The receptor tyrosine kinases of the TAM family ? Tyro3, Axl, and Mer ? are essential regulators of infection by enveloped viruses, and Axl and Mer are especially important to arbovirus infection of cells of the central nervous system (CNS). Infection of the CNS by encephalitic arboviruses, including West Nile virus (WNV), often has devastating consequences, both acutely and after recovery, and deciphering the molecular mechanisms through which TAM receptors control virus entry, propagation, and clearance is therefore a key objective. Genetic, molecular biologic, cell biologic, and behavioral assays will be used to elucidate these mechanisms.
In Aim 1, a set of new conditional mouse mutants and cell-specific Cre drivers will be used to investigate the CNS cell types through which TAM receptors control infection by WNV and two other neurotropic enveloped arboviruses - La Crosse encephalitis virus and Venezuelan equine encephalitis virus. These studies will elucidate the specific roles played by Axl and Mer in brain microvascular endothelial cells (BMECs), microglia, astrocytes, and pericytes in neuroinvasion and CNS pathogenesis by these viruses.
In Aim 2, a new mouse model of learning impairment after recovery from CNS infection by WNV will be used to probe the role that Axl and Mer in microglia and astrocytes play in spatial learning and memory after infection. These experiments also will assess the role that cell-specific TAM signaling plays in synapse elimination and neurogenesis subsequent to WNV infection of the brain.
In Aim 3, molecular genetics and cell-based signaling assays will be used to elucidate the molecular architecture of TAM receptor-Interferon receptor (IFNAR) interaction, which is crucial to the phenomena of Aims 1 and 2, in BMECs, microglia, macrophages, and dendritic cells. These studies will identify the signaling pathways activated by cooperative TAM receptor/INFAR signaling in these cells, and assess the ability of these interacting receptor systems to reorganize actin cytoskeletons. Together, the experiments of this proposal will guide the formulation of novel strategies for inhibiting virus entry into the CNS, attenuating virus infection of neural cells, and promoting the repair and recovery of infected neural tissues.
Since West Nile virus (WNV) arrived in the U.S. in 1999, there have been more than 41,000 cases of symptomatic WNV infection, with half of these including meningitis, encephalitis, or flaccid paralysis. Worldwide, encephalitic arboviruses cause neurologic illness at the rate of 50-100,000 cases/year. As there is no specific therapy available for most of these infections, it is essential to public health to understand fully the genetic, cell biological, and biochemical mechanisms that underlie the regulation of arbovirus infection of the CNS by receptor tyrosine kinases of the TAM family.
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