Interaction ofListeria monocytogeneswith Human Brain Microvascular Endothelial Cells: InlB-Dependent Invasion, Long-Term Intracellular Growth, and Spread from Macrophages to Endothelial Cells

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Abstract
Invasion of endothelial tissues may be crucial in aListeria monocytogenesinfection leading to meningitis and/or encephalitis. Internalization ofL. monocytogenesinto endothelial cells has been previously demonstrated by using human umbilical vein endothelial cells as a model system. However, during the crossing of the blood-brain barrier,L. monocytogenesmost likely encounters brain microvascular endothelial cells which are strikingly different from macrovascular or umbilical vein endothelial cells. In the present study human brain microvascular endothelial cells (HBMEC) were used to study the interaction ofL. monocytogeneswith endothelial cells, which closely resemble native microvascular endothelial cells of the brain. We show thatL. monocytogenesinvades HBMEC in an InlB-dependent and wortmannin-insensitive manner. Once within the HBMEC,L. monocytogenesreplicates efficiently over a period of at least 18 h, moves intracellularly by inducing actin tail formation, and spreads from cell to cell. Using a green fluorescent protein-expressingL. monocytogenesstrain, we present direct evidence that HBMEC are highly resistant to damage by intracellularly growingL. monocytogenes. Infection of HBMEC withL. monocytogenesresults in foci of heavily infected, but largely undamaged endothelial cells. Heterologous plaque assays withL. monocytogenes-infected P388D1macrophages as vectors demonstrate efficient spreading ofL. monocytogenesinto HBMEC, fibroblasts, hepatocytes, and epithelial cells, and this phenomenon is independent of theinlCgene product.