Trends in Microbiology
OpinionWhat role does the quorum-sensing accessory gene regulator system play during Staphylococcus aureus bacteremia?
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Staphylococcus aureus bacteremia: the challenge of hitting a moving target
Entry of S. aureus into the bloodstream most frequently occurs via colonisation of intravenous catheters or wounds [1]. In itself, staphylococcal bacteremia is serious and can lead to septic shock. However, S. aureus has a remarkable ability to exit the bloodstream and establish secondary infection foci in almost any tissue, resulting in a diverse range of infections including infective endocarditis, tissue abscesses, meningitis, osteomyelitis, and septic arthritis [2]. Overall, mortality can
The Agr links quorum-sensing with cytolytic toxin production
The agr operon constitutes a global regulatory system that controls cell density-dependent virulence factor expression. Several studies have demonstrated that Agr activity is essential for skin and soft tissue infections, and there is considerable interest in developing inhibitors of this system as novel antivirulence drugs for therapeutic use 14, 15, 16, 17, 18, 19, 20.
The agr operon consists of two divergent promoters, P2 and P3; where expression from P2 produces the components of a
agr-defective S. aureus is a frequent cause of bacteremia
Despite the importance of Agr in many infections, strains lacking detectable Agr activity have been isolated in 3–82% of cases of S. aureus bacteremia 10, 26, 27, 28, 29, 30, 31, 32. The methods used to determine Agr functionality vary from simple haemolysis assays on solid media to sequencing of the agr operon, which may contribute to the variation in their reported frequency (Table 1). The wide variation in reported frequency may also relate to differences in study design, patient
Is agr expressed in the bloodstream?
One plausible explanation for the prevalence of agr-defective S. aureus strains causing bacteremia is that Agr activity is either not required, or may even be detrimental, for the survival of S. aureus in the human bloodstream. In support of this hypothesis, transcriptomic analysis of S. aureus incubated in whole human blood revealed a total lack of agr expression in an Agr-functional strain [41]. The most obvious reason for this finding is that the density of bacteria in the bloodstream is
Serum-mediated Agr suppression: for better or worse?
As described above, the suppression of Agr activity by lipoproteins is a host defence mechanism which prevents cytolytic toxin production [42]. However, suppression of Agr is not entirely beneficial, since diminished Agr activity promotes the expression of the immune evasion molecule SpA and adhesive FnBPs, both of which promote dissemination from the bloodstream 41, 49, 50. In addition, Agr negatively regulates the expression of the staphylococcal superantigen-like (SSL) proteins, which are
The enemy within: Agr is required for S. aureus to kill neutrophils from inside
The suppression of Agr activity by serum may suggest that this system is redundant during bacteremia and it is, therefore, easy to understand how agr-defective mutants can cause infection. However, despite the expression of SpA and SSLs, a high proportion of S. aureus in blood are apparently phagocytosed by neutrophils [41]. Once S. aureus is ingested by a neutrophil, it is trafficked to the phagosome, which fuses with primary and secondary granules to form the phagolysosome, a hostile
Is Agr dysfunction the price of antibiotic resistance?
Staphylococcal bacteremia is treated aggressively with high doses of intravenous antibiotics, placing a tremendous selection pressure on the acquisition of resistance or tolerance. Unsurprisingly, resistance to methicillin is strongly associated with persistent bacteremia 3, 4, 6. However, resistance to methicillin and vancomycin has also been linked to loss of Agr activity, suggesting a trade-off between antibiotic resistance and virulence 4, 75, 76, 77, 78, 79, 80, 81, 82, 83 (Box 1).
Work by
Is the price of resistance worth paying?
As S. aureus must overcome both the host immune response and antibiotic therapy. The relative importance of each threat is determined by the host environment, which includes a combination of immune function and antibiotic therapy. Therefore, when assessing the significance of agr-dysfunction in bacteremia, it is essential to consider the immune status of the patient. The ability of S. aureus to escape from neutrophils is likely crucial for infection in relatively healthy individuals with
Beyond bacteremia: agr-defective strains are found in multiple infection types.
In addition to bacteremia, agr-defective strains have been isolated from several other types of infection, including those of medical devices, osteomyelitis, and from the lungs of individuals with cystic fibrosis 8, 92. These infections are often chronic in nature and this may be explained by the loss of Agr activity, which creates phenotypes compatible with persistent infection. For example, agr inactivating mutations or PBP2a-mediated Agr inhibition, can promote biofilm formation via
Concluding remarks
The interaction of S. aureus with the host environment is enormously complex, involving a raft of bacterial and host factors, together with therapeutic antibiotics (Figure 4). Several host factors have been shown to modulate Agr activity, which can have a dramatic effect on the S. aureus phenotype, in turn affecting the host response 42, 43, 49, 50, 59, 62, 73, 84 (Figure 4). This creates numerous selection pressures, some of which result in loss of Agr function either via mutation or by the
Acknowledgements
A.E. acknowledges funding from the Royal Society and Department of Medicine, Imperial College. K.L.P. is supported by a Department of Medicine PhD scholarship. A.K. is supported by an Imperial College PhD studentship. Work in S.W.’s laboratory is supported by a Wellcome Trust New Investigator award and funding from the BBSRC.
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