STING-dependent sensing of polyomavirus infection (VIR9P.1158)

Abstract

Abstract Polyomaviruses (PyV) are nonenveloped DNA viruses that persist as low-level asymptomatic infections in a variety of vertebrates, including humans. In immunosuppressed individuals, the human BK and JC PyVs may cause transplant-associated nephropathy and progressive multifocal leukoencephalopathy, respectively. Mouse polyomavirus (MPyV) allows investigation of PyV immunity in a natural host. After caveolae-/clathrin-mediated endocytosis, PyV virions traffic in microtubule-guided microvesicles from endosomes to the ER, where uncoating is initiated. Unknown is whether complete uncoating occurs in the cytosol, exposing the viral DNA to cytosolic DNA sensors, before it is transported to the nucleus where viral replication and assembly occur. Here, we report that persistent MPyV infection in mice is associated with chronically elevated IFN-β transcripts, and that WT primary mouse embryo fibroblasts (MEFs) infected with MPyV upregulate IFN-β, TNF-α and ISG (PKR and MDA-5) mRNAs. However, MPyV infection failed to induce expression for these transcripts in MEFs from STING-/- mice. Interestingly, MPyV acute infection activated NK cells in WT, but not in IFNαβR-/- mice or in STING-deficient (Goldenticket) mice. Together, these data suggest that MPyV-induced activation of NK cells requires Type I IFN and a STING-dependent cytosolic DNA sensing pathway(s). Moreover, these data provide strong evidence that PyV DNA is exposed in the cytosol and activate innate immune sensors.