One hundred and twenty years after its initial description as the pathogen that causes sepsis and abscesses (1), Staphylococcus aureus remains a dangerous organism. Staphylococcal endocarditis is on the rise (2) and still causes significant mortality (3). The methicillin-resistant S. aureus (MRSA) epidemic has entered a new era due to the spread of MRSA into the community (4) and acquisition of new resistance cassettes with the potential for genetic transfer (5). The advent of fully vancomycin-resistant, methicillin-resistant clinical isolates (6) has further weakened the available armamentarium against this pathogen.

A particular role of platelets in the pathogenesis of staphylococcal endocarditis has been suggested since the early observation by Durack of bacterial interaction with fibrin-platelet matrices at sites of nonbacterial thrombotic endocarditis (15) and the series of reports by Clawson et al. on the interaction of S. aureus with purified platelets (16). In the early 1990s, experiments with surface-activated platelets suggested to our group the importance of fibrinogen and S. aureus clumping factor in the bacteria-platelet interaction (17). These observations were subsequently confirmed and extended by use of a low-platelet-binding mutant expressing a mutated ClfA protein (18) that displays diminished virulence in an endocarditis model (19), and by identification of the secreted fibrinogen-binding proteins Coa and Efb in phage-display panning assays (20) (Figure ​(Figure11).

In this issue of the JCI, Kupferwasser and colleagues (27) extend these exciting findings. In a careful approach using a number of strains with functional gene regulator deletions and complementations in various genetic backgrounds, they demonstrated an acid stress–independent, SAL-mediated activation of the alternative staphylococcal stress response gene sigB, and consequently a downregulation of the sarA and agr regulons with a concomitant decrease in the expression of hla and fnbA (Figure ​(Figure2).2). These effects resulted in decreased bacterial adherence, and reduced toxin-mediated hemolysis and thrombolysis. Most importantly, SAL pretreatment attenuated the course of disease by decreasing the vegetation weight, the vegetation bacterial density, and the renal bacterial density.

The study by Kupferwasser et al. (27) leaves a number of open questions. Firstly, is there any role of SAL in established endocarditis? As downregulation of attachment factors may be of prime importance to prevent initial steps of pathogenesis, SAL may come too late for a salutary effect in treatment. In fact, the above-mentioned “paradoxic” effect due to hyperexpression of α-hemolysin may be abrogated, resulting in diminished release of platelet microbicidal proteins. Secondly, how do the findings regarding agr suppression relate to the findings of others, that in a serum milieu (32) or in established infection (33), agr expression is already largely diminished, and other regulators such as sae may play a more prominent role in the in vivo infection? Lastly, what is the mechanism of the effect of SAL on S. aureus regulation? SAL is known to exert a plethora of effects on various eukaryotic and prokaryotic cells. More specifically, SAL treatment enhances resistance of S. aureus to fluoroquinolones and fusidic acid. Even more interesting, SAL inhibits biofilm production in Staphylococcus epidermidis (34), apparently because of multiple effects on proteinaceous and nonproteinaceous cell wall and cell surface components (35). Biofilm production in S. aureus (36) and S. epidermidis (37) has been demonstrated to depend on the icaADBC gene cluster that confers production of the polysaccharide intercellular adhesin (PIA, also known as PS/A). Expression of the icaADBC gene cluster is environmentally controlled and, at least in part, regulated by sigB. sigB expression, on the other hand, is controlled by a cascade of sigB activators and inhibitors (38).