No. 6: CA-MRSA—Not Your Father’s HA-MRSA

The flurry of 2007 lay-press reports that described isolated and clustered cases of methicillin-resistant Staphylococcus aureus (MRSA) produced more confusion than clarity by largely failing to discriminate between community- and healthcare-associated disease. The CDC defines community-associated (CA)-MRSA as a MRSA infection in an individual who has not been hospitalized or undergone a medical procedure (eg, catheter placement) within the last year. CA-MRSA infections are further distinguished from healthcare-associated (HA)-MRSA disease (which has been recognized for decades) when the diagnosis is established either in the outpatient setting or within 24 hours of hospital admission (by culture) and when there is no prior history of MRSA infection or colonization.

In November, investigators from the NAIAD, Germany, and Washington state published online their study of a group of protein toxins in S. aureus that are related to the proinflammatory peptide toxins of S. epidermidis, labeled phenol-soluble modulin (PSM). Production of PSMs (α, β, and δ) in cultures of the most prevalent CA-MRSA strains was observed to be considerably higher than that in cultures of HA-MRSA strains. By using murine abscess and bacteremia models, they then examined the relative virulence of 2 common CA-MRSA strains, USA300* and USA400,^† from which various PSM genes were deleted. Notably, USA300 strains lacking PSMα genes—but not those lacking other PSM genes—were significantly less likely to cause severe skin lesions in mice, prompting the authors to conclude that PSMα peptides play an essential role in the generation of CA-MRSA skin infections. In the bacteremia model, mortality was significantly reduced when PSMα, and to a lesser extent δ-toxin, was deleted.

In their in vitro experiments, synthetic PSMα peptides, and particularly PSMα3, produced the greatest neutrophil-associated proinflammatory activity but also generated substantial neutrophil lysis. The latter finding was consistent with the considerably reduced ability of PSMα-deleted strains of CA-MRSA and of HA-MRSA to lyse human neutrophils.

The authors claim that the primary role of PSMs is to destroy leukocytes. But given the observed proinflammatory activity of PSMs, they also conjecture that, for CA-MRSA survival, PSM secretion should be confined to times when immune cells can be destroyed. Evidently all S. aureus PSMs are tightly controlled through the process of so-called quorum sensing via the accessory gene regulator (agr). Quorum sensing links gene expression to the local concentration of bacterial signaling molecules. They conclude that agr-mediated quorum sensing of CA-MRSA dictates the activation of PSM-producing genes when PSMs are needed for pathogenesis and the repression of PSM production when they endanger CA-MRSA survival.

*Aka LAC; most common cause of community-associated skin or soft-tissue infections in the United States.