Wall Teichoic Acid Mediates Staphylococcus aureus Binding to Endothelial Cells via the Scavenger Receptor LOX-1.

The success of Staphylococcus aureus as a major cause for endovascular infections depends on effective interactions with blood-vessel walls. We have previously shown that S. aureus uses its wall teichoic acid (WTA), a surface glycopolymer, to attach to endothelial cells. However, the endothelial WTA receptor remained unknown. We show here that the endothelial oxidized low-density lipoprotein receptor 1 (LOX-1) interacts with S. aureus WTA and permits effective binding of S. aureus to human endothelial cells. Purified LOX-1 bound to isolated S. aureus WTA. Ectopic LOX-1 expression led to increased binding of S. aureus wild type but not of a WTA-deficient mutant to a cell line, and LOX-1 blockage prevented S. aureus binding to endothelial cells. Moreover, WTA and LOX-1 expression levels correlated with the efficacy of the S. aureus-endothelial interaction. Thus, LOX-1 is an endothelial ligand for S. aureus, whose blockage may help to prevent or treat severe endovascular infections.

Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF.

The pandemic of antibiotic resistance represents a major human health threat demanding new antimicrobial strategies. Multiple peptide resistance factor (MprF) is the synthase and flippase of the phospholipid lysyl-phosphatidylglycerol that increases virulence and resistance of methicillin-resistant Staphylococcus aureus (MRSA) and other pathogens to cationic host defense peptides and antibiotics. With the aim to design MprF inhibitors that could sensitize MRSA to antimicrobial agents and support the clearance of staphylococcal infections with minimal selection pressure, we developed MprF-targeting monoclonal antibodies, which bound and blocked the MprF flippase subunit. Antibody M-C7.1 targeted a specific loop in the flippase domain that proved to be exposed at both sides of the bacterial membrane, thereby enhancing the mechanistic understanding of bacterial lipid translocation. M-C7.1 rendered MRSA susceptible to host antimicrobial peptides and antibiotics such as daptomycin, and it impaired MRSA survival in human phagocytes. Thus, MprF inhibitors are recommended for new antivirulence approaches against MRSA and other bacterial pathogens.

Staphylococcus epidermidis clones express Staphylococcus aureus-type wall teichoic acid to shift from a commensal to pathogen lifestyle.

Most clonal lineages of Staphylococcus epidermidis are commensals present on human skin and in the nose. However, some globally spreading healthcare-associated and methicillin-resistant S. epidermidis (HA-MRSE) clones are major causes of difficult-to-treat implant or bloodstream infections. The molecular determinants that alter the lifestyle of S. epidermidis have remained elusive, and their identification might provide therapeutic targets. We reasoned that changes in surface-exposed wall teichoic acid (WTA) polymers of S. epidermidis, which potentially shape host interactions, may be linked to differences between colonization and infection abilities of different clones. We used a combined epidemiological and functional approach to show that while commensal clones express poly-glycerolphosphate WTA, S. epidermidis multilocus sequence type 23, which emerged in the past 15 years and is one of the main infection-causing HA-MRSE clones, contains an accessory genetic element, tarIJLM, that leads to the production of a second, Staphylococcus aureus-type WTA (poly-ribitolphosphate (RboP)). Production of RboP-WTA by S. epidermidis impaired in vivo colonization but augmented endothelial attachment and host mortality in a mouse sepsis model. tarIJLM was absent from commensal human sequence types but was found in several other HA-MRSE clones. Moreover, RboP-WTA enabled S. epidermidis to exchange DNA with S. aureus via siphovirus bacteriophages, thereby creating a possible route for the inter-species exchange of methicillin resistance, virulence and colonization factors. We conclude that tarIJLM alters the lifestyle of S. epidermidis from commensal to pathogenic and propose that RboP-WTA might be a robust target for preventive and therapeutic interventions against MRSE infections.