Abstract
Clostridium difficile, a Gram positive, anaerobic, spore-forming bacterium is an emergent pathogen and the most common cause of nosocomial diarrhea. Although transmission of C. difficile is mediated by contamination of the gut by spores, the regulatory cascade controlling spore formation remains poorly characterized. During Bacillus subtilis sporulation, a cascade of four sigma factors, σF and σG in the forespore and σE and σK in the mother cell governs compartment-specific gene expression. In this work, we combined genome wide transcriptional analyses and promoter mapping to define the C. difficile σF, σE, σG and σK regulons. We identified about 225 genes under the control of these sigma factors: 25 in the σF regulon, 97 σE-dependent genes, 50 σG-governed genes and 56 genes under σK control. A significant fraction of genes in each regulon is of unknown function but new candidates for spore coat proteins could be proposed as being synthesized under σE or σK control and detected in a previously published spore proteome. SpoIIID of C. difficile also plays a pivotal role in the mother cell line of expression repressing the transcription of many members of the σE regulon and activating sigK expression. Global analysis of developmental gene expression under the control of these sigma factors revealed deviations from the B. subtilis model regarding the communication between mother cell and forespore in C. difficile. We showed that the expression of the σE regulon in the mother cell was not strictly under the control of σF despite the fact that the forespore product SpoIIR was required for the processing of pro-σE. In addition, the σK regulon was not controlled by σG in C. difficile in agreement with the lack of pro-σK processing. This work is one key step to obtain new insights about the diversity and evolution of the sporulation process among Firmicutes.
Highlights
Clostridium difficile, a Gram positive, anaerobic, spore-forming bacterium is a major cause of nosocomial infections associated with antibiotic therapy and is a major burden to health care services
[15,17,18,20] involves a smaller collection of proteins. This has already been observed for the initiation of sporulation where the complex signaling transduction pathway involving in B. subtilis a phosphorelay that modulates Spo0A activity is replaced by a simple two-component system [18,20,29]
The most significant variations between the B. subtilis and C. difficile sporulation process are observed at the interface with their environment: the signal transduction pathway triggering sporulation initiation, composition of the coat shell and the germinationactivating pathways [16,18,20,47]
Summary
Clostridium difficile, a Gram positive, anaerobic, spore-forming bacterium is a major cause of nosocomial infections associated with antibiotic therapy and is a major burden to health care services. This enteropathogen can lead to antibiotic-associated diarrhea and pseudo-membranous colitis, a potentially lethal disease. The enterotoxin TcdA and the cytotoxin TcdB are the main virulence factors required for the development of symptoms of C. difficile infection (CDI). Transmission of C. difficile is further mediated by contamination of the gut by spores as demonstrated recently using a murine model for CDI [1,2]. The molecular mechanisms involved in sporulation and germination are still poorly studied in C. difficile and our current knowledge on these processes is based mainly on data derived from the studies on Bacillus subtilis
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