Lack of Wall Teichoic Acids inStaphylococcus aureusLeads to Reduced Interactions with Endothelial Cells and to Attenuated Virulence in a Rabbit Model of Endocarditis

Abstract

Wall teichoic acids (WTAs) are major surface components of gram-positive bacteria that have recently been shown to play a key role in nasal colonization by Staphylococcus aureus. In the present study, we assessed the impact that WTAs have on endovascular infections by using a WTA-deficient S. aureus mutant (DtagO). There were no significant differences detected between the isogenic parental strain (SA113) and the DtagO mutant in polymorphonuclear leukocyte-mediated opsonophagocytosis; killing by a prototypic platelet microbicidal protein; or binding to platelets, fibronectin, or fibrinogen. However, compared with the parental strain, the DtagO mutant adhered considerably less well to human endothelial cells, especially under flow conditions (70.3% reduction;). Beads coated with WTA bound to endothelium in a dose-dependent manner, P ! .05 suggesting that WTA contributes specifically to this interaction. These in vitro data closely paralleled those from a rabbit model of infective endocarditis in which the DtagO mutant was compared with the parental strain. Clearances of staphylococcus from the bloodstream were equivalent, but the DtagO mutant showed a significantly reduced capacity to both colonize sterile cardiac vegetations ( ) and proliferate within these P ! .05 vegetations, the kidneys, and the spleen ( ). We conclude that WTA is an important factor in the P ! .001 induction and progression of endovascular S. aureus infection, likely through a specific interaction with endothelial cells.An important feature of Staphylococcus aureus bacteremia is the high frequency with which the organism spreads from the bloodstream to other targets, such as

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

“…Lipoteichoic acids (LTAs) are glycerol phosphate polymers linked to a glycolipid terminus in the cytoplasmic membrane (186). The functions of WTAs and LTAs are still being elucidated, with the recent generation of defined mutants, strains producing reduced amounts of teichoic acids, and strains producing altered teichoic acids providing significant insight into their functional roles (68,78,163,248,377,381). It appears that many teichoic acid functions may be nonessential and may possibly involve indirect interactions with other cell wall components (379); however, the complete loss of LTA leads to cell death in S. aureus (104).…”

Structure and mechanism ofStaphylococcus aureusTarM, the wall teichoic acid α-glycosyltransferase

“…Indeed, efforts to study these extraordinary polymers have yielded some important findings. For instance, it is known that, in the absence of WTA, S. aureus is viable under laboratory conditions, but that its ability to colonize and infect is greatly compromised (5,6). Deletion of LTA leads to temperature-sensitive strains only viable at temperatures lower than 30°C, and, interestingly, strains with deletions of both WTA and LTA are nonviable, suggesting some degree of redundancy in their respective roles (7).…”

“…Deletion of LTA leads to temperature-sensitive strains only viable at temperatures lower than 30°C, and, interestingly, strains with deletions of both WTA and LTA are nonviable, suggesting some degree of redundancy in their respective roles (7). TAs have furthermore been implicated in resistance to antimicrobial molecules (8)(9)(10)(11), resistance to lysozyme (11), coping with environmental stresses (7,12), mediating interactions with receptors and biomaterials (6,13), induction of inflammation (14)(15)(16), phage binding (17,18), and biofilm formation (19). Faced with so many functions in an uncertain environment, TAs must remain highly adaptive, a large part of which is achieved by the D-alanylation and glycosylation of polyol hydroxyl groups.…”

Synthesis of glycerol phosphate lipoteichoic acid in Staphylococcus aureus

“…Earlier work presumed that synthesis of these secondary wall polymers might be essential for bacterial growth and might therefore serve as a target for antibiotic development (11), similar to peptidoglycan, the primary wall polymer and target of penicillin (12). More recent work showed that, although WTA is dispensable for growth under laboratory conditions (13)(14)(15), staphylococcal mutants unable to synthesize WTA display colonization and virulence defects in animal models of infection (15,16). S. aureus LTA, a 1,3-linked glycerol phosphate polymer, is retained by a glycolipid anchor, diglucosyl diacylglycerol (Glc 2 -DAG), in bacterial membranes (Fig.…”