The clostridia are Gram-positive, chemoorganotrophic, mainly obligate anaerobes that are found in a wide range of environments and can form heat-stable endospores. The genus includes important human pathogens, such as the food pathogen Clostridium botulinum and Clostridium difficile, a cause of healthcare-associated infections; cellulolytic strains, such as Clostridium thermocellum; and solventogenic strains such as Clostridium acetobutylicum.
The complete genome sequences for three clostridia species — C. acetobutylicum ATCC 824, Clostridium perfringens strain 13 and Clostridium tetani E88 — have been published, the genomes of two more — C. difficile strain 630 and Clostridium botulinum Hall strain A (ATCC 3502) — have been completed although the annotation has not been finished, and genome-sequence data from two additional C. perfringens strains in the form of contigs are also readily available. Here, we use these genome-sequence data and recent results from transcriptomics to give a comparative genomics perspective on clostridial physiology and sporulation, with reference to the model endospore-forming organism Bacillus subtilis.
In B. subtilis, the sporulation programme is initiated in response to various extracellular and intracellular signals. The signals are sensed by a phosphorelay system comprising five sensory histidine kinases (KinA–KinE), which phosphorylate the sporulation initiation phosphotransferase Spo0F, the response regulator Spo0B and the master regulator Spo0A, in turn. The genome-sequence data indicate that, with some exceptions, the clostridia largely share the key genes downstream of Spo0A, but there is little conservation of the genes involved in the upper part of the sporulation cascade (the sensory histidine kinases through the phosphorelay).
This leads to the question of how Spo0A is phosphorylated in the clostridia. Three different, and not necessarily mutually exclusive, models have been proposed. These are all considered in light of the available genomic and transcriptomic data, and plausible candidate kinases are identified.
The stress response is also considered. B. subtilis contains four classes of stress proteins; the available genomic data indicate that the clostridia contain only classes I, III and IV, and not class II, and DNA microarray studies have also indicated that stress-gene expression might not be necessary for sporulation.
In B. subtilis, motility and chemotaxis show reciprocal regulation with sporulation, and the same appears to be true in the clostridia species analysed. The interesting observation that asporogenous, non-solventogenic mutants of C. acetobutylicum have impaired or no motility has led to the suggestion that Spo0A could directly or indirectly regulate glycosytransferases, and this is an interesting area for further study.
To date, progress in clostridial genetics and genomics has been much slower than in the bacilli. However, this article demonstrates the insights that can be gained by using the publicly available genome-sequence data. Additionally, recent publications (mostly on bacilli, but a few on clostridia) have demonstrated that DNA microarrays and other transcriptomic analyses such as ChIP-on-chip studies can also be used to great effect. The small size of the clostridial research community has been a disadvantage in the past. As this analysis has shown that the pathogenic and non-pathogenic clostridia have much in common, perhaps now it can be turned to an advantage, and clostridial researchers from different fields can come together to form research consortia and useful databases that will allow a detailed description of the regulatory network in a model clostridium to be delineated.
Clostridia are anaerobic, endospore-forming prokaryotes that include strains of importance to human and animal health and physiology, cellulose degradation, solvent production and bioremediation. Their differentiation and related developmental programmes are not well understood at the molecular level. Recent genome sequencing and transcriptional-profiling studies have offered a glimpse of their inner workings and indicate that a better understanding of the orchestration of the molecular events that underlie their unique physiology, capabilities and diversity will pay major dividends.
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This work was supported by National Science Foundation (USA) grants, a US Department of Energy grant and an NIH/NIGMS Biotechnology Training Grant fellowship to K.V.A. C. difficile and C. botulinum sequence data were generated by the Wellcome Trust Sanger Institute Pathogen Sequencing Unit, and can be obtained from http://www.sanger.ac.uk/Projects/C_difficile and http://www.sanger.ac.uk/Projects/C_botulinum. We thank M. Jankowski from V. Hatzimanikatis' group at Northwestern University from his calculations on the ΔGo of hydrolysis of BuP.
The authors declare no competing financial interests.
- ANTI-σ FACTOR
A negative transcriptional regulator that acts by binding to a σ factor and inhibiting its activity. An anti-anti-σ factor, in turn, counteracts the action of an anti-σ factor.
A small compartment that is formed after asymmetric division. It is sometimes used specifically for the small compartment after completion of engulfment.
- MOTHER CELL
The large compartment in which the spore develops.
- Z RING
The ring-shaped structure that is formed from FtsZ polymers during cell division. The Z ring recruits proteins that are required for septal-wall synthesis and cell division.
Equivalent to the forespore, but sometimes used specifically for the small compartment before completion of engulfment.
The combination of chromatin immunoprecipitation (ChIP) with microarray (DNA 'chip') analysis for the high-throughput detection of immunoprecipitated DNA fragments. This method has been applied to the determination of the DNA-binding sites of a transcription factor at the genome level.
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Paredes, C., Alsaker, K. & Papoutsakis, E. A comparative genomic view of clostridial sporulation and physiology. Nat Rev Microbiol 3, 969–978 (2005). https://doi.org/10.1038/nrmicro1288
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