PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts.
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 invasi...
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2013
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oai:doaj.org-article:615951f176744a948d2105ac0c9b85342021-11-18T07:45:53ZPSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts.1932-620310.1371/journal.pone.0063176https://doaj.org/article/615951f176744a948d2105ac0c9b85342013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23690994/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Epidemic 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.Jean-Philippe RasigadeSophie Trouillet-AssantTristan FerryBinh An DiepAnaïs SapinYannick LhosteJérémy RanfaingCédric BadiouYvonne BenitoMichèle BesFlorence CouzonSylvestre TigaudGérard LinaJérôme EtienneFrançois VandeneschFrédéric LaurentPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e63176 (2013) |
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DOAJ |
| collection |
DOAJ |
| language |
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| topic |
Medicine R Science Q |
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Medicine R Science Q Jean-Philippe Rasigade Sophie Trouillet-Assant Tristan Ferry Binh An Diep Anaïs Sapin Yannick Lhoste Jérémy Ranfaing Cédric Badiou Yvonne Benito Michèle Bes Florence Couzon Sylvestre Tigaud Gérard Lina Jérôme Etienne François Vandenesch Frédéric Laurent PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. |
| description |
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. |
| format |
article |
| author |
Jean-Philippe Rasigade Sophie Trouillet-Assant Tristan Ferry Binh An Diep Anaïs Sapin Yannick Lhoste Jérémy Ranfaing Cédric Badiou Yvonne Benito Michèle Bes Florence Couzon Sylvestre Tigaud Gérard Lina Jérôme Etienne François Vandenesch Frédéric Laurent |
| author_facet |
Jean-Philippe Rasigade Sophie Trouillet-Assant Tristan Ferry Binh An Diep Anaïs Sapin Yannick Lhoste Jérémy Ranfaing Cédric Badiou Yvonne Benito Michèle Bes Florence Couzon Sylvestre Tigaud Gérard Lina Jérôme Etienne François Vandenesch Frédéric Laurent |
| author_sort |
Jean-Philippe Rasigade |
| title |
PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. |
| title_short |
PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. |
| title_full |
PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. |
| title_fullStr |
PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. |
| title_full_unstemmed |
PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. |
| title_sort |
psms of hypervirulent staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/615951f176744a948d2105ac0c9b8534 |
| work_keys_str_mv |
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1718422974017568768 |