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

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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.