The alternative sigma factor σ^B plays a crucial role in adaptive strategies of Clostridium difficile during gut infection

Abstract

Clostridium difficile is a major cause of diarrhoea associated with antibiotherapy. Exposed to stresses in the gut, C. difficile can survive by inducing protection, detoxification and repair systems. In several firmicutes, most of these systems are controlled by the general stress response involving σ . In this work, we studied the role of σ in the physiopathology of C. difficile. We showed that the survival of the sigB mutant during the stationary phase was reduced. Using a transcriptome analysis, we showed that σ controls the expression of ∼25% of genes including genes involved in sporulation, metabolism, cell surface biogenesis and the management of stresses. By contrast, σ does not control toxin gene expression. In agreement with the up-regulation of sporulation genes, the sporulation efficiency is higher in the sigB mutant than in the wild-type strain. sigB inactivation also led to increased sensitivity to acidification, cationic antimicrobial peptides, nitric oxide and ROS. In addition, we showed for the first time that σ also plays a crucial role in oxygen tolerance in this strict anaerobe. Finally, we demonstrated that the fitness of colonisation by the sigB mutant is greatly affected in a dixenic mouse model of colonisation when compared to the wild-type strain.

Clostridium difficile: A bad bug goes into defensive mode

“…tryptone‐yeast extract (TY)] used to propagate C. difficile . However, the survival rate of the sigB mutant in TY medium was much more strongly impaired then its isogenic sigB + parent strain (Kint et al ., ), consistent with the function of SigB as a stationary phase sigma factor. Kint et al .…”

“…Importantly, Kint et al . () found that SigB does not affect the expression of the genes for the TcdA and TcdB toxins present in the strain they studied. Hence, SigB influences pathophysiology and gut colonization by C. difficile in ways that are different from those afforded by the TcdA and TcdB virulence factors (Aktories, ; Abt et al ., ; Janoir, ; Martin‐Verstraete et al ., ).…”

“…The major aim of the study directed by Isabelle Martin‐Verstraete (Institut Pasteur & Universite Paris Diderot; France) on the role played by SigB during gut infections by C. difficile was to elucidate processes and regulatory circuits that allow this pathogen to induce protective, detoxification, and repair systems to foster its survival in the gut (Kint et al ., ). To this end, Kint et al .…”

“…The authors have complemented these studies by exploring the ability of the sigB mutant to colonize the intestinal tract of mice. Taken together, the data derived from these studies provide solid support for the notion that SigB and members of the general stress regulon are critically involved, in a multi‐factorial manner, in the colonization of the intestinal tract by C. difficile and the management of different types of stresses the enteropathogen might encounter in this environment (Kint et al ., ). Importantly, Kint et al .…”

“…To this end, Kint et al . () have compared the growth, physiology and transcriptional profile of an isogenic pair of sigB + and sigB mutant strains at the onset of the stationary phase, conditions that lead to the activation of SigB. The authors have complemented these studies by exploring the ability of the sigB mutant to colonize the intestinal tract of mice.…”