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

Laura J Pettit, Hilary P Browne, Lu Yu, Wiep Klaas Smits, Robert P Fagan, Lars Barquist, Melissa J Martin, David Goulding, Sylvia H Duncan, Harry J Flint, Gordon Dougan, Jyoti S Choudhary, Trevor D Lawley

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number160
Number of pages15
JournalBMC Genomics
Volume15
DOIs
Publication statusPublished - 25 Feb 2014

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Clostridium difficile
Genomics
Virulence
Spores
Genes
Genome
Flagella
Butyrates
Immunocompromised Host
Gram-Positive Bacteria
Virulence Factors
Proteome
Metabolic Networks and Pathways
Proteomics
Fermentation
Diarrhea
Anti-Bacterial Agents
Phenotype
Glucose
Research

Cite this

Pettit, L. J., Browne, H. P., Yu, L., Smits, W. K., Fagan, R. P., Barquist, L., ... Lawley, T. D. (2014). Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism. BMC Genomics, 15, [160]. https://doi.org/10.1186/1471-2164-15-160

Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism. / Pettit, Laura J; Browne, Hilary P; Yu, Lu; Smits, Wiep Klaas; Fagan, Robert P; Barquist, Lars; Martin, Melissa J; Goulding, David; Duncan, Sylvia H; Flint, Harry J; Dougan, Gordon; Choudhary, Jyoti S; Lawley, Trevor D.

In: BMC Genomics, Vol. 15, 160, 25.02.2014.

Research output: Contribution to journalArticle

Pettit, LJ, Browne, HP, Yu, L, Smits, WK, Fagan, RP, Barquist, L, Martin, MJ, Goulding, D, Duncan, SH, Flint, HJ, Dougan, G, Choudhary, JS & Lawley, TD 2014, 'Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism', BMC Genomics, vol. 15, 160. https://doi.org/10.1186/1471-2164-15-160
Pettit, Laura J ; Browne, Hilary P ; Yu, Lu ; Smits, Wiep Klaas ; Fagan, Robert P ; Barquist, Lars ; Martin, Melissa J ; Goulding, David ; Duncan, Sylvia H ; Flint, Harry J ; Dougan, Gordon ; Choudhary, Jyoti S ; Lawley, Trevor D. / Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism. In: BMC Genomics. 2014 ; Vol. 15.
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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.",
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AU - Pettit, Laura J

AU - Browne, Hilary P

AU - Yu, Lu

AU - Smits, Wiep Klaas

AU - Fagan, Robert P

AU - Barquist, Lars

AU - Martin, Melissa J

AU - Goulding, David

AU - Duncan, Sylvia H

AU - Flint, Harry J

AU - Dougan, Gordon

AU - Choudhary, Jyoti S

AU - Lawley, Trevor D

N1 - This project was funded by the Wellcome Trust (grants 098051 and 086418) and a Medical Research Council New Investigator Research Grant (TDL; grant 93614). HJF and SHD receive support from the Scottish Government Food, Land and People programme. WKS was supported by a Gisela Thier Fellowship and a VENI fellowship of the Netherlands Organisation for Scientific Research (NWO-ZonMW).

PY - 2014/2/25

Y1 - 2014/2/25

N2 - 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.

AB - 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.

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