Role of non-coding RNAs in the pathogenesis of infections related to an emerging human enteropathogen, Clostridium difficile

Le résumé fourni par la source

Clostridioides difficile is a Gram-positive pathogenic bacterium found mainly in the soils and intestines of mammals. It is the leading cause of adult health care associated diarrhea in industrialized countries. The incidence of these infections continues to increase and this trend is accentuated by the general aging of the population. C. difficile now represents a real danger to human and animal health. A better understanding of the regulation of the colonization process of the digestive tract therefore seems essential for the study of this emerging pathogen. In most bacteria, non-coding RNAs (ncRNAs) govern the regulation of many physiological processes, including virulence processes. Recent transcriptomic experiments initiated by my laboratory have identified a large number of regulatory RNAs in C. difficile. The objective of this thesis is to characterize the role of non-coding RNAs in the control of the infectious cycle in C. difficile, but also to better understand the regulatory networks controlling the processes essential for the development of C. difficile in contact with its host. To do this, a transcriptomic approach making it possible to simultaneously visualize the RNAs induced or repressed in the host and the pathogen during the infection was implemented, which made it possible to identify certain RNAs differentially expressed during the infection versus a controlled condition. On the other hand, several regulatory RNAs specific to a hypervirulent ribotype 027 strain had already been identified during a comparative transcriptomic experiment between this same strain and a reference strain 630. The study of one of these non-coding RNAs located in a prophagic region made it possible to characterize a new riboswitch, located upstream of a gene involved in a process of defense against phage infection (Abi). Finally, a last original aspect of virulence control by C. difficile is also explored by studying the role of an RNA chaperone protein (Hfq) known to be involved in numerous regulatory networks of bacterial physiology, but also in the control of virulence processes in most Gram-negative bacteria. The characterization of a deletion mutant for this protein made it possible to study the role of this protein in C. difficile in the regulation of virulence through the characterization of various phenotypes related to virulence and during in vivo tests in mice. This project has thus enabled a better understanding of the regulatory mechanisms of certain original aspects of virulence control by non-coding RNA in C. difficile.

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