NanI sialidase enhances C. perfringens host cell adherence and toxin action

描述（由申请人提供）：产气荚膜梭菌是人类和农业重要动物的主要病原体。这种细菌的毒性主要归因于其产生15种以上毒素的能力。根据四种类型毒素（？、？、？和？）的产生，这种微生物的分离物通常分为五种毒素型（A型至E型）。C.源自肠的产气荚膜杆菌感染是细菌粘附于肠上皮细胞。我们的小组最近已经证明，这种坚持需要生产的C。产气荚膜杆菌唾液酸酶NanI. NanI还显示出增强C.产气荚膜杆菌菌株CN 3718、ETX结合和ETX诱导的对MDCK细胞的细胞毒性。最终评估潜在的C。尽管NanI抑制剂的目的是干扰细菌粘附和毒素与靶细胞的结合，但该提议将开始评估NanI抑制剂是否代表可能干扰C.产气荚膜杆菌肠粘附和/或减少毒素结合。本R 03申请的目标1将确定其他C。产气荚膜杆菌菌株需要NanI用于这种粘附。目的2将测试NanI是否也增强其他C.产气荚膜杆菌毒素。Aim 3研究将测试 唾液酸酶抑制剂对体外NanI活性、毒素结合和细菌粘附的影响。这项工作是一个试点研究，通过随后的R 01应用可能会导致新的治疗方法对C。产气荚膜杆菌疾病，类似于唾液酸酶抑制剂在治疗由甲型流感病毒和B流感病毒引起的流感中的用途。

DESCRIPTION (provided by applicant): Clostridium perfringens is a major pathogen of humans and agriculturally important animals. The virulence of this bacterium is largely attributable to its ability to produce more than 15 toxins. Based upon production of four typing toxins (¿, ¿, ¿ and ?), isolates of this organism are commonly classified into five toxino-types (type A through E). The initial step of C. perfringens infections originating in the intestines is bacterial adherence to enterocytes. Our group has recently demonstrated that this adherence requires production of the C. perfringens sialidase NanI. NanI was also shown to enhance for C. perfringens strain CN3718, ETX binding and ETX-induced cytotoxicity to MDCK cells. To eventually evaluate potential C. perfrigens disease therapy aimed at interfering with bacterial adherence and toxin binding to target cells, this proposal will begin assessing whether NanI inhibitors represent potential therapeutics that might interfere with C. perfringens intestinal adherence and/or reduce toxin binding. Aim 1 of this R03 application will determine if other C. perfringens strains require NanI for this adherence. Aim 2 will test whether NanI also enhances the binding and cytotoxicity of other C. perfringens toxin besides ETX. Aim 3 studies will test the effects of sialidase inhibitors on in vitro NanI activity, toxin binding and bacterial adherence. Tis work is a pilot study that via a subsequent R01 application may lead to novel therapeutic approaches against C. perfringens diseases, similar to the use of sialidase inhibitors in the treatment of influenza caused by influenza A virus and influenza B virus.