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首页> 外文期刊>Applied Microbiology >Using an Endogenous CRISPR-Cas System for Genome Editing in the Human Pathogen Clostridium difficile
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Using an Endogenous CRISPR-Cas System for Genome Editing in the Human Pathogen Clostridium difficile

机译：使用内源性CRISPR-Cas系统进行人类致病性艰难梭菌基因组编辑

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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 {"type":"entrez-nucleotide","attrs":{"text":"R20291","term_id":"774925","term_text":"R20291"}}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.
机译：人肠病原体艰难梭菌是工业化国家的关键公共卫生问题。宿主内部艰难梭菌的病理生理学和适应的许多方面仍然知之甚少。我们最近报道，该细菌具有活跃的I-B亚型CRISPR-Cas系统，可防御噬菌体和其他可能在感染过程中取得成功的移动遗传元件。在本文中，我们证明了将这种内源性CRISPR-Cas系统重定向至自身免疫可以在艰难梭菌中进行有效的基因组编辑。我们提供了这种新开发方法的详细说明，并作为原理证明，证明了该方法可有效删除参考菌株630Δerm和流行性梭状芽胞杆菌菌株{“ type”：“ entrez-nucleotide”中的特定基因， “ attrs”：{“ text”：“ R20291”，“ term_id”：“ 774925”，“ term_text”：“ R20291”}} R20291。这种新方法扩展了目前可用于研究艰难梭菌的有限基因工程工具集的范围，并可能成为控制艰难梭菌感染的新策略的基础。艰难梭菌今天对人类和动物健康构成了真正的威胁。它是工业化国家成年人与保健相关的腹泻的主要原因。这些感染的发生率继续增加，人口的总体老龄化加剧了这一趋势。关于导致艰难梭菌在宿主内成功的机制的许多问题仍未得到解答。可用于该病原体的遗传工具集有限，并且迫切需要新的发展。艰难梭菌已开发出针对外来DNA的有效防御系统，并可能有助于其在富含噬菌体的肠道群落中的生存。我们展示了如何将一种名为CRISPR-Cas的防御系统劫持，用于艰难梭菌基因组编辑。我们的结果也显示了使用CRISPR-Cas系统开发针对艰难梭菌感染的新治疗策略的巨大潜力。

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