Abstract
Neurobrucellosis is an inflammatory disease caused by the invasion of Brucella spp. to the central nervous system (CNS). The pathogenesis of the disease is not well characterized; however, for Brucella to gain access to the brain parenchyma, traversing of the blood-brain barrier (BBB) must take place. To understand the CNS determinants of the pathogenesis of B. abortus, we have used the in vitro BBB model of human brain microvascular endothelial cells (HBMEC) to study the interactions between B. abortus and brain endothelial cells. In this study, we showed that B. abortus is able to adhere and invade HBMEC which was dependent on microtubules, microfilaments, endosome acidification and de novo protein synthesis. After infection, B. abortus rapidly escapes the endosomal compartment of HBMEC and forms a replicative Brucella-containing vacuole that involves interactions with the endoplasmic reticulum. Despite the ability of B. abortus to invade and replicate in HBMEC, the bacterium was unable by itself to traverse HBMEC, but could traverse polarized HBMEC monolayers within infected monocytes. Importantly, infected monocytes that traversed the HBMEC monolayer were a bacterial source for de novo infection of glial cells. This is the first demonstration of the mechanism whereby B. abortus is able to traverse the BBB and infect cells of the CNS. These results may have important implications in our understanding of the pathogenesis of neurobrucellosis.
Highlights
Invasion of the central nervous system (CNS) is a severe event during the course of many infectious diseases which can lead to severe neurological sequelae (Kim, 2003; Saez-Llorens and McCracken, 2003; van de Beek et al, 2006)
In this paper we demonstrate the capacity of B. abortus to adhere, invade and replicate in human brain microvascular endothelial cells (HBMEC), revealing the eukaryotic mechanisms for the invasion process
We have previously demonstrated the capacity of B. abortus to invade and replicate in human umbilical vein endothelial cells (HUVEC) (Ferrero et al, 2011) as a model of endothelial cells from peripheral vasculature
Summary
Invasion of the central nervous system (CNS) is a severe event during the course of many infectious diseases which can lead to severe neurological sequelae (Kim, 2003; Saez-Llorens and McCracken, 2003; van de Beek et al, 2006). Invasion of the nervous system by Brucella results in an inflammatory disorder called neurobrucellosis. It affects the CNS, and has a fateful prognosis (McLean et al, 1992; Giambartolomei et al, 2008). Neurobrucellosis may manifest as meningoencephalitis, brain abscesses, meningovascular disease, demyelinating syndromes, and myelitis (Bouza et al, 1987; McLean et al, 1992; Giambartolomei et al, 2008)
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