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Degeneration of a CRISPR/Cas system and its regulatory target during the evolution of a pathogen.

ABSTRACT: CRISPR/Cas systems are bacterial RNA-guided endonuclease machineries that target foreign nucleic acids. Recently, we demonstrated that the Cas protein Cas9 controls gene expression and virulence in Francisella novicida by altering the stability of the mRNA for an immunostimulatory bacterial lipoprotein (BLP). Genomic analyses, however, revealed that Francisella species with increased virulence harbor degenerated CRISPR/Cas systems. We hypothesize that CRISPR/Cas degeneration removed a barrier against genome alterations, which resulted in enhanced virulence. Importantly, the BLP locus was also lost; likely a necessary adaptation in the absence of Cas9-mediated repression. CRISPR/Cas systems likely play regulatory roles in numerous bacteria, and these data suggest additional genomic changes may be required to maintain fitness after CRISPR/Cas loss in such bacteria, having important evolutionary implications.

SUBMITTER: Sampson TR

PROVIDER: S-EPMC3866243 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Degeneration of a CRISPR/Cas system and its regulatory target during the evolution of a pathogen.

Sampson Timothy R TR Weiss David S DS

RNA biology 20130920 10

CRISPR/Cas systems are bacterial RNA-guided endonuclease machineries that target foreign nucleic acids. Recently, we demonstrated that the Cas protein Cas9 controls gene expression and virulence in Francisella novicida by altering the stability of the mRNA for an immunostimulatory bacterial lipoprotein (BLP). Genomic analyses, however, revealed that Francisella species with increased virulence harbor degenerated CRISPR/Cas systems. We hypothesize that CRISPR/Cas degeneration removed a barrier ag ...[more]

PMID: 24100224

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Project description:The human enteropathogen Clostridium difficile constitutes a key public health issue in industrialized countries. Many aspects of C. difficile pathophysiology and adaptation inside the host remain poorly understood. We have recently reported that this bacterium possesses an active CRISPR-Cas system of subtype I-B for defense against phages and other mobile genetic elements that could contribute to its success during infection. In this paper, we demonstrate that redirecting this endogenous CRISPR-Cas system toward autoimmunity allows efficient genome editing in C. difficile We provide a detailed description of this newly developed approach and show, as a proof of principle, its efficient application for deletion of a specific gene in reference strain 630Δerm and in epidemic C. difficile strain R20291. The new method expands the arsenal of the currently limiting set of gene engineering tools available for investigation of C. difficile and may serve as the basis for new strategies to control C. difficile infections.IMPORTANCEClostridium difficile represents today a real danger for human and animal health. It is the leading cause of diarrhea associated with health care in adults in industrialized countries. The incidence of these infections continues to increase, and this trend is accentuated by the general aging of the population. Many questions about the mechanisms contributing to C. difficile's success inside the host remain unanswered. The set of genetic tools available for this pathogen is limited, and new developments are badly needed. C. difficile has developed efficient defense systems that are directed against foreign DNA and that could contribute to its survival in phage-rich gut communities. We show how one such defense system, named CRISPR-Cas, can be hijacked for C. difficile genome editing. Our results also show a great potential for the use of the CRISPR-Cas system for the development of new therapeutic strategies against C. difficile infections.

Dataset Information

Degeneration of a CRISPR/Cas system and its regulatory target during the evolution of a pathogen.

Publications

Degeneration of a CRISPR/Cas system and its regulatory target during the evolution of a pathogen.

Similar Datasets

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