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Staphylococcal alpha-phenol soluble modulins contribute to neutrophil lysis after phagocytosis.

ABSTRACT: Staphylococcus aureus community-acquired (CA) MRSA strains are highly virulent and can cause infections in otherwise healthy individuals. The most important mechanism of the host for clearing S. aureus is phagocytosis by neutrophils and subsequent killing of the pathogen. Especially CA-MRSA strains are very efficient in circumventing this neutrophil killing. Interestingly, only a relative small number of virulence factors have been associated with CA-MRSA, one of which are the phenol soluble modulins (PSMs). We have recently shown that the PSMs are functionally inhibited by serum lipoproteins, indicating that PSMs may exert their cytolytic function primarily in the intracellular environment. To further investigate the intracellular role of the PSMs we measured the effect of the ?-type and ?-type PSMs on neutrophil killing after phagocytosis. Using fluorescently labelled S. aureus, we measured bacterial survival after phagocytosis in a plate reader, which was employed next to flow cytometry and time-lapse microscopy. Phagocytosis of the CA-MRSA strain MW2 by human neutrophils resulted in rapid host cell death. Using mutant strains of MW2, we demonstrated that in the presence of serum, the intracellular expression of only the psm? operon is both necessary and sufficient for both increased neutrophil cell death and increased survival of S. aureus. Our results identify PSM? peptides as prominent contributors to killing of neutrophils after phagocytosis, a finding with major implications for our understanding of S. aureus pathogenesis and strategies for S. aureus vaccine development.

SUBMITTER: Surewaard BG

PROVIDER: S-EPMC4784422 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Staphylococcal alpha-phenol soluble modulins contribute to neutrophil lysis after phagocytosis.

Surewaard B G J BG de Haas C J C CJ Vervoort F F Rigby K M KM DeLeo F R FR Otto M M van Strijp J A G JA Nijland R R

Cellular microbiology 20130322 8

Staphylococcus aureus community-acquired (CA) MRSA strains are highly virulent and can cause infections in otherwise healthy individuals. The most important mechanism of the host for clearing S. aureus is phagocytosis by neutrophils and subsequent killing of the pathogen. Especially CA-MRSA strains are very efficient in circumventing this neutrophil killing. Interestingly, only a relative small number of virulence factors have been associated with CA-MRSA, one of which are the phenol soluble mod ...[more]

PMID: 23470014

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Project description:INTRODUCTION:In bone and joint infections (BJIs), bacterial toxins are major virulence factors: Panton-Valentine leukocidin (PVL) expression leads to severe local damage, including bone distortion and abscesses, while ?-hemolysin (Hla) production is associated with severe sepsis-related mortality. Recently, other toxins, namely phenol-soluble modulins (PSMs) expressed by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300 (LAC WT) were shown to have ex vivo intracellular cytotoxic activity after S. aureus invasion of osteoblasts, but their in vivo contribution in a relatively PVL-sensitive osteomyelitis model remains poorly elucidated. MATERIALS AND METHODS:We compared the outcomes of experimental rabbit osteomyelitises induced with pvl+hla+psms+ LAC WT and its isogenic ?psm derivatives (LAC ?psm? and LAC ?psm??hld) using an inoculum of 3 × 108 CFUs. Mortality, hematogenous spread (blood culture, spleen and kidney), lung and bone involvements were assessed in two groups (non-survivors of severe sepsis and survivors sacrificed on day (D) 14). RESULTS:Severe sepsis-related mortality tended to be lower for ?psm derivatives (Kaplan-Meier curves, P = .06). Non-survivors' bone LAC-?psm? (6.9 log10 CFUs/g of bone, P = .04) or -?psm??hld (6.86 log10 CFUs/g of bone, P = .014) densities were significantly higher than LAC WT (6.43 log10 CFUs/g of bone). Conversely, lung ?psm??hld CFUs were significantly lower than LAC WT (P = .04). LAC ?psm?, ?psm??hld and WT induced similar bone damage in D14 survivors, with comparable bacterial densities (respectively: 5.89, 5.91, and 6.15 log10 CFUs/g of bone). Meanwhile, pulmonary histological scores of inflammation were significantly higher for LAC ?psm?- and ?psm??hld-infected rabbits compared to LAC WT (P = .04 and .01, respectively) but with comparable lung bacterial densities. CONCLUSION:Our experimental results showed that deactivating PSM peptides significantly limited bacterial dissemination from bone during the early phase of infection, but did not affect local severity of USA300 rabbit osteomyelitis.

Dataset Information

Staphylococcal alpha-phenol soluble modulins contribute to neutrophil lysis after phagocytosis.

Publications

Staphylococcal alpha-phenol soluble modulins contribute to neutrophil lysis after phagocytosis.

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