Is Panton-Valentine Leukocidin the Major Virulence Determinant in Community-Associated Methicillin-Resistant Staphylococcus aureus Disease?

Is Panton-Valentine Leukocidin the Major Virulence Determinant in Community-Associated Methicillin-Resistant Staphylococcus aureus Disease? Voyich J, et al. J Infect Dis. 2006;194:1761–1770 Methicillin-resistant S. aureus (MRSA) has emerged as a community associated pathogen (CA-MRSA) in individuals without traditional risk factors for MRSA infection. These infections are generally more severe than hospital-acquired MRSA-related infections. The most common pulsed-field types of S. aureus associated with CA-MRSA, USA300 and USA400 contain Panton-Valentine leukocidin (PVL). USA300 and USA400 have been epidemiologically linked to unusually severe staphylococcal infections, such as necrotizing pneumonia and necrotizing fasciitis, as well as to recurrent skin and soft tissue infections. However, the specific role of PVL in the virulence of CA-MRSA has never been proved. The authors set out to determine if PVL is responsible for the enhanced virulence of CA-MRSA. They used mouse sepsis and skin infection models to evaluate the virulence of PVL-positive and PVL-negative strains of the most representative pulsed-field types in the U.S. as well as PVL-negative isogenic mutants derived from 2 of the PVL-positive isolates (PVL knockout strains). In addition, they assessed the ability of the various strains to lyse or cause membrane damage to human neutrophils in vitro. Findings from this study were surprising. The PVL-positive MW2 strain was the most lethal among tested strains in the sepsis model. However, 3 of 4 PVL-negative strains were as or more virulent in the sepsis model as genetically similar PVL-positive strains. In the skin infection model, abscess volume in mice infected with PVL-negative strains was slightly greater than that of mice infected with PVL-positive strains. Certain strains (LAC and BK2394, both PVL-positive) were more likely to cause dermonecrosis than other strains including other PVL-positive strains (eg, MW2). There was no difference in the virulence of the PVL knockout strains when compared with the parent wild-type strains in either model. The results of in vitro neutrophil destruction assays demonstrated similar results. There was identical lysis of neutrophils by the PVL knockout and wild-type stains, and survival of the organisms after interaction with neutrophils was similar. Comment by Sandy Arnold, MD, Memphis, TN: PVL, encoded by the lukS-PV and lukF-PV genes, is a two-component extracellular toxin produced by S. aureus that targets leukocyte membranes. It emerged as a likely candidate to explain the enhanced virulence of CA-MRSA as it has been epidemiologically linked to recurrent and or severe skin and soft tissue infections and necrotizing pneumonia. In fact, most CA-MRSA causing infection in the United States harbor the PVL genes (USA300 and USA400 pulsed-field types). In contrast, PVL is not routinely found in the most common hospital-acquired MRSA types. In addition, the role of PVL as a major virulence factor for this emergent pathogen could be linked to PVL's neutrophil lysing activity as the cause of necrosis (skin, lung) seen with some CA-MRSA infections. However, all the evidence for PVL as the main factor in these severe infections has been circumstantial, and it has been postulated by some researchers in the field that PVL may only be a marker for other virulence factors, as yet unidentified.