|
Identification
and Inhibition of Cytokines Induced During OHFV Infection Collaborating Institution: University of Texas Medical Branch at Galveston (UTMB), Galveston, TX
Principal Investigator: Micheal R. Holbrook, Ph.D.
Expected Product: Therapeutics for Omsk hemorrhagic fever virus infection
Description: Omsk hemorrhagic fever virus (OHFV) is a tick-borne flavivirus that causes viscerotropic disease in humans. Unlike other viscerotropic flaviviruses, such as yellow fever virus and dengue virus, OHFV causes viscerotropic disease in a small animal model. OHFV is closely related genetically to other members of the tick-borne encephalitis virus (TBEV) serocomplex, but, unlike all other members of this complex, does not cause neurologic disease. We have previously described OHFV infection in the Balb/c mouse where we found that viral tropism and histopathologic changes in this model were markedly different from infection with the neurotropic Powassan virus. Preliminary work has also shown a disease phenotype that is distinct from other TBEV serocomplex viruses. In this application we propose to characterize OHFV infection in the C57BL/6 mouse model with a fundamental examination of the host cytokine response to infection in mouse-derived macrophages and dendritic cells and mouse tissues. Furthermore, we also propose to examine the susceptibility of knockout mice to OHFV infection and to examine the efficacy of cytokine specific siRNA at limiting OHFV propagation and OHFV-induced cytokine expression. The objective of this project is to examine the initial host response to infection and to identify which aspects of the host response may play a role in limiting or exacerbating disease. We will also use cytokine specific siRNA for cell culture studies to determine the potential therapeutic value of this technology for limiting cytokine expression during disease. This project will provide a significant amount of fundamental knowledge regarding the pathogenesis of a poorly understood pathogen and may also provide insight into the pathogenic mechanisms of other viral hemorrhagic fevers, none of which have a good small animal model.
|
