The hypervirulent Group BStreptococcusHvgA adhesin promotes brain invasion through transcellular crossing of the choroid plexus

Abstract

ABSTRACTBackgroundGroup BStreptococcus(GBS) is the leading cause of neonatal meningitis responsible for a substantial cause of death and disability worldwide. The vast majority of GBS neonatal meningitis cases are due to the CC17 hypervirulent clone. However, the cellular and molecular pathways involved in brain invasion by GBS CC17 isolates remain largely elusive. Here, we studied the specific interaction of the CC17 clone with the choroid plexus, the main component of the blood-cerebrospinal fluid (CSF) barrier.MethodsThe interaction of GBS CC17 or non-CC17 strains with choroid plexus cells was studied using anin vivomouse model of meningitis andin vitromodels of primary and transformed rodent choroid plexus epithelial cells (CPEC and Z310).In vivointeraction of GBS with the choroid plexus was assessed by microscopy. Bacterial invasion and cell barrier penetration were examinedin vitro, as well as chemokines and cytokines in response to infection.ResultsGBS CC17 was found associated with the choroid plexus of the lateral, 3rdand 4thventricles. Infection of choroid plexus epithelial cells revealed an efficient internalization of the bacteria into the cells with GBS CC17 displaying a greater ability to invade these cells than a non-CC17 strain. Internalization of the GBS CC17 strain involved the CC17-specific HvgA adhesin and occurredviaa clathrin-dependent mechanism leading to transcellular transcytosis across the choroid plexus epithelial monolayer. CPEC infection resulted in the secretion of several chemokines, including CCL2, CCL3, CCL20, CX3CL1, and the matrix metalloproteinase MMP3, as well as immune cell infiltration.ConclusionOur findings reveal a GBS strain-specific ability to infect the blood-CSF barrier, which appears to be an important site of bacterial entry and an active site of immune cell trafficking in response to infection.