Autoinducing peptide-based quorum signaling systems in Clostridioides difficile

Abstract

The autoinducing peptide-based Agr system in Clostridioides difficile is involved in virulence factor expression, motility, and sporulation. This review highlights several of the recent discoveries regarding C. difficile Agr. Typical Agr systems rely on the combined activities of four proteins involved in peptide expression, peptide processing, peptide sensing, and transcriptional regulation. As emphasized in this review, at least two C. difficile Agr systems (Agr1 and Agr3) lack the set of proteins associated with this regulatory network. In line with this, recent finding indicate Agr1 can function in ways that may not depend on accumulation of extracellular peptide. Also, described are the similarities and differences in Agr systems within the pathogenic Clostridia.

Fig. 1.. The prototypical four-protein Agr system in comparison to C. difficile Agr systems.

The agr locus encodes for four genes- agrB, agrD, agrC, and agrA that express a transmembrane protease AgrB, a peptide AgrD, a histidine kinase AgrC, and a response regulator AgrA, respectively. The transmembrane protease AgrB processes the AgrD peptide into a mature AIP. Mature AIP is secreted to the extracellular milieu to bind to and activate the membrane-bound AgrC. Activated AgrC then activates AgrA, which binds to the P2 and P3 promoter to induce transcription of the agr locus genes and the small regulatory RNA, RNAIII. As shown in the image, in comparison to the typical Agr system found in S. aureus, various strains of C. difficile utilize variations of the Agr system that lack a known RNAIII and do not contain the entire suite of genes typically associated with Agr (Created with inkscape.org)

Fig. 2.. agr loci in C. difficile and in other Clostridia.

A. sequence homology and organization of the agr genes vary among C. difficile agr loci. B. The C. acetobutylicum agr and C. difficile agr2 encode for a complete Agr system. The agr loci in C. perfringens, C. botulinum, C. difficile agr1 encode for only AgrB (transmembrane protease) and AgrD (peptide), and C. difficile agr3 locus lacks gene encoding the response regulator. HG, hypothetical gene. (Created with geneious.com)