Microbiology Unit, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, UK
Correspondence
Keith G. H. Dyke
keith.dyke{at}wadham.ox.ac.uk
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Staphylococcus special issue |
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The virulence of staphylococci is a very complex subject both because of the large number of factors involved and because of the many distinct systems for testing virulence that have been devised. One area that merits more attention is study of the virulence of small colony variants such as that shown to be a high protease producer (Jonsson et al., 2003). There are many staphylococcal virulence factors and they are regulated by a series of accessory elements that include two-component signalling systems such as agr, sae, arlRS, srrAB and the newly described global regulator mgrA (Luong et al., 2003
). Novick (2003)
has comprehensively reviewed the regulation of staphylococcal virulence and hypothesized that the regulatory genes act in a time- and population-density-dependent manner. In this special issue, the interactions of the sae components with agr are described and interpreted by Novick & Jiang (2003)
as a contribution to this subject.
New methods of study appear regularly and many remain to be fully exploited in research on staphylococci. A review by Hecker et al. (2003) includes discussion of how proteomics of Staphylococcus aureus can be applied to areas such as pathogenicity, antibiotic resistance and analysis of metabolism, and also provides a proteomic map of the organism. Utaida et al. (2003)
have followed up proteomic studies with investigation of changes in the transcriptional profiling of S. aureus in response to each of three cell-wall-active antibiotics. The problem is that the result shows up-regulation of a large number of genes and a time course will be needed to help to sort out which are the primary effects. However, there is a group of genes concerned with cell-wall metabolism that responded similarly to all three antibiotics, suggesting that there may be a cell-wall stimulon on the chromosome coordinated by an unknown mechanism. A clue to the coordination may be the two-component system VraSR that has been shown to influence the transcriptional regulation of a large number of genes including some of those involved in synthesis of the cell wall (Kuroda et al., 2003
). A bacterial two-hybrid system (Karimova et al., 1998
) has been exploited to demonstrate that the S. aureus proteins FemA and FemB interact both with themselves and with each other (Rohrer & Berger-Bächi, 2003
). Another new method is the use of fluorescent staining techniques to demonstrate that formation of the septal peptidoglycan in S. aureus is dependent on FtsZ that recruits a penicillin-binding protein. If FtsZ is depleted, the cell-wall synthetic machinery becomes dispersed and new wall material is now made over the entire surface (Mariana Pinho, personal communication). There is plenty of room to exploit the use of these fluorescent tags in understanding the location and interaction of staphylococcal proteins.
The adhesins of staphylococci have been a fruitful area of research for some time. The presence of the sortase signal LPXT/AG in 21 proteins as judged from analysis of S. aureus genome sequences revealed that there are 10 such proteins yet to be characterized (Roche et al., 2003a). These 21 putative adhesins are by no means the whole picture. Staphylococci produce a large array of surface and extracellular proteins that show the ability to bind to mammalian proteins. The largest staphylococcal protein reported so far (10 498 amino acids) is Ebh from strain COL that specifically binds human fibronectin (Clarke et al., 2002
) but it almost certainly has other properties. Some of the variety of functions of such proteins is illustrated in this issue by Roche et al. (2003b)
, who describe the adhesin SasG that, when produced in trans by Lactococcus lactis, promotes binding of S. aureus to desquamated human nasal cells, and by Harraghy et al. (2003)
, who describe the adhesin Eap (also known as Map or p70) that has a role in the modulation of the immune response but the nature of that role is unclear. Heilmann et al. (2003)
describe yet another autolysin (Aae) produced by Staphylococcus epidermidis which not only has bacteriolytic activity but also, in a separate domain, has the ability to bind vitronectin, fibrinogen and fibronectin.
S. aureus is a very adaptable organism and can live in a wide variety of environments, many of which will be stressful. Therefore, it needs and has regulatory systems to manage the stress. In this issue, there are two articles dealing with oxidative stress from superoxide radicals (Karavalos et al., 2003) and from hydrogen peroxide (Singh & Moskowitz, 2003
). They illustrate the complexity and interrelationship of the response to stress systems with those involved in metal-ion homeostasis. More research is needed into stress responses with particular reference to the precise conditions at the sites of infection.
The adaptability of S. aureus is also seen in the acquisition of genes conferring resistance to most usable antibiotics. The long-predicted acquisition by S. aureus of high-level resistance to vancomycin, probably from enterococci, was reported by the Centers for Disease Control (2002) and there are also reports from many countries of isolates with reduced susceptibility to vancomycin and teicoplanin frequently associated with a significant thickening of the cell wall (Cui et al., 2003
). Microarray analysis has shown that vancomycin induces 139 genes (Kuroda et al., 2003
) and so we are a long way from a complete understanding of how vancomycin acts and the relationship between cell-wall thickness and susceptibility. Despite a large amount of effort over many years, the regulation of resistance to methicillin and its relationship to regulation of
-lactamase synthesis in methicillin-resistant S. aureus (MRSA) is still not fully understood (Rosato et al., 2003
) but it has been shown, at least in Staphylococcus hominis, that mecA is part of a site-specific mobile chromosome cassette (Katayama et al., 2003
). This cassette may well have been transferred from an MRSA to a previously methicillin-susceptible strain present in the general community and so has given rise to the observed increased prevalence of MRSA outside the hospital environment in the last few years (Fey et al., 2003
). However, there is evidence from multilocus sequence typing that, in S. aureus, point mutations occur at least 15-fold more often than recombination (Feil et al., 2003
), so presumably such transfers are rare. Feil et al. (2003)
also conclude that there may not be specific hypervirulent strains of staphylococci, since they found no significant difference in the distribution of genotypes between isolates from carriers and those from patients.
Prevention of disease is better than cure; therefore, studies into ways of stopping staphylococci from spreading and infecting, together with the development of vaccines, will be valuable. There is little prospect of eradicating staphylococcal disease in the short term so effective antibiotics are of great importance. Fortunately, both linezolid and Synercid (a streptogramin A/B combination) are newly licensed for use against staphylococci but resistance to streptogramins is already present among hospital staphylococci and its prevalence can be expected to increase with the widespread use of Synercid (Haroche et al., 2003).
What will be important in combating staphylococcal disease is collaborative research with free dissemination of information. It is hoped that this special issue will play a part in this.
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