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Open Access Highly Accessed Research article

Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism

Laura J Pettit1, Hilary P Browne1, Lu Yu1, Wiep Klaas Smits2, Robert P Fagan3, Lars Barquist14, Melissa J Martin1, David Goulding1, Sylvia H Duncan5, Harry J Flint5, Gordon Dougan1, Jyoti S Choudhary1 and Trevor D Lawley16*

  • * Corresponding author: Trevor D Lawley tl2@sanger.ac.uk

  • † Equal contributors

Author Affiliations

1 Wellcome Trust Sanger Institute, Hinxton, UK

2 Department of Medical Microbiology, Leiden University Medical Centre, Leiden, The Netherlands

3 Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK

4 European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK

5 Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK

6 Bacterial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK

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BMC Genomics 2014, 15:160  doi:10.1186/1471-2164-15-160

Published: 25 February 2014

Abstract

Background

Clostridium difficile is an anaerobic, Gram-positive bacterium that can reside as a commensal within the intestinal microbiota of healthy individuals or cause life-threatening antibiotic-associated diarrhea in immunocompromised hosts. C. difficile can also form highly resistant spores that are excreted facilitating host-to-host transmission. The C. difficile spo0A gene encodes a highly conserved transcriptional regulator of sporulation that is required for relapsing disease and transmission in mice.

Results

Here we describe a genome-wide approach using a combined transcriptomic and proteomic analysis to identify Spo0A regulated genes. Our results validate Spo0A as a positive regulator of putative and novel sporulation genes as well as components of the mature spore proteome. We also show that Spo0A regulates a number of virulence-associated factors such as flagella and metabolic pathways including glucose fermentation leading to butyrate production.

Conclusions

The C. difficile spo0A gene is a global transcriptional regulator that controls diverse sporulation, virulence and metabolic phenotypes coordinating pathogen adaptation to a wide range of host interactions. Additionally, the rich breadth of functional data allowed us to significantly update the annotation of the C. difficile 630 reference genome which will facilitate basic and applied research on this emerging pathogen.

Keywords:
Clostridium difficile; Spo0A; RNAseq; Proteomics; Sporulation; Virulence; Metabolism; Butyrate; Transmission; Genome annotation