Sherman, DavidBarlow, Russell2015-09-292015-09-292015Barlow_washington_0250O_15121.pdfhttp://hdl.handle.net/1773/33487Thesis (Master's)--University of Washington, 2015Dengue virus circulates as 4 distinct serotypes that are transmitted to humans by the bite of an infected Aedes mosquito. Infection usually results in mild or asymptomatic febrile illness that resolves. In a minority of cases dengue infection can lead to “severe” life-threatening illness characterized by extravascular leakage of fluid, thrombocytopenia, hypovolemia, and shock. Risk factors for acquiring severe disease include pre-existing humoral immunity, age, type I interferon levels (IFN), the level of viraemia, and the frequency of plasmacytoid dendritic cells in the bloodstream during acute infection. During secondary infection pre-existing antibodies against a different serotype are thought to bind virus and enhance infection through FCyR mediated endocytosis in a phenomenon known as antibody dependent enhancement of infection (ADE). However the cellular mechanism during ADE and cell intrinsic consequences that lead to reduced type I IFN or reduced plasmacytoid dendritic cell (pDCs) frequency are not known. Therefore, we studied the innate immune consequences of Dengue virus infection during ADE infection of myeloid cells and investigated the role of pDCs during flavivirus infection. Our results indicate that during ADE, dengue virus infects predominately monocyte cells in a manner that enables virus to transiently overcome a pre-existing interferon response. We also found that flaviviruses efficiently infect pDCS resulting in robust type I IFN production that is dependent on the RIG-I like receptors with no impairment on cell viability. However, virus replication persisted despite robust IFN induction. Collectively these data highlight Dengue virus’s promiscuity for infecting relevant innate immune cell types and demonstrate the virus’s adept ability to persist during a productive anti-viral response.application/pdfen-USCopyright is held by the individual authors.Virologyglobal healthThesis