Comparative RNAi Screening Reveals Host Factors Involved in Enterovirus Infection of Polarized Endothelial Monolayers

SummaryEnteroviruses, including coxsackievirus B (CVB) and poliovirus (PV), can access the CNS through the blood brain barrier (BBB) endothelium to cause aseptic meningitis. To identify cellular components required for CVB and PV infection of human brain microvascular endothelial cells, an in vitro BBB model, we performed comparative RNAi screens and identified 117 genes that influenced infection. Whereas a large proportion of genes whose depletion enhanced infection (17 of 22) were broadly antienteroviral, only 46 of the 95 genes whose depletion inhibited infection were required by both CVB and PV and included components of cell signaling pathways such as adenylate cyclases. Downregulation of genes including Rab GTPases, Src tyrosine kinases, and tyrosine phosphatases displayed specificity in their requirement for either CVB or PV infection. These findings highlight the pathways hijacked by enteroviruses for entry and replication in the BBB endothelium, a specialized and clinically relevant cell type for these viruses.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (125 K)Download as PowerPoint slideHighlights► RNAi screens reveal 117 host molecules involved in enterovirus infection ► Components of immune signaling including MAPKs, Akts, and TLR8 restrict infection ► Adenylate cyclases are required for both PV and CVB infection ► Rab GTPases, Src tyrosine kinases, and tyrosine phosphatases control infection