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.
Clostidium perfringens isolates cause diseases originating in the intestine of humans (e.g. food poisoning, antibiotic-associated diarrhea, and enteritis necroticans) and agriculturally-important aimals (e.g. enteritis and/or enterotoxemia). Development of C. perfringens therapeutics and prophylates has been hindered by the multitude of toxins produced by different type C. perfringens. This project seeks to gain feasibility information to: i) better understand C. perfringens and toxin adherence to host cells and ii) explore whether NanI sialidase might be novel therapeutic approaches involving inhibition of the NanI silaidase against these C. perfringens illnesses.
|Theoret, James R; Li, Jihong; Navarro, Mauricio A et al. (2018) Native or Proteolytically Activated NanI Sialidase Enhances the Binding and Cytotoxic Activity of Clostridium perfringens Enterotoxin and Beta Toxin. Infect Immun 86:|
|Li, Jihong; Freedman, John C; McClane, Bruce A (2015) NanI Sialidase, CcpA, and CodY Work Together To Regulate Epsilon Toxin Production by Clostridium perfringens Type D Strain CN3718. J Bacteriol 197:3339-53|
|Li, Jihong; McClane, Bruce A (2014) The Sialidases of Clostridium perfringens type D strain CN3718 differ in their properties and sensitivities to inhibitors. Appl Environ Microbiol 80:1701-9|
|Li, Jihong; McClane, Bruce A (2014) Contributions of NanI sialidase to Caco-2 cell adherence by Clostridium perfringens type A and C strains causing human intestinal disease. Infect Immun 82:4620-30|
|Li, Jihong; Ma, Menglin; Sarker, Mahfuzur R et al. (2013) CodY is a global regulator of virulence-associated properties for Clostridium perfringens type D strain CN3718. MBio 4:e00770-13|