Short-Term Genome Stability of Serial Clostridium difficile Ribotype 027 Isolates in an Experimental Gut Model and Recurrent Human Disease

David W. Eyre, A. Sarah Walker, Jane Freeman, Simon D. Baines, Warren N. Fawley, Caroline H. Chilton, David Griffiths, Alison Vaughan, Derrick W. Crook, Tim E.A. Peto, Mark H. Wilcox

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13 Citations (Scopus)

Abstract

Background:Clostridium difficile whole genome sequencing has the potential to identify related isolates, even among otherwise indistinguishable strains, but interpretation depends on understanding genomic variation within isolates and individuals.Methods:Serial isolates from two scenarios were whole genome sequenced. Firstly, 62 isolates from 29 timepoints from three in vitro gut models, inoculated with a NAP1/027 strain. Secondly, 122 isolates from 44 patients (2-8 samples/patient) with mostly recurrent/on-going symptomatic NAP-1/027 C. difficile infection. Reference-based mapping was used to identify single nucleotide variants (SNVs).Results:Across three gut model inductions, two with antibiotic treatment, total 137 days, only two new SNVs became established. Pre-existing minority SNVs became dominant in two models. Several SNVs were detected, only present in the minority of colonies at one/two timepoints. The median (inter-quartile range) [range] time between patients' first and last samples was 60 (29.5-118.5) [0-561] days. Within-patient C. difficile evolution was 0.45 SNVs/called genome/year (95%CI 0.00-1.28) and within-host diversity was 0.28 SNVs/called genome (0.05-0.53). 26/28 gut model and patient SNVs were non-synonymous, affecting a range of gene targets.Conclusions:The consistency of whole genome sequencing data from gut model C. difficile isolates, and the high stability of genomic sequences in isolates from patients, supports the use of whole genome sequencing in detailed transmission investigations.

Original languageEnglish
Article numbere63540
JournalPLoS ONE
Volume8
Issue number5
DOIs
Publication statusPublished - 15 May 2013
Externally publishedYes

Bibliographical note

Funding Information:
The institution of DWC and TEAP received per-case funding from Optimer Pharmaceuticals to support fidaxomicin trial patient expenses. DWC and TEAP also received honoraria from Optimer Pharmaceuticals for participation in additional meetings related to investigative planning for fidaxomicin. MHW has received research support from Actelion, Astellas, Biomerieux, Cubist, Pfizer, Summit and The Medicines Company have funded research in the past 2 years. MHW has received consultancies and/or lecture honoraria in the past 2 years from Actelion, Astellas, Astra-Zeneca, Bayer, Cubist, Durata, J&J, Merck, Nabriva, Novacta, Novartis, Optimer, Pfizer, Sanofi-Pasteur, The Medicines Company, VH Squared, Viropharma. No other author has any conflict of interest. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

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