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Author Notes:

E-mail address: Rita_tamayo@med.unc.edu

We thank the University of North Carolina (UNC) Microscopy Services Laboratory for assistance with SEM.

Subjects:

Research Funding:

This work was supported by National Institutes of Health awards AI107029 and AI143638 to RT, AI116933 and AI121684 to SMM.

OS is supported by a postdoctoral training fellowship from the Canadian Institutes of Health Research (CIHR).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Biology
  • Life Sciences & Biomedicine - Other Topics
  • ESCHERICHIA-COLI
  • LISTERIA-MONOCYTOGENES
  • POPULATION HETEROGENEITY
  • BORDETELLA-PERTUSSIS
  • TOXIN PRODUCTION
  • EXPRESSION
  • PROTEIN
  • GENE
  • IDENTIFICATION
  • SPORULATION

Phase variation of a signal transduction system controls Clostridioides difficile colony morphology, motility, and virulence

Journal Title:

PLoS Biology

Volume:

Volume 17, Number 10

Publisher:

, Pages e3000379-e3000379

Type of Work:

Article | Final Publisher PDF

Abstract:

Recent work has revealed that Clostridioides difficile, a major cause of nosocomial diarrheal disease, exhibits phenotypic heterogeneity within a clonal population as a result of phase variation. Many C. difficile strains representing multiple ribotypes develop two colony morphotypes, termed rough and smooth, but the biological implications of this phenomenon have not been explored. Here, we examine the molecular basis and physiological relevance of the distinct colony morphotypes produced by this bacterium. We show that C. difficile reversibly differentiates into rough and smooth colony morphologies and that bacteria derived from the isolates display discrete motility behaviors. We identified an atypical phase-variable signal transduction system consisting of a histidine kinase and two response regulators, named herein colony morphology regulators RST (CmrRST), which mediates the switch in colony morphology and motility behaviors. The CmrRST-regulated surface motility is independent of flagella and type IV pili, suggesting a novel mechanism of cell migration in C. difficile. Microscopic analysis of cell and colony structure indicates that CmrRST promotes the formation of elongated bacteria arranged in bundled chains, which may contribute to bacterial migration on surfaces. In a hamster model of acute C. difficile disease, the CmrRST system is required for disease development. Furthermore, we provide evidence that CmrRST phase varies during infection, suggesting that the intestinal environment impacts the proportion of CmrRST-expressing C. difficile. Our findings indicate that C. difficile employs phase variation of the CmrRST signal transduction system to generate phenotypic heterogeneity during infection, with concomitant effects on bacterial physiology and pathogenesis.

Copyright information:

© 2019 Garrett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. CC BY 4.0

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