Penetration of the blood–brain barrier by Staphylococcus aureus: contribution of membrane-anchored lipoteichoic acid

Abstract

Staphylococcus aureus is one of the most prevalent organisms responsible for nosocomial infections, and cases of community-acquired S. aureus infection have continued to increase despite wide-spread preventative measures. Pathologies attributed to S. aureus infection are diverse; ranging from dermal lesions to bacteremia, abscesses, and endocarditis. Reported cases of S. aureus-associated meningitis and brain abscesses have also increased in recent years, however the precise mechanism whereby S. aureus leave the bloodstream and gain access to the central nervous system (CNS) are not known. Here we demonstrate for the first time that S. aureus efficiently adheres to and invades human brain microvascular endothelial cells (hBMEC), the single-cell layer which constitutes the blood-brain barrier (BBB). The addition of cytochalasin D, an actin microfilament aggregation inhibitor, strongly reduced bacterial invasion, suggesting an active hBMEC process is required for efficient staphylococcal uptake. Furthermore, mice injected with S. aureus exhibited significant levels of brain bacterial counts and histopathologic evidence of meningeal inflammation and brain abscess formation, indicating that S. aureus was able to breech the BBB in an experimental model of hematogenous meningitis. We found that a YpfPdeficient mutant, defective in lipoteichoic acid (LTA) membrane anchoring, exhibited a decreased ability to invade hBMEC and correlated to a reduced risk for the development of meningitis in vivo. Our results demonstrate that LTA mediated penetration of the BBB may be a primary step in the pathogenesis of staphylococcal CNS disease.

Cryptococcus neoformans Activates RhoGTPase Proteins Followed by Protein Kinase C, Focal Adhesion Kinase, and Ezrin to Promote Traversal across the Blood-Brain Barrier

“…Cytochalasin D inhibits Cryptococcus association, internalization, and transmigration of HBMEC monolayer. These findings are consistent with previous reports showing that inhibition of actin polymerization blocks adherence and invasion of the HBMEC by pathogens that cause the CNS infection (11,34,37,38). Genistein also blocks interaction of C. neoformans with HBMEC including association, invasion, and transmigration, suggesting the involvement of phosphorylation of host signaling proteins regulating host actin cytoskeleton.…”

The Role of Autophagy during Group B Streptococcus Infection of Blood-Brain Barrier Endothelium

“…All GBS strains were grown in Todd-Hewitt broth (THB) with antibiotic selection, 2 g/ml chloramphenicol or 5 g/ml erythromycin, as needed. The B. anthracis Sterne strain and the methicillin-sensitive S. aureus ISP479C strains were cultured as described previously (31,32).…”

Concepts and Mechanisms: Crossing Host Barriers

“…Significant progress has been made in understanding the molecular interactions between the BBB and microbial pathogens with the availability of in vitro tissue culture models of human BMEC (hBMEC) (Stins et al 1994;Weksler et al 2005) and in vivo animal models (Smith et al 1973;Doran et al 2002;Wickham et al 2007;Uchiyama et al 2009;Sheen et al 2010). Microbial interactions with the BBB may involve crossing of BMEC in a vacuole (transcytosis), through the intercellular junctional spaces ( paracytosis), or while inside a host cell (e.g., infected phagocyte) using it as a vehicle to cross the barrier (Trojan horse) (Kim 2008(Kim , 2010 (Fig.…”