Abstract
Bacteriophages (phages) are bacterial viruses that parasitize bacteria. They are highly prevalent in nature, with an estimated 1031 viral particles in the whole biosphere, and they outnumber bacteria by at least 10-fold. Hence, phages represent important drivers of bacterial evolution, although our knowledge of the role played by phages in the mammalian gut is still embryonic. Several pathogens owe their virulence to the integrated phages (prophages) they harbor, which encode diverse virulence factors such as toxins. Clostridioides (Clostridium) difficile is an important opportunistic pathogen and several phages infecting this species have been described over the last decade. However, their exact contribution to the biology and virulence of this pathogen remains elusive. Current data have shown that C. difficile phages can alter virulence-associated phenotypes, in particular toxin production, by interfering with bacterial regulatory circuits through crosstalk with phage proteins for example. One phage has also been found to encode a complete binary toxin locus. Multiple regulatory genes have also been identified in phage genomes, suggesting that their impact on the host can be complex and often subtle. In this minireview, the current state of knowledge, major findings, and pending questions regarding C. difficile phages will be presented. In addition, with the apparent role played by phages in the success of fecal microbiota transplantation and the perspective of phage therapy for treatment of recurrent C. difficile infection, it has become even more crucial to understand what C. difficile phages do in the gut, how they impact their host, and how they influence the epidemiology and evolution of this clinically important pathogen.
Highlights
Date of ReleaseFirst C. difficile phage genome to be sequenced The phage repressor RepR was shown to repress transcription of the five PaLoc genes through binding to the tcdR promoter element
The role of prophages in the physiology and virulence of C. difficile is a topic of great interest, considering their prevalence and diversity, and the historical role prophages played in the virulence of other bacterial pathogens (Brüssow et al, 2004; Fortier and Sekulovic, 2013)
One way to investigate the impact of a prophage on its host is to introduce a given temperate phage into a susceptible bacterial host to create a new lysogen and to study various phenotypes in comparison with the parental strain lacking that prophage
Summary
First C. difficile phage genome to be sequenced The phage repressor RepR was shown to repress transcription of the five PaLoc genes through binding to the tcdR promoter element. The presence of partition genes like parA has been reported in other phages, including phiCD6356 (Horgan et al, 2010), φCD38-2 (Sekulovic et al, 2011), and phiSemix9P1 (Riedel et al, 2017), the latter two known to be maintained as extrachromosomal DNAs in lysogenic cells. Large phage genomes such as phiCD211/phiCDIF1296T and phiCD5763 seem to be frequently found as extrachromosomal DNA, and ParM homologs were identified in some of them (Garneau et al, 2018; Ramírez-Vargas et al, 2018). The functional role of Diffocins remains to be clarified, but they possibly provide a competitive advantage to C. difficile strains carrying them by killing surrounding competitors (Kirk et al, 2017)
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