Neurovascular pericytes are susceptible to infection by JC polyomavirus

Progressive multifocal leukoencephalopathy (PML), an often-fatal neurodegenerative disease, is caused by the neuroinvasive polyomavirus JCPyV. Peripheral organs, including the kidney, are the site of lifelong persistent infections that are asymptomatic. In a subset of immunosuppressed or immunomodulated patients, the virus invades the central nervous system infecting oligodendrocytes, which leads to the multifocal white matter disease known as PML. The mechanisms that lead to neuroinvasion by JCPyV have not been well described. The brain is protected from viruses and other pathogens by physiological barriers, including the blood-cerebrospinal fluid barrier and the blood-brain barrier. To better understand the mechanism by which the virus breaches these barriers, we focused our attention on studying virus interactions with pericytes, which are an essential component of the blood-brain barrier. We found that the virus binds to pericytes in a receptor-dependent manner and that pericytes are susceptible to JCPyV infection. Previous work from our group demonstrated that JCPyV was capable of penetrating an intact endothelial cell barrier. Once across the endothelium, JCPyV would come in direct contact with pericytes, and we hypothesize pericyte infection would amplify and facilitate robust penetration into the brain parenchyma. This is the first demonstration that pericytes, a principal component of the blood-brain barrier, are susceptible to the neuroinvasive human polyomavirus JCPyV.IMPORTANCEJCPyV infects at least half the adult population worldwide. An asymptomatic, persistent infection is typically established in the kidney and possibly other peripheral organs. In immunosuppressed individuals, the virus can reactivate and cause progressive multifocal leukoencephalopathy, a deadly disease of the central nervous system (CNS). The pathogenic route the virus takes from the periphery to the CNS is unknown. Here, we demonstrate for the first time that JCPyV can infect human cerebrovascular pericytes, a cell type that contributes to the blood-brain barrier. This observation suggests that the virus could use the pericytes as a means to penetrate the blood-brain barrier to reach its pathogenic targets in the brain parenchyma.