STING balances encephalopathy and neuroinflammation to polyomavirus infection 2260096

Abstract

Abstract Introduction Type I interferons (IFN-Is) modulate the differentiation and recruitment of T cells. JC polyomavirus causes the often-fatal brain demyelinating disease, PML. Polyomavirus infection activates STING to produce IFN-Is in vitro, but STING’s effects in vivo on T cell expansion, entry, and function in the CNS are unknown. Methods Using mouse polyomavirus (MuPyV) CNS infection and STING-KO mice, we hypothesize that STING enhances MuPyV control and recruitment of functional T cells to the brain. Results Although MuPyV genome copies are equivalent, STING-KO mice developed severe ventriculomegaly and 40% lethality at day 60 post-infection. Virus-specific CD8+ and CD4+ T cells in STING-KO mice exhibit higher PD-1 levels and produce less IFN-γ after direct ex vivo virus peptide stimulation. To determine whether this effect is T cell—intrinsic or -extrinsic, we adoptively transferred wild-type CD45.1+ virus-specific CD8+ T cells into CD45.2+ wild-type or STING-KO mice. CD45.1+ donor T-cells upregulated PD-1 in STING-KO brains despite equivalent IFN-γ production after peptide stimulation, suggesting STING is acting extrinsic to T cells. T cell numbers in the brain during acute and persistent infection were similar in WT and STING-KO mice. Conclusion These findings suggest that STING is dispensable in controlling MuPyV levels or in recruiting T cells but is involved in mitigating neuroinflammation. Ongoing work aims to examine STING’s involvement in MuPyV-induced neuropathology and neuroinflammation. Funding Source F31 NINDS Topic Categories Neuroimmunology (NEUR)