Mini reviewStaphylococcus aureus host cell invasion and post-invasion events
Introduction
Staphylococcus aureus can cause a broad spectrum of serious community-acquired and nosocomial infections, including boils, abscess formation, wound infection, endocarditis, osteomyelitis, and sepsis/septic shock. In addition, it is a frequent pathogen in foreign body infections, such as intravascular lines, pacemakers, artificial heart valves, and joint implants. Intracellular localization of S. aureus has been suggested to contribute to the often prolonged course and frequent relapse of severe S. aureus infections, such as endocarditis and osteomyelitis (Lowy, 1998). Treatment of infections is further complicated by the emergence of methicillin-resistant S. aureus (MRSA) (Gordon and Lowy, 2008), some of them have also acquired multi-resistance.
Adherence of S. aureus to host structures (host cells or extracellular matrix) is a prerequisite for asymptomatic colonization and overt disease. S. aureus expresses a large number of cell surface proteins (adhesins) of the MSCRAMM (Clarke and Foster, 2006; Patti and Höök, 1994) and SERAM (Chavakis et al., 2005) classes. Fibronectin-binding proteins (FnBPs) and extracellular adherence protein (Eap) serve also as host cell invasins, (reviewed in Sinha and Herrmann, 2005). Whereas S. aureus has been classically regarded as a purely extracellularly located microorganism, in 1986 first in vitro observations have been published, demonstrating intracellular localization of S. aureus upon co-incubation with non-professional phagocytes (Hamill et al., 1986). Despite numerous other reports, it was not earlier than 1999, when several groups published the first details on the molecular mechanism of S. aureus invasion nearly simultaneously with virtually complete concordance (Dziewanowska et al., 1999; Fowler et al., 2000; Jevon et al., 1999; Lammers et al., 1999; Peacock et al., 1999; Sinha et al., 1999). Subject of ongoing controversy and discussion has been the question of a potential phagosomal escape by S. aureus, meaning the functional and morphological breakdown of the membrane defining the phagosomal/endosomal compartment, which has been suggested as early as 1998 (Bayles et al., 1998).
Recent reviews have discussed the issue of intracellular persistence of S. aureus (Garzoni and Kelley, 2009) and the role of small colony variants (SCV) therein (Sendi and Proctor, 2009). These two reviews have put special emphasis on a thorough discussion of the data supporting in vivo relevance of intracellularly located S. aureus in human infections. In this respect, it is important to note that most careful attention has to be paid to experimental details, such as host cell type and species, S. aureus strains, multiplicity of infection (MOI), and observation time.
The aim of the present review is to discuss novel data regarding the invasion mechanism and post-invasion events with a focus on the fate of the phagosome in non-professional phagocytes and the role of S. aureus α-toxin.
Section snippets
Recent additions to the S. aureus invasion mechanism
Cellular invasiveness is a general property of S. aureus, albeit it is developed to different extents in various strains. It appears that the genetic background of the pathogen, as determined by the spa type of a given isolate, largely predicts the extent of invasiveness at the cellular level in vitro (Werbick et al., 2007). The molecular mechanism of S. aureus host cell invasion has been reviewed in detail previously (Sinha and Herrmann, 2005). In summary, invasion is mediated via fibronectin
Intracellular persistence, replication, and killing of S. aureus
Several studies have reported a prolonged survival of S. aureus in human leukocytes as early as 1952 (Kapral and Shayegani, 1959; Melly et al., 1960; Rogers and Tompsett, 1952) and in the meantime intracellular persistence of S. aureus has been described for a variety of host cells and pathogen strains as discussed in depth in two recent reviews focusing on S. aureus in general (Garzoni and Kelley, 2009) and on SCV (Sendi and Proctor, 2009). One recently elaborated aspect is the persistence in
Cell death induction by S. aureus
Cell death induction by S. aureus is much less predictable than cellular invasiveness and depends on the specific cell types and strains investigated, as well as the MOI used. This is also true for the pathway and molecular mechanism of cell death, and the exact S. aureus virulence factor as a trigger. Strains with both, an invasive and haemolytic phenotype (e.g. S. aureus strains 6850 and ST239), induce apoptosis in human endothelial cells, whereas either non-invasive haemolytic strains or
Phagosomal escape and role of S. aureus α-toxin
Destruction of the phagosomal compartment has been described for several bacterial species, such as Listeria monocytogenes, Shigella, and Rickettsia (reviewed in Hybiske and Stephens, 2008), which use pore-forming toxins as well as phospholipases for phagolysosomal membrane destruction. It has been suggested as early as 1998 that S. aureus escapes the phagosomal compartment in non-professional phagocytes (Bayles et al., 1998). Phagosomal escape of S. aureus seems to be a prerequisite for
Pitfalls investigating the fate of intracellular S. aureus
Analysis of intracellular S. aureus localisation is hampered by expression of staphylococcal protein A. Protein A has – among other functions – strong immunoglobulin-binding activity against human and rabbit antisera as well as a battery of other organisms used as production hosts for antibodies. Thus, the alternative antibody binding activity of protein A renders important cell biological methods such as IF microscopy difficult (Fig. 3). Spa is negatively regulated by the agr system (Novick et
Conclusions
During the last years, it has become clear that the interaction of S. aureus with host cells is more complex than often presented previously. Published data are sometimes highly variable or even contradictory. Apparently, study outcomes vary depending on bacterial strains, genetic background of the host cells, MOI, and other parameters. Thus, care has to be taken with regard to what aspects of infection and which end points in analyses thereof are investigated.
Some areas of research are still
Acknowledgements
We would like to thank all members of the groups for their contributions. Funding for work of the authors has been provided by Deutsche Forschungsgemeinschaft (Collaborative Research Center SFB-TR34, project C6; IRTG 1522), and by the German Ministry for Science and Research (BMBF) within the programme “Entrepreneurial Regions: Competence Centers” under code ZIK011.
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