Sunday, May 18, 2025
5/18/2025
Dissecting Neuroglial Innate Immunity in vivo against Polyomavirus CNS Infection - PRORJECT ABSTRACT: JC Polyomavirus (JCPyV) is a ubiquitous asymptomatic virus that infects up to 90% of humans. In immunocompromised individuals, JCPyV can cause progressive multifocal leukoencephalopathy (PML), an often-lethal demyelinating neurodegenerative disease. Because polyomaviruses (PyV) are species-specific, mechanisms of PML pathogenesis are incompletely understood. The Lukacher group studies Mouse Polyomavirus (MuPyV), a natural murine virus, to define virologic and immunologic factors involved in PyV CNS infection and disease. Published work from the Lukacher group has shown that Type I Interferons (IFNs) directly inhibit MuPyV replication and are necessary to mitigate MuPyV encephalitis. The pathway(s) of Type I IFN induction during PyV infection in vivo is unknown. In vitro, cyclic GMP-AMP Synthase (cGAS) and Stimulator of IFN Genes (STING) have been implicated in limiting viral infections by a number of viruses with double-stranded (ds) genomes, including JCPyV and MuPyV. Our preliminary data using STING-/- cells confirms the importance of STING in inducing Type I IFN upon MuPyV infection in tissue culture. In this way, STING is the central adapter protein responsible for the first wave of Type I IFNs. Signal Transducer and Activator of Transcription (STAT) 1 is a downstream target of Type I IFNs. Signaling via STAT1 potently inhibits MuPyV replication. How STAT1 acts as a mediator of antiviral activity in MuPyV infected cells in vivo is unknown. The goal of this proposal is to determine whether cGAS-STING (Aim 1) and/or STAT1 (Aim 2) act in MuPyV-infected neuroglia in vivo to promote the antiviral Type I IFN axis and control virus- induced neurovirulence.
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