title: 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.
authors.affiliation: Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Ching Wen
authors.initials: CW
authors.lastname: Tseng
authors.forename: Pierre
authors.initials: P
authors.lastname: Kyme
authors.forename: Jennifer
authors.initials: J
authors.lastname: Low
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Rocha
authors.forename: Randa
authors.initials: R
authors.lastname: Alsabeh
authors.forename: Loren G
authors.initials: LG
authors.lastname: Miller
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Terence M
authors.initials: TM
authors.lastname: Doherty
authors.forename: David O
authors.initials: DO
authors.lastname: Beenhouwer
authors.forename: George Y
authors.initials: GY
authors.lastname: Liu
mesh_terms: D000818:Animals; D001427:Bacterial Toxins; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005098:Exotoxins / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D007956:Leukocidins / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009132:Muscles / Q000293:injuries*; D016297:Mutagenesis, Site-Directed; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D001427:Bacterial Toxins; D017931:DNA Primers; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin