Sticky connections: extracellular matrix protein recognition and integrin-mediated cellular invasion by Staphylococcus aureus
Introduction
Staphylococcus aureus is an extremely versatile pathogen, causing a wide spectrum of diseases ranging from mild, superficial skin infections to life-threatening septicaemia, endocarditis and pneumonia [1]. Currently, S. aureus is one of the leading nosocomial pathogens in hospitals around the globe. In particular, the extraordinary capacity of this microorganism to acquire antibiotic resistance determinants is regarded as a major reason for the increase of nosocomial infections caused by S. aureus. The pathogen has genes that encode several virulence factors, the expression of which is controlled by a complex regulatory network including the quorum-sensing agr system, transcriptional regulators of the Sar family, the two-component regulatory systems ArlRS and SaeRS, and the alternative sigma factor SigB [2]. During in vitro cultivation, bacterial surface-associated virulence factors are preferentially expressed in the logarithmic growth phase, whereas secreted virulence factors are released in the post-logarithmic phase. It is assumed that this biphasic expression of virulence factors orchestrates the infection process. Initially, surface-bound adhesins recognize host surface structures, facilitating colonization, which is then followed by further growth of the microbes and secretion of toxins and enzymes, such as hemolytic toxins (α-, β-, γ- and δ-toxin), leucotoxins (e.g. Panton-Valentine leukocidin and LukFS), enterotoxins (e.g. EntB), toxic shock syndrome toxine-1, several proteases [e.g. metalloprotease aureolysin (Aur), serine proteases (SspA) and cysteine protease (SspB)], and lipases (e.g. Geh). Although in most cases the infection remains localized, the bacteria can also spread into deeper tissues and, importantly, are able to cause chronic diseases [1, 3, 4].
A characteristic feature of pathogenic S. aureus is the presence of adhesins that bind host extracellular-matrix (ECM) proteins and serum components. These proteins either remain associated with the surface of the bacteria or are released into the culture supernatant. Accordingly, the former have been collectively termed MSCRAMMs (microbial surface components recognizing adhesive matrix molecules), whereas the latter are referred to as SERAMs (secretable expanded repertoire adhesive molecules). Both types of protein are involved in colonizing host tissues and in the evasion of host immune response (Table 1) [5, 6]. However, the contribution of isolated MSCRAMMs or SERAMs to the infection process in vivo, as analysed by experimental models, is often not clear. This ambiguity might be caused by the functional redundancy seen, for example, in the case of fibrinogen binding, where S. aureus strains express at least seven proteins with the ability to associate with this serum component (Table 1). Moreover, individual MSCRAMMs or SERAMs might only be important in particular pathological conditions that are not fully addressed by current experimental models.
One of the pathogenic properties of S. aureus that has been difficult to assess in vivo is the role of host-cell invasion during infection. Such behaviour might be necessary for the pathogen to escape from the host immune surveillance and the antibiotic pressure and might also contribute to the persistence of the microorganism. Recent in vitro studies have provided convincing evidence that S. aureus can invade non-professional phagocytes, including epithelial and endothelial cells, fibroblasts, osteoblasts, keratinocytes and kidney cells [7, 8, 9, 10, 11]. The molecular events guiding the uptake of S. aureus by host cells were the focus of numerous investigations during recent years. Interestingly, and despite the presence of numerous adhesins in this microbe, the fibronectin-binding proteins A and B (FnBP-A and FnBP-B) were identified as major factors in initiating the internalization of S. aureus.
Section snippets
In vivo relevance of fibronectin recognition by S. aureus
FnBP expression and fibronectin (Fn) recognition are found in most clinical isolates of S. aureus [12]. Furthermore, evidence from several experimental models suggests that interfering with the ability of the bacteria to associate with Fn attenuates S. aureus virulence (for review, see [13]). Importantly, earlier studies did not address if the full pathogenic potential of S. aureus requires Fn recognition per se or if it depends on FnBP–Fn-mediated invasion into host cells. However, recent
Structure-function relationship of S. aureus fibronectin-binding proteins
Most strains of S. aureus harbor two closely related genes, fnbA and fnbB, that are located in tandem on the chromosome. The proteins encoded by these two genes, FnBP-A and FnBP-B, are anchored by an LPXTG motif to the cell wall of S. aureus and therefore belong to the group of MSCRAMMs. Both FnBPs are crucial for invasion of eukaryotic cell types by S. aureus and mutants lacking FnBP-A and FnBP-B are severely impaired in host-cell invasion [11, 17, 18]. Moreover, heterologous expression of
Host cell factors involved in integrin-mediated uptake of S. aureus
The engagement and clustering of integrin α5β1 by Fn-coated bacteria triggers characteristic signaling pathways in the host-cell. A crucial outcome of these signaling events is the reorganization of the actin cytoskeleton, which is essential for integrin-initiated uptake [28••, 29]. Under physiological conditions, a similar clustering can be observed when integrins are bound to ECM proteins and cluster in ‘focal contacts’ at the cell-ECM interface. Focal contacts integrate the binding of
Conclusions
Considerable progress has been made in our understanding of ECM recognition by S. aureus and on the role that Fn recognition plays in these bacteria. From several in vitro and in vivo studies, it appears that Fn-binding is a major virulence trait that enables this pathogen to cause invasive forms of disease and to persist within host cells. Approaches to target FnBPs of S. aureus and, thereby, to inhibit binding to Fn in vivo are being explored and initial results are encouraging [13]. An
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors would like to thank the BMBF (01 KI 8906/0) and the Deutsche Forschungsgemeinschaft (Ha2568/3-2 to CRH and SFB630 to KO) for financial support.
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