Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027) Clostridioides difficile

Qiwen Dong; Huaiying Lin; Marie-Maude Allen; Julian R Garneau; Jonathan K Sia; Rita C Smith; Fidel Haro; Tracy McMillen; Rosemary L Pope; Carolyn Metcalfe; Victoria Burgo; Che Woodson; Nicholas Dylla; Claire Kohout; Anitha Sundararajan; Evan S Snitkin; Vincent B Young; Louis-Charles Fortier; Mini Kamboj; Eric G Pamer

doi:10.1016/j.celrep.2023.112861

Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027) Clostridioides difficile

Cell Rep. 2023 Aug 29;42(8):112861. doi: 10.1016/j.celrep.2023.112861. Epub 2023 Jul 30.

Authors

Qiwen Dong¹, Huaiying Lin², Marie-Maude Allen³, Julian R Garneau³, Jonathan K Sia⁴, Rita C Smith², Fidel Haro², Tracy McMillen⁵, Rosemary L Pope⁶, Carolyn Metcalfe², Victoria Burgo², Che Woodson², Nicholas Dylla², Claire Kohout², Anitha Sundararajan², Evan S Snitkin⁷, Vincent B Young⁸, Louis-Charles Fortier³, Mini Kamboj⁵, Eric G Pamer⁹

Affiliations

¹ Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA. Electronic address: qiwendong0721@gmail.com.
² Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA.
³ Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
⁴ Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁵ Infection Control, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁶ Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
⁷ Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
⁹ Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.

Abstract

Clostridioides difficile produces toxins that damage the colonic epithelium, causing colitis. Variation in disease severity is poorly understood and has been attributed to host factors and virulence differences between C. difficile strains. We test 23 epidemic ST1 C. difficile clinical isolates for their virulence in mice. All isolates encode a complete Tcd pathogenicity locus and achieve similar colonization densities. However, disease severity varies from lethal to avirulent infections. Genomic analysis of avirulent isolates reveals a 69-bp deletion in the cdtR gene, which encodes a response regulator for binary toxin expression. Deleting the 69-bp sequence in virulent R20291 strain renders it avirulent in mice with reduced toxin gene transcription. Our study demonstrates that a natural deletion within cdtR attenuates virulence in the epidemic ST1 C. difficile isolates without reducing colonization and persistence. Distinguishing strains on the basis of cdtR may enhance the specificity of diagnostic tests for C. difficile colitis.

Keywords: C. difficile; CDT; CP: Microbiology; RT027; ST1; binary toxin; clinical isolates; prophage; toxins; virulence.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Bacterial Proteins / genetics
Bacterial Proteins / metabolism
Clostridioides / metabolism
Clostridioides difficile* / genetics
Colitis* / genetics
Genomics
Mice
Virulence / genetics

Substances

nucleic acid probe 1
Bacterial Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding