The Anti-Sigma Factor TcdC Modulates Hypervirulence in an Epidemic BI/NAP1/027 Clinical Isolate of Clostridium difficile

PLoS Pathogens

Despina Kotsanas¹  Grant A. Jenkin¹  Glen P. Carter²  Dena Lyras²  Julian I. Rood²  Pauline M. Howarth²  Kate E. Mackin²  Revathi Govind³  Janice Spencer⁴  Gillian R. Douce⁴  Anthony M. Buckley⁴  Ana Antunes⁵  Bruno Dupuy⁵ 

[1] Department of Infectious Diseases, Southern Health, Monash Medical Centre, Clayton, Victoria, Australia;Department of Microbiology, Monash University, Clayton, Victoria, Australia;Division of Biology, Kansas State University, Manhattan, Kansas, United States of America;Division of Infection and Immunity, FBLS Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom;Laboratoire Pathogenèse des Bactéries Anaérobies, Institut Pasteur, Paris, France

关键词: Clostridium difficile;    Toxins;    Plasmid construction;    Virulence factors;    Hamsters;    Clostridium perfringens;    Infectious disease control;    Nonsense mutation;   

DOI  :  10.1371/journal.ppat.1002317

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Nosocomial infections are increasingly being recognised as a major patient safety issue. The modern hospital environment and associated health care practices have provided a niche for the rapid evolution of microbial pathogens that are well adapted to surviving and proliferating in this setting, after which they can infect susceptible patients. This is clearly the case for bacterial pathogens such as Methicillin Resistant Staphylococcus aureus (MRSA) and Vancomycin Resistant Enterococcus (VRE) species, both of which have acquired resistance to antimicrobial agents as well as enhanced survival and virulence properties that present serious therapeutic dilemmas for treating physicians. It has recently become apparent that the spore-forming bacterium Clostridium difficile also falls within this category. Since 2000, there has been a striking increase in C. difficile nosocomial infections worldwide, predominantly due to the emergence of epidemic or hypervirulent isolates that appear to possess extended antibiotic resistance and virulence properties. Various hypotheses have been proposed for the emergence of these strains, and for their persistence and increased virulence, but supportive experimental data are lacking. Here we describe a genetic approach using isogenic strains to identify a factor linked to the development of hypervirulence in C. difficile. This study provides evidence that a naturally occurring mutation in a negative regulator of toxin production, the anti-sigma factor TcdC, is an important factor in the development of hypervirulence in epidemic C. difficile isolates, presumably because the mutation leads to significantly increased toxin production, a contentious hypothesis until now. These results have important implications for C. difficile pathogenesis and virulence since they suggest that strains carrying a similar mutation have the inherent potential to develop a hypervirulent phenotype.

【 授权许可】

CC BY