Why Is Staphylococcus aureus so Virulent?
Why Is Staphylococcus aureus so Virulent?
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Synopsis: Recombinant Panton-Valentine leukocidin (PVL) toxins showed lytic activity against human (but not murine) neutrophils. The lytic activity of culture supernatants of USA400 and USA300 strains of MRSA were completely neutralized by anti-PVL monoclonal antibodies. In contrast, phenol-soluble modulin alpha3 (PSM) failed to lyse human neutrophils but did enhance PVL-mediated neutrophil lysis.
Source: Hongo I, et al. Phenol-soluble modulin alpha3 enhances the human neutrophil lysis mediated by Panton-Valentine leukocidin. J Infect Dis. 2009;200:715-723.
Well-characterized strains of Staphylococcus aureus were grown in broth culture and after lysis PCR primers amplifying the lukS-PV and lukF-PV genes were employed. The amplicon was inserted into a pGEX vector and was transfected into E. coli. Recombinant PVL proteins overexpressed in E. coli were purified using standard methods. Phenol-soluble modulin (PSM) was synthesized directly for the experiments. Human PMNs were obtained by density gradient separation, and mouse PMNs were harvested by peritoneal lavage from mice in which casein was used to produce peritonitis. Neither LukS-PVnor LukF-PV could cause lysis of human PMNs when tested individually, but when mixed in equimolar concentrations they did produce cell lysis in a concentration and time-dependent fashion. PSM only produced human PMN lysis at very high concentrations. However, PSM caused synergistic lysis of human PMNs when mixed with LukS-PV, LukF-PV and markedly so with combined LukS-PV + LukF-PV. Monoclonal antibody to PVL effectively neutralized the PMN lysing activity of recombinant PVL proteins.
Commentary
Panton and Valentine originally described the staphylococcal leukocidin bearing their name in 1932.1 PVL consists of two non-associated soluble proteins encoded by the genes, LukS-PV and LukF-PV. PVL-producing isolates of S. aureus have been clinically associated with particularly aggressive skin and soft tissue infections, fulminant septicemia and necrotizing pneumonia. However in vitro studies and animal models of S. aureus infection with PVL-producing strains of S. aureus have yielded conflicting results in terms of the contribution of PVL to both neutrophil lysis and virulence.
In the same issue of JID, Villaruz et al2 show that an unintended point mutation in the agr P2 promoter of S. aureus may have been responsible for the virulence phenotype seen in earlier studies of experimental murine pneumonia, which had previously been attributed to PVL.3 Li et al4 in an earlier paper presented data on well-studied strains of USA300/USA500 MRSA, which suggested that the observed increased virulence of these strains was attributable to differential expression of core genome-encoded virulence determinants such as PSMs and alpha-toxin and not on factors (such as PVL) which are encoded on mobile genetic elements.
Bottom line from my perspective is that certain isolates of S. aureus (whether methicillin susceptible or methicillin resistant) can produce rapidly fatal disease in previously healthy hosts. Experimental data seem to be increasingly pointing to the fact that virulence can not be easily attributed to one or two exotoxins (such as PVL), but rather a larger pattern of bacterial gene expression and that susceptibility to particular clinical manifestations may be host/pathogen specific.
References
- Panton PN, Valentine FCO. Staphylococcal toxin. Lancet. 1932;222:506-508.
- Villaruz AE, et al. A point mutation in the agr locus rather than expression of the Panton-Valentine leukocidin caused previously reported phenotypes in Staphylococcus aureus pneumonia and gene regulation. J Infect Dis. 2009;200:724-734.
- Labandeira-Ray M, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007;315:1130-1133.
- Li M, et al. Evolution of virulence in epidemic community-associated methicillin-resistant Staphylococcus aureus. PNAS. 2009;106:5883-5888.
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