Polyomavirus ependyma infection induces region-specific and Stat1-dependent expression of chemokines in the CNS

Abstract

Abstract Immunity of the central nervous system to pathogens is partly established by critical barrier sites. One barrier within the four ventricles, the blood-cerebrospinal fluid (CSF)-brain barrier, is comprised of the choroid plexus epithelial cells separating the vasculature from the CSF, and the CSF from the brain parenchyma by the ependymal cells lining the ventricles. Intracerebroventricular delivery of mouse polyomavirus (MuPyV) in wild-type mice leads to infection of ependymal cells. In Stat1 null mice, viral infection is increased, and ependyma effacement is associated with hydrocephalus. Unknown is whether innate immunity and immune cell recruitment via Stat1 signaling by the ependyma limits MuPyV infection of the parenchyma. Dcdc2α-Cre mice, which show recombination in the ependyma and choroid plexus, were crossed with Stat1 fl/flmice to yield ependyma-specific Stat1 knockout. MuPyV infection was greater in Dcdc2αCre+ x Stat1 fl/flmice than in wild-type (WT) controls at 4 days post infection (dpi), but by 7 dpi the Dcdc2α-Cre+ x Stat1 fl/flmice exhibited higher levels of MuPyV infection in the periventricular region. Prior studies using the MuPyV-infected Stat1 null mice showed increased monocyte and T cell recruitment. Several chemokines (Ccl2, Cxcl10, Cxcl11, and Cxcl16) were elevated at 7 dpi in Dcdc2αCre+ x Stat1 fl/flmice relative to WT mice, while Cxcl13 was reduced at 4 and 7 dpi. Of these, Ccl2, Cxcl10 and Cxcl11 showed greater levels near the ventricles in both wild-type and Dcdc2αCre+ x Stat1 fl/flmice. Our data highlight the ependyma as a critical barrier protecting the brain from MuPyV infection that is dependent on Stat1 signaling. This work was supported by grants from the NIH (R35NS127217-01, T32CA60395-25).