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 under...

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Bibliographic Details
Published in:PLoS pathogens 2017-02, Vol.13 (2), p.e1006153-e1006153
Main Authors: Qin, Li, Da, Fei, Fisher, Emilie L, Tan, Daniel C S, Nguyen, Thuan H, Fu, Chih-Lung, Tan, Vee Y, McCausland, Joshua W, Sturdevant, Daniel E, Joo, Hwang-Soo, Queck, Shu Y, Cheung, Gordon Y C, Otto, Michael
Format: Article
Language:English
Subjects:
Animals
Bacterial Toxins - toxicity
Bacteriology
Biology and Life Sciences
Causes of
Colleges & universities
Cytokines
Disease Models, Animal
Epidermis
Female
Humans
Infections
Infectious diseases
Laboratories
Medicine and Health Sciences
Methicillin Resistance
Mice
Mice, Inbred C57BL
Mortality
Oligonucleotide Array Sequence Analysis
Pathogenesis
Pathogens
Real-Time Polymerase Chain Reaction
Risk factors
Sepsis
Staphylococcal infections
Staphylococcal Infections - microbiology
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus epidermidis - pathogenicity
Virulence - physiology
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1006153