Predictive Understanding of the Effects of Encephalitic Virus Exposure on the Blood Brain Barrier
Abstract
We propose to compare the mechanisms of neuroinvasion employed by three highly pathogenic mosquito-borne viruses, Venezuelan (VEEV) and eastern (EEEV) equine encephalitis viruses and Rift Valley Fever Virus (RVFV), following infection by the subcutaneous (sc) or aerosol (aero) routes. These viruses appear to cross the blood-brain barrier (BBB) via different mechanisms likely determined by differential cell tropisms, receptor utilization, and patterns of host response, in part, arising from different sites of extraneural virus replication. The assembled research team combines tremendous expertise in arboviral pathogenesis, in vivo and in vitro biologic imaging, and the generation of in vitro BBB models from stem cells. By studying infections with virus following sc and aero administration, in vivo data sets will be collected for in silico modeling of neuroinvasion, immune responses and prediction of pathways involved. In vitro BBB models will be further developed and customized for these studies, and once validated, will be used for molecular studies and testing of potential therapeutics that maintain or protect the BBB. The ultimate goal is to facilitate the selection and optimization of potential single or combinatorial drug interventions to alter neuroinvasion and ameliorate encephalitic disease. We will utilize state-of-the art reporter-expressing wild-type viruses, microscopy, and in vivo imaging approaches available within BSL-3 containment, as well as stem cell derived in vitro BBB models. We aim to improve predictive understanding of the BBB exposed to encephalitic arboviruses, VEEV, EEEV and RVFV with the long-term goal of facilitating the development of medical countermeasures for the warfighter and civilians.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 26, 2016
- Source ID
- HDTRA11510047
Entities
People
- William B Klimstra
Organizations
- Defense Threat Reduction Agency
- University of Pittsburgh