing and angiogenesis that may be related to viral acceleration of vascular disease  5) mechanisms of CMV assembly and glycoprotein trafficking 6) analysis of the CMV proteome; and  7) the use of recombinant CMV as a vaccine vector for SIV/HIV and Monkeypox. Another focus of the laboratory has been elucidation of West Nile Virus (WNV) replication and pathogenesis. In collaboration with the Frueh laboratory using microarray analysis of up and down-regulated cellular genes, we observed that WNV significantly up-regulated the cellular Src kinase cYes. Inhibition of c-Yes production by siRNA or activity by the SFK inhibitor PP2 resulted in a significant drop in viral production (5-6 logs) in WNV infected cells. We have observed that cYes is involved in the maturation of the virion glycoprotein preventing viral egress from the ER. These observations will allow us to explore mechanisms of flavivirus assembly and egress as well as identify potential targets for therapeutic intervention. We have also observed that WNV sequesters cYes from cellular tight junctions perturbing barrier function that may be related to CNS disease observed in infected animals. Together with the Nikolich-Zugich and Moses laboratories we are investigating the role of the cYes kinase in the age-related disease associated with the virus.