SummaryThe ability of Staphylococcus aureus to invade mammalian cells may explain its capacity to colonize mucosa and to persist in tissues after bacteraemia. To date, the underlying molecular mechanisms of cellular invasion by S. aureus are unknown, despite its high prevalence and dif®culties in treatment. Here, we show cellular invasion as a novel function for an S. aureus adhesin, previously implicated solely in attachment. S. aureus, but not S. epidermidis, invaded epithelial 293 cells in a temperature-and F-actindependent manner. Formaldehyde-®xed and live bacteria were equally invasive, suggesting that no active bacterial process was involved. All clinical S. aureus isolates analysed, but only a subset of laboratory strains, were invasive. Fibronectin-binding proteins (FnBPs) acted as S. aureus invasins, because: (i) FnBP deletion mutants of invasive laboratory strains lost invasiveness; (ii) expression of FnBPs in noninvasive strains conferred invasiveness; and (iii) the soluble isolated ®bronectin-binding domain of FnBP (D1±D4) completely blocked invasion. Integrin a 5 b 1 served as host cell receptor, which interacted with staphylococcal FnBPs through cellular or soluble ®bronectin. FnBP-de®cient mutants lost invasiveness for epithelial cells, endothelial cells and ®broblasts. Thus, ®bronectin-dependent bridging between S. aureus FnBPs and host cell integrin a 5 b 1 is a conserved mechanism for S. aureus invasion of human cells. This may prove useful in developing new therapeutic and vaccine strategies for S. aureus infections.

Staphylococcus aureus uses a plethora of virulence factors to accommodate a diversity of niches in its human host. Aside from the classical manifestations of S. aureus-induced diseases, the pathogen also invades and survives within mammalian host cells.The survival strategies of the pathogen are as diverse as strains or host cell types used. S. aureus is able to replicate in the phagosome or freely in the cytoplasm of its host cells. It escapes the phagosome of professional and non-professional phagocytes, subverts autophagy, induces cell death mechanisms such as apoptosis and pyronecrosis, and even can induce anti-apoptotic programs in phagocytes. The focus of this review is to present a guide to recent research outlining the variety of intracellular fates of S. aureus.

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SummaryIt has become clearthat Staphylococcusaureus is afacultativeintracellular microorganism. Adherencea nd invasion areaprerequisite forendovascular infections caused by S. aureus,such as infectiveendocarditis.Thesephenomenamay also be involved in the pathogenesis of invasivea nd metastatici nfection upon hematogenous dissemination, such as osteomyelitis and abscess formation.The underlying molecular mechanismhas been elucidated in detail, including its likelyrelevance in vivo.However,the mode of actiono fr ecentlyi dentified modulators of invasion, KeywordsBacterial invasion, hostc ells, Staphylococcus aureus,i nfective endocarditis, pathogenesis such as pls/Plshavenot yetbeen clarified.Thepotential outcome forh ost cellsa nd S. aureus following invasion ared iverse.Surprisingly,i nductiono fa poptosis in human endothelialc ells is more complext han previously thought, since it appearst oi nvolvem ultiple virulence factors. In the light of increasing resistance to antimicrobial therapy,understanding the multifacetted pathogenesis of S. aureus infection in detail is needed forabetter prevention and therapy.

Advances in molecular-based methods complementary to conventional blood culture diagnostics and antimicrobial stewardship programmes may optimize infection management by allowing rapid identification of pathogens and relevant antimicrobial resistance genes. Rapid diagnosis of the causing microorganism and relevant resistance determinants is important for early administration and modification of appropriate antimicrobial therapy. Ultimately, this may lead to improved quality and cost-effectiveness of health care, as well as reduced antimicrobial resistance selection.

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Recent data suggest that a-toxin, the major hemolysin of Staphylococcus aureus, induces cell death via the classical apoptotic pathway. Here we demonstrate, however, that although zVAD-fmk or overexpression of Bcl-2 completely abrogated caspase activation and internucleosomal DNA fragmentation, they did not significantly affect a-toxin-induced death of Jurkat T or MCF-7 breast carcinoma cells. Caspase inhibition had also no effect on a-toxin-induced lactate dehydrogenase release and ATP depletion. Furthermore, whereas early assessment of apoptosis induction by CD95 resulted solely in the generation of cells positive for active caspases that were, however, not yet permeable for propidium iodide, a substantial proportion of a-toxin-treated cells were positive for both active caspases and PI. Finally, electron microscopy demonstrated that even in the presence of active caspases, a-toxin-treated cells displayed a necrotic morphology characterized by cell swelling and cytoplasmic vacuolation. Together, our data suggest that a-toxin-induced cell death proceeds even in the presence of activated caspases, at least partially, in a caspase-independent, necrotic-like manner.