Toxin Mediates Sepsis Caused by Methicillin-Resistant Staphylococcus epidermidis.
Bacterial sepsis is a major killer in hospitalized patients. Coagulase-negative staphylococci (CNS) with the leading species Staphylococcus epidermidis are the most frequent causes of nosocomial sepsis, with most infectious isolates being methicillin-resistant. However, which bacterial factors underlie the pathogenesis of CNS sepsis is unknown. While it has been commonly believed that invariant structures on the surface of CNS trigger sepsis by causing an over-reaction of the immune system, we show here that sepsis caused by methicillin-resistant S. epidermidis is to a large extent mediated by the methicillin resistance island-encoded peptide toxin, PSM-mec. PSM-mec contributed to bacterial survival in whole human blood and resistance to neutrophil-mediated killing, and caused significantly increased mortality and cytokine expression in a mouse sepsis model. Furthermore, we show that the PSM-mec peptide itself, rather than the regulatory RNA in which its gene is embedded, is responsible for the observed virulence phenotype. This finding is of particular importance given the contrasting roles of the psm-mec locus that have been reported in S. aureus strains, inasmuch as our findings suggest that the psm-mec locus may exert effects in the background of S. aureus strains that differ from its original role in the CNS environment due to originally "unintended" interferences. Notably, while toxins have never been clearly implied in CNS infections, our tissue culture and mouse infection model data indicate that an important type of infection caused by the predominant CNS species is mediated to a large extent by a toxin. These findings suggest that CNS infections may be amenable to virulence-targeted drug development approaches.
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.|Department of Dermatology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
Li
L
Qin
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.|Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Fei
F
Da
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Emilie L
0000-0001-9186-7512
EL
Fisher
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Daniel C S
DC
Tan
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Thuan H
TH
Nguyen
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Chih-Lung
CL
Fu
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Vee Y
VY
Tan
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Joshua W
0000-0001-6585-0506
JW
McCausland
Research Technology Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Hamilton, Montana, United States of America.
Daniel E
DE
Sturdevant
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Hwang-Soo
0000-0003-4668-3225
HS
Joo
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Shu Y
0000-0002-3538-2032
SY
Queck
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Gordon Y C
0000-0003-1796-6058
GY
Cheung
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, Maryland, United States of America.
Michael
0000-0002-2222-4115
M
Otto
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016106:Methicillin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D013203:Staphylococcal Infections / Q000382:microbiology*; D013212:Staphylococcus epidermidis / Q000472:pathogenicity*; D014774:Virulence / Q000502:physiology
D001427:Bacterial Toxins; C025971:staphylococcal delta toxin