Phenol-Soluble Modulins Contribute to Early Sepsis Dissemination Not Late Local USA300-Osteomyelitis Severity in Rabbits.
BACKGROUND
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 α-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.


METHODS
We compared the outcomes of experimental rabbit osteomyelitises induced with pvl+hla+psms+ LAC WT and its isogenic Δpsm derivatives (LAC Δpsmα and LAC Δpsmαβhld) 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 Δpsm derivatives (Kaplan-Meier curves, P = .06). Non-survivors' bone LAC-Δpsmα (6.9 log10 CFUs/g of bone, P = .04) or -Δpsmαβhld (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 Δpsmαβhld CFUs were significantly lower than LAC WT (P = .04). LAC Δpsmα, Δpsmαβhld 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 Δpsmα- and Δpsmαβhld-infected rabbits compared to LAC WT (P = .04 and .01, respectively) but with comparable lung bacterial densities.


CONCLUSIONS
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.
Département de Médecine Aigüe Spécialisée, Hôpital Universitaire Raymond-Poincaré, Assistance Publique-Hôpitaux de Paris, Garches, and EA 3647, Faculté de Médecine Paris-Île-de-France Ouest, Université Versailles-Saint-Quentin, Versailles, France.
Benjamin
B
Davido
Département de Médecine Aigüe Spécialisée, Hôpital Universitaire Raymond-Poincaré, Assistance Publique-Hôpitaux de Paris, Garches, and EA 3647, Faculté de Médecine Paris-Île-de-France Ouest, Université Versailles-Saint-Quentin, Versailles, France.
Azzam
A
Saleh-Mghir
CIRI, International Center for Infectiology Research, Inserm U1111-CNRS UMR5308, ENS Lyon-Université Lyon 1, Hospices Civils de Lyon, Lyon, France.
Frédéric
F
Laurent
Département de Pathologie, UFR de Médecine Paris 7, site Bichat, Paris, France.
Claire
C
Danel
CIRI, International Center for Infectiology Research, Inserm U1111-CNRS UMR5308, ENS Lyon-Université Lyon 1, Hospices Civils de Lyon, Lyon, France.
Florence
F
Couzon
Département de Médecine Aigüe Spécialisée, Hôpital Universitaire Raymond-Poincaré, Assistance Publique-Hôpitaux de Paris, Garches, and EA 3647, Faculté de Médecine Paris-Île-de-France Ouest, Université Versailles-Saint-Quentin, Versailles, France.
Laure
L
Gatin
CIRI, International Center for Infectiology Research, Inserm U1111-CNRS UMR5308, ENS Lyon-Université Lyon 1, Hospices Civils de Lyon, Lyon, France.
François
F
Vandenesch
CIRI, International Center for Infectiology Research, Inserm U1111-CNRS UMR5308, ENS Lyon-Université Lyon 1, Hospices Civils de Lyon, Lyon, France.
Jean-Philippe
JP
Rasigade
Département de Médecine Aigüe Spécialisée, Hôpital Universitaire Raymond-Poincaré, Assistance Publique-Hôpitaux de Paris, Garches, and EA 3647, Faculté de Médecine Paris-Île-de-France Ouest, Université Versailles-Saint-Quentin, Versailles, France.
Anne-Claude
AC
Crémieux
D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D055624:Methicillin-Resistant Staphylococcus aureus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D010019:Osteomyelitis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011817:Rabbits; D018805:Sepsis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D013203:Staphylococcal Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology
D001427:Bacterial Toxins