Phage biology and diversity in Clostridium difficile

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Clostridium difficile is currently the most frequent cause of healthcare-associated infectious diarrhea in industrialized countries. Recently, a hypervirulent strain, called NAP1/027, has emerged and has caused several outbreaks since 2001. The epidemiology of C. difficile seems to be evolving rapidly and despite intensive research on this pathogen in recent years, we don't know much about factors that drive C. difficile evolution and the events that might have contributed to the emergence of the NAP1/027 strain. Moreover, recent studies suggest that animals might be natural reservoirs for C. difficile propagation, but the molecular determinants specifying host specificity (e.g. human or animal hosts) are unknown. Prophages, i.e. viruses (or phages) integrated into the chromosome of bacteria, are mobile genetic elements well known to affect their host by multiple ways. However, their role in C. difficile has remained relatively unexplored so far, although several prophages have been isolated. Our long-term objective is thus to assess the role of prophages in C. difficile lifestyle and host specificity, genetic diversity, virulence and evolution. To achieve this goal, we will characterize prophages present in C. difficile isolates from human, animal and environmental origin. Whole genome sequencing and comparative prophage genomics will be performed, which will provide important and novel data regarding genetic diversity and evolution of both prophages and their host, i.e. C. difficile. Phage as well as bacterial gene expression during lysogeny (latent prophage infection) and during active phage replication (lytic cycle) will be studied in the NAP1/027 strain, which will bring important data regarding phage/pathogen/host interactions. In summary, our study will bring highly novel data and new insights on the genetic diversity and contribution of phages in the diversity and rapid evolution of one of the most deadly human pathogens. We also believe that phage/pathogen interaction studies will lead to the discovery of bacterial targets for novel antimicrobial agents.