Different Involvement of Vimentin during Invasion by Listeria monocytogenes at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers In Vitro.

The human central nervous system (CNS) is separated from the blood by distinct cellular barriers, including the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CFS) barrier (BCSFB). Whereas at the center of the BBB are the endothelial cells of the brain capillaries, the BCSFB is formed by the epithelium of the choroid plexus. Invasion of cells of either the BBB or the BCSFB is a potential first step during CNS entry by the Gram-positive bacterium Listeria monocytogenes (Lm). Lm possesses several virulence factors mediating host cell entry, such as the internalin protein family-including internalin (InlA), which binds E-cadherin (Ecad) on the surface of target cells, and internalin B (InlB)-interacting with the host cell receptor tyrosine kinase Met. A further family member is internalin (InlF), which targets the intermediate filament protein vimentin. Whereas InlF has been shown to play a role during brain invasion at the BBB, its function during infection at the BCSFB is not known. We use human brain microvascular endothelial cells (HBMEC) and human choroid plexus epithelial papilloma (HIBCPP) cells to investigate the roles of InlF and vimentin during CNS invasion by Lm. Whereas HBMEC present intracellular and surface vimentin (besides Met), HIBCPP cells do not express vimentin (except Met and Ecad). Treatment with the surface vimentin modulator withaferin A (WitA) inhibited invasion of Lm into HBMEC, but not HIBCPP cells. Invasion of Lm into HBMEC and HIBCPP cells is, however, independent of InlF, since a deletion mutant of Lm lacking InlF did not display reduced invasion rates.

Potential Roles and Functions of Listerial Virulence Factors during Brain Entry.

Although it rarely induces disease in humans, Listeria monocytogenes (Lm) is important due to the frequency of serious pathological conditions-such as sepsis and meningitis-it causes in those few people that do get infected. Virulence factors (VF) of Lm-especially those involved in the passage through multiple cellular barriers of the body, including internalin (Inl) family members and listeriolysin O (LLO)-have been investigated both in vitro and in vivo, but the majority of work was focused on the mechanisms utilized during penetration of the gut and fetoplacental barriers. The role of listerial VF during entry into other organs remain as only partially solved puzzles. Here, we review the current knowledge on the entry of Lm into one of its more significant destinations, the brain, with a specific focus on the role of various VF in cellular adhesion and invasion.