Staphylococcus aureus Panton-Valentine Leukocidin Contributes to Inflammation and Muscle Tissue Injury

Abstract

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) threatens public health worldwide, and epidemiologic data suggest that the Panton-Valentine Leukocidin (PVL) expressed by most CA-MRSA strains could contribute to severe human infections, particularly in young and immunocompetent hosts. PVL is proposed to induce cytolysis or apoptosis of phagocytes. However, recent comparisons of isogenic CA-MRSA strains with or without PVL have revealed no differences in human PMN cytolytic activity. Furthermore, many of the mouse studies performed to date have failed to demonstrate a virulence role for PVL, thereby provoking the question: does PVL have a mechanistic role in human infection? In this report, we evaluated the contribution of PVL to severe skin and soft tissue infection. We generated PVL mutants in CA-MRSA strains isolated from patients with necrotizing fasciitis and used these tools to evaluate the pathogenic role of PVL in vivo. In a model of necrotizing soft tissue infection, we found PVL caused significant damage of muscle but not the skin. Muscle injury was linked to induction of pro-inflammatory chemokines KC, MIP-2, and RANTES, and recruitment of neutrophils. Tissue damage was most prominent in young mice and in those strains of mice that more effectively cleared S. aureus, and was not significant in older mice and mouse strains that had a more limited immune response to the pathogen. PVL mediated injury could be blocked by pretreatment with anti-PVL antibodies. Our data provide new insights into CA-MRSA pathogenesis, epidemiology and therapeutics. PVL could contribute to the increased incidence of myositis in CA-MRSA infection, and the toxin could mediate tissue injury by mechanisms other than direct killing of phagocytes.

Antibody-mediated enhancement of community-acquired methicillin-resistant Staphylococcus aureus infection

“…We also note that Tseng et al (32) claimed that antibody to PVL blocked muscle injury by two PVL-producing S. aureus strains in a skin infection model using CD1 mice when infections were established with 10 9 cfu. Interestingly, these investigators did not observe differences in muscle injury between PVL-producing and PVL − strains at lower inocula of 10 7 or 10 8 , or when SKH1 or C57BL-6 mouse strains were infected with 10 9 cfu.…”

Enhancement of bacterial virulence by antibody neutralization of immune-activating toxins

“…6 In some of those studies, PVL behaved as a virulence factor, as it enhanced the pathogenicity of S. aureus. 7,14,15 This result was not surprising given the high inocula of PVL-producing S. aureus used in those infections, where PVL levels likely rapidly rose to those needed to exceed the lytic threshold, and the pore-forming, cytotoxic functions of PVL were likely dominant. We established a skin abscess infection model in mice that required significantly lower inocula of S. aureus (on the order of 10 4 -10 5 CFU per animal).…”

Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury

“…PVL targets phagocytic leukocytes, especially polymorphonuclear leukocytes (PMNs), the first line of defense against S. aureus infections (6)(7)(8)(9). Compelling epidemiological data point to PVL as an important virulence factor in S. aureus necrotizing infections, but experimental data in rodent models are inconclusive (10)(11)(12)(13)(14)(15)(16)(17)(18).…”