Regulation of Clostridioides difficile toxin production

Abstract

Clostridioides difficile produces toxins TcdA and TcdB during infection. Since the severity of the illness is directly correlated with the level of toxins produced, researchers have long been interested in the regulation mechanisms of toxin production. The advent of new genetics and mutagenesis technologies in C. difficile has allowed a slew of new investigations in the last decade, which considerably improved our understanding of this crucial regulatory network. The current body of work shows that the toxin regulatory network overlaps with the regulatory networks of sporulation, motility, and key metabolic pathways. This implies that toxin production is a complicated process initiated by bacteria in response to numerous host factors during infection. We summarize the existing knowledge about the toxin gene regulatory network here.

Figure 1.. Toxin gene regulatory network in response to various stimuli.

TcdR activates the expression of its gene (tcdR) and both toxin genes tcdA and tcdB, while SigD activates the expression of tcdR. The repressors CodY, CcpA, and RstA bind to the promoter-regulatory regions at tcdR. CodY and CcpA also repress tcdA, tcdB directly by binding to their promoter region (not shown). All the other regulatory proteins influence toxin gene transcription indirectly, by regulating tcdR expression. Blue arrowed lines indicate positive controls, while lines ending with a bar across correspond to negative controls. Blue dashed arrows indicate mechanisms that are not fully understood. Enzymatic reactions are marked in red arrows. Abbreviations used: AI-2 (Auto inducers), GTP (Guanosine triphosphate), pGpG (5′-phosphoguanylyl-(3′−5′)-guanosine), c-di-GMP (cyclic di-guanosyl-5′monophosphate), BCCAs (branch chain amino acids), NAD (Nicotinamide adenine dinucleotide), DGCs (Di-Guanylate cyclases), PDEs (Phosphodiesterases).