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Hype or hypervirulence: a reflection on problematic C. difficile strains.

ABSTRACT: Clostridium difficile infections (CDI) have emerged as a major cause of healthcare associated disease, and recent epidemiological evidence also suggests an important role in community-acquired diarrhea. This increase is associated with specific types, especially PCR ribotypes 027 and 078, which are sometimes referred to as "hypervirulent". Over the past years major advances have been made in our understanding of C. difficile pathogenicity, with the identification and characterization of the major clostridial toxins TcdA and TcdB. However, the relation between the toxins, their regulation, and "hypervirulence" remain unclear. Here I review our current understanding of C. difficile pathogenicity and argue that "hypervirulent" is an inadequate term to describe PCR ribotypes 027 and 078, that the ability of C. difficile to cause problematic infections is a consequence of a multifactorial process that extends beyond toxins, sporulation, and antimicrobial resistance, and that vigilance is in order toward types that are closely related to ribotypes 027 and 078, but are currently not considered problematic.

SUBMITTER: Smits WK

PROVIDER: S-EPMC3906292 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Hype or hypervirulence: a reflection on problematic C. difficile strains.

Smits Wiep Klaas WK

Virulence 20130910 7

Clostridium difficile infections (CDI) have emerged as a major cause of healthcare associated disease, and recent epidemiological evidence also suggests an important role in community-acquired diarrhea. This increase is associated with specific types, especially PCR ribotypes 027 and 078, which are sometimes referred to as "hypervirulent". Over the past years major advances have been made in our understanding of C. difficile pathogenicity, with the identification and characterization of the majo ...[more]

PMID: 24060961

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Project description:Clostridiodes difficile (C. difficile) was ranked an "urgent threat" by the Centers for Disease Control and Prevention (CDC) in 2019. C. difficile infection (CDI) is the most common healthcare-associated infection (HAI) in the United States of America as well as the leading cause of antibiotic-associated gastrointestinal disease. C. difficile is a gram-positive, rod-shaped, spore-forming, anaerobic bacterium that causes infection of the epithelial lining of the gut. CDI occurs most commonly after disruption of the human gut microflora following the prolonged use of broad-spectrum antibiotics. However, the recurrent nature of this disease has led to the hypothesis that biofilm formation may play a role in its pathogenesis. Biofilms are sessile communities of bacteria protected from extracellular stresses by a matrix of self-produced proteins, polysaccharides, and extracellular DNA. Biofilm regulation in C. difficile is still incompletely understood, and its role in disease recurrence has yet to be fully elucidated. However, many factors have been found to influence biofilm formation in C. difficile, including motility, adhesion, and hydrophobicity of the bacterial cells. Small changes in one of these systems can greatly influence biofilm formation. Therefore, the biofilm regulatory system would need to coordinate all these systems to create optimal biofilm-forming physiology under appropriate environmental conditions. The coordination of these systems is complex and multifactorial, and any analysis must take into consideration the influences of the stress response, quorum sensing (QS), and gene regulation by second messenger molecule cyclic diguanosine monophosphate (c-di-GMP). However, the differences in biofilm-forming ability between C. difficile strains such as 630 and the "hypervirulent" strain, R20291, make it difficult to assign a "one size fits all" mechanism to biofilm regulation in C. difficile. This review seeks to consolidate published data regarding the regulation of C. difficile biofilms in order to identify gaps in knowledge and propose directions for future study.

Project description:BACKGROUND:The hypervirulent Clostridium difficile ribotype 027 can be classified into subtypes, but it unknown if these differ in terms of severity of C. difficile infection (CDI). Genomic studies of C. difficile 027 strains have established that they are rich in mobile genetic elements including prophages. This study combined physiological studies, electron microscopy analysis and molecular biology to determine the potential role of temperate bacteriophages in disease and diversity of C. difficile 027. METHODOLOGY/PRINCIPAL FINDINGS:We induced prophages from 91 clinical C. difficile 027 isolates and used transmission electron microscopy and pulsed-field gel electrophoresis to characterise the bacteriophages present. We established a correlation between phage morphology and subtype. Morphologically distinct tailed bacteriophages belonging to Myoviridae and Siphoviridae were identified in 63 and three isolates, respectively. Dual phage carriage was observed in four isolates. In addition, there were inducible phage tail-like particles (PT-LPs) in all isolates. The capacity of two antibiotics mitomycin C and norfloxacin to induce prophages was compared and it was shown that they induced specific prophages from C. difficile isolates. A PCR assay targeting the capsid gene of the myoviruses was designed to examine molecular diversity of C. difficile myoviruses. Phylogenetic analysis of the capsid gene sequences from eight ribotypes showed that all sequences found in the ribotype 027 isolates were identical and distinct from other C. difficile ribotypes and other bacteria species. CONCLUSION/SIGNIFICANCE:A diverse set of temperate bacteriophages are associated with C. difficile 027. The observed correlation between phage carriage and the subtypes suggests that temperate bacteriophages contribute to the diversity of C. difficile 027 and may play a role in severity of disease associated with this ribotype. The capsid gene can be used as a tool to identify C. difficile myoviruses present within bacterial genomes.

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Hype or hypervirulence: a reflection on problematic C. difficile strains.

Publications

Hype or hypervirulence: a reflection on problematic C. difficile strains.

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