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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI105635-02
Application #
8604686
Study Section
Special Emphasis Panel (ZRG1-IDM-A (80))
Program Officer
Ranallo, Ryan
Project Start
2013-01-15
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$76,625
Indirect Cost
$26,625
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213