Is Panton‐Valentine Leukocidin the Major Virulence Determinant in Community‐Associated Methicillin‐ResistantStaphylococcus aureusDisease?

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major problem in hospitals, and it is now spreading in the community. A single toxin, Panton-Valentine leukocidin (PVL), has been linked by epidemiological studies to community-associated MRSA (CA-MRSA) disease. However, the role that PVL plays in the pathogenesis of CA-MRSA has not been tested directly. To that end, we used mouse infection models to compare the virulence of PVL-positive with that of PVL-negative CA-MRSA representing the leading disease-causing strains. Unexpectedly, strains lacking PVL were as virulent in mouse sepsis and abscess models as those containing the leukotoxin. Isogenic PVL-negative (lukS/F-PV knockout) strains of USA300 and USA400 were as lethal as wild-type strains in a sepsis model, and they caused comparable skin disease. Moreover, lysis of human neutrophils and pathogen survival after phagocytosis were similar between wild-type and mutant strains. Although the toxin may be a highly linked epidemiological marker for CA-MRSA strains, we conclude that PVL is not the major virulence determinant of CA-MRSA.

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

“…Our findings suggest that rAT maybe a more immunogenic vaccine candidate than LukS-PV, although cautious interpretation is required given the poor correlation between serologic biomarkers and protection against infection. The role of PVL as a virulence factor [40][41][42] and the effectiveness of neutralizing antibodies in disease prevention are not fully understood. 30,31 PVL is associated with a pro-inflammatory effect in mouse models that is independent of its pore-forming properties.…”

The role of virulence determinants in community-associated MRSA pathogenesis

“…As animal models can only partially reproduce how pathogens cause disease in humans, the null effect of PVL in the mouse and rabbit models may be due to a specific interaction of PVL with human neutrophils. Surprisingly, culture supernatants prepared from MW2 and USA300 clinical strains and their Δpvl isogenic mutants did not exhibit differences in capacity for pore formation or lysis of human neutrophils, even though PVL was secreted in abundance into the supernatants of the parental strains [48]. Thus, despite a detailed understanding of the molecular mechanistic basis of the leukolytic activities of purified PVL [57], the relevance of this toxin in the context of host-pathogen interactions remains unclear, particularly because CA-MRSA strains also secrete other exotoxins with much more potent leukolytic activities than PVL (see the section on PSMs below).…”

“…No significant difference in weight loss, abscess size, or bacteria colony forming units per abscess were detected when using Crl:SKH1-hrBR hairless and BALB/c mice to compare the following isogenic strain pairs: 1) MW2Δpvl mutant, in which lukPV operon was deleted by allelic replacement with a spectinomycin resistance cassette, and the parental strain MW2; and 2) LACΔpvl mutant and the parental strain LAC (Los Angeles County), which is a prototypical USA300 strain [48,49]. As bacteremia accounted for 65% of invasive CA-MRSA disease [24], the same isogenic strain pairs were compared in a CD1 Swiss mouse bacteremia model but no differences in lethality were observed, indicating that PVL is dispensable for CA-MRSA pathogenesis [48]. As rabbit and human PMNs are 10-100 times more sensitive than murine PMNs to the leukolytic effects of purified PVL [50,51], a rabbit model of bacteremia was used to test the potential effects of PVL.…”

Chronique d’une controverse sur une bactérie équipée pour tuer

“…Cependant, ces résultats n'étaient pas retrouvés par l'équipe de Deleo (NIH, États-Unis) qui avait recherché d'autres déterminants de virulence des SARM communautaires dans différents modèles d'infections cutanées, pulmonaires ou de sepsis chez la souris. Ces auteurs avaient abondamment publié pour contester le rôle de la PVL comme facteur majeur de virulence [15][16][17]. Cette controverse scientifique est relancée avec la publication récente de notre travail dans PLoS One [18] qui démontre le rôle de la PVL dans l'extension musculaire des infections osseuses chez le lapin.…”