1. PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts
- Author
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Jerome Etienne, Jérémy Ranfaing, Gerard Lina, Florence Couzon, Sylvestre Tigaud, Yvonne Benito, Frédéric Laurent, Sophie Trouillet-Assant, Anaïs Sapin, Cédric Badiou, Binh An Diep, Michèle Bes, François Vandenesch, Yannick Lhoste, Tristan Ferry, Jean-Philippe Rasigade, Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Reference des Staphylocoques, Université de Lyon, Département de Microbiologie Clinique [HCL Groupement Hospitalier Nord, Lyon], Hospices Civils de Lyon (HCL)-HCL Groupement Hospitalier Nord [Lyon], Department of Medicine [San Francisco], University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UCSF), University of California-University of California, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Messenger ,Leukocidin ,Intracellular Space ,Pathogenesis ,medicine.disease_cause ,Pathogen ,Staphylococci ,0303 health sciences ,Staphylococcal infection ,Multidisciplinary ,Cell Death ,Phenol-soluble modulin ,Bacterial ,Osteoblast ,Osteomyelitis ,3. Good health ,Bacterial Pathogens ,Panton-Valentine leukocidin ,Host-Pathogen Interaction ,Community-Acquired Infections ,medicine.anatomical_structure ,Staphylococcus aureus ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Medicine ,Infectious diseases ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Intracellular ,Research Article ,Methicillin-Resistant Staphylococcus aureus ,Science ,Bacterial diseases ,Bacterial Toxins ,Virulence ,Biology ,Microbiology ,03 medical and health sciences ,Species Specificity ,Virology ,medicine ,Humans ,RNA, Messenger ,030304 developmental biology ,Osteoblasts ,030306 microbiology ,Intracellular parasite ,Gene Expression Regulation, Bacterial ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,Methicillin-resistant Staphylococcus aureus ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Bacterial Load ,Gene Expression Regulation ,Virulence Factors and Mechanisms ,RNA ,Delivery of Health Care - Abstract
International audience; Epidemic community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is associated with more severe and acute forms of osteomyelitis than healthcare-associated (HA-) MRSA. Although S. aureus is now recognized as a facultative intracellular pathogen, the contribution of osteoblast invasion by CA-MRSA to the pathogenesis of osteomyelitis is unknown. Using an ex vivo model of intracellular infection of human osteoblasts, we demonstrated that CA-MRSA strains of diverse lineages share an enhanced ability to kill infected osteoblasts compared to HA-MRSA. Cytotoxicity comparisons of CA-MRSA isogenic deletion mutants revealed that phenol-soluble modulins (PSMs), a class of membrane-damaging exoproteins that are expressed at higher levels in CA-MRSA than in HA-MRSA, are involved in this osteoblast killing, whereas other major CA-MRSA virulence determinants, the Panton-Valentine leukocidin and alpha-toxin, are not involved. Similarly, functional agr and sarA regulators, which control the expression of PSMs and alpha-toxin, were required for the expression of the intracellular cytotoxic phenotype by CA-MRSA, whereas the saeRS regulator, which controls the expression of alpha-toxin but not PSMs, had no impact on cytotoxicity. Finally, PSM transcript levels determined by quantitative reverse-transcriptase PCR were significantly higher in CA-MRSA than in HA-MRSA strains and associated with cell damage in MRSA-infected osteoblasts. These findings provide new insights into the pathogenesis of severe CA-MRSA osteomyelitis and unravel a novel virulence strategy of CA-MRSA, based on the invasion and subsequent killing of osteoblasts by PSMs acting as intracellular toxins.
- Published
- 2013
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