The Contribution of Bacteriophages to the Biology and Virulence of Pathogenic Clostridia

Bacteriophages are key players in the evolution of most bacteria. Temperate phages have been associated with virulence of some of the deadliest pathogenic bacteria. Among the most notorious cases, the genes encoding the botulinum neurotoxin produced by Clostridium botulinum types C and D and the α-toxin (TcnA) produced by Clostridium novyi are both encoded within prophage genomes. Clostridium difficile is another important human pathogen and the recent identification of a complete binary toxin locus (CdtLoc) carried on a C. difficile prophage raises the potential for horizontal transfer of toxin genes by mobile genetic elements. Although the TcdA and TcdB toxins produced by C. difficile have never been found outside the pathogenicity locus (PaLoc), some prophages can still influence their production. Prophages can alter the expression of several metabolic and regulatory genes in C. difficile, as well as cell surface proteins such as CwpV, which confers phage resistance. Homologs of an Agr-like quorum sensing system have been identified in a C. difficile prophage, suggesting that it could possibly participate in cell-cell communication. Yet, other C. difficile prophages contain riboswitches predicted to recognize the secondary messenger molecule c-di-GMP involved in bacterial multicellular behaviors. Altogether, recent findings on clostridial phages underline the diversity of mechanisms and intricate relationship linking phages with their host. Here, milestone discoveries linking phages and virulence of some of the most pathogenic clostridial species will be retraced, with a focus on C. botulinum, C. novyi, C. difficile, and Clostridium perfringens phages, for which evidences are mostly available.