Toxin Mediates Sepsis Caused by Methicillin-Resistant Staphylococcus epidermidis

PLoS Pathogens

Fei Da¹  Daniel C. S. Tan²  Gordon Y. C. Cheung³  Vee Y. Tan³  Chih-Lung Fu³  Joshua W. McCausland³  Hwang-Soo Joo³  Emilie L. Fisher³  Michael Otto³  Li Qin³  Thuan H. Nguyen³  Daniel E. Sturdevant³  Shu Y. Queck⁴ 

[1] Department of Dermatology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China;Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, China;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;Research Technology Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Hamilton, Montana, United States of America

关键词: Sepsis;    Staphylococcus epidermidis;    Toxins;    Blood;    Gene regulation;    Neutrophils;    Staphylococcus aureus;    Staphylococcal infection;   

DOI  :  10.1371/journal.ppat.1006153

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY