艰难梭菌是一种产孢子的专性厌氧菌，属厚壁菌门梭菌属。该细菌是一种条件致病菌，在正常的人体肠道菌群遭到破坏后，其得以感染肠道并大量繁殖，造成包括伪膜性肠炎、腹泻等疾病，严重时危及生命。目前艰难梭菌感染（CDI）已经成为了一个全球性的健康问题，每年都造成数百万的感染病例和数以万计的死亡。艰难梭菌的致病机理取决于其表达的两种外毒素TcdA和TcdB，而研究TcdA的作用机制是理解CDI病理发生的关键之一。本研究旨在利用CRISPR/Cas9介导的全基因组敲除文库筛选技术，寻找并验证参与TcdA毒素作用的重要宿主因子，尤其是此前从未发现过的非CROPs依赖型受体途径。之后我们将在CDI的主要病理部位——肠道上皮细胞层中作深入研究，阐示受体在CDI的发生过程中起到的作用和贡献。我们坚信该研究将进一步从机制上提升人们对CDI发生和发展得认识，从而为该疾病的预防和治疗提供有益的思路和手段。

Clostridium difficile is a spore-forming anaerobic bacterium, which belongs to the family of Firmicutes. C. difficile is a typical opportunistic pathogen. Disruption of normal gut flora by antibiotics allows C. difficile to colonize the colon, leading to diarrhea and life-threatening pseudo-membranous colitis. C. difficile infection (CDI) has gradually become a worldwide health problem, leading to millions of cases and thousands of death every year. Most C. difficile strains produce two exotoxins TcdA and TcdB, which are the major virulence factors for the bacterium. Investigations on the mechanism of TcdA action is one of the keys to understand the pathogenesis of CDI. In this study, we aim to define the critical host factors, especially the CROPs-independent receptors, which involve the toxin actions of TcdA via genome-wide CRISPR/Cas9 screens. We further manage to elucidate their role in the disease development of CDI in the intestinal epithelium, which is the pathological relevant site for CDI. We firmly believe that this study will help to further understand the pathogenesis of CDI, and provide new strategy and methods for the disease prevention and therapeutics.