Clostridium perfringens epsilon toxin (ETX) is a class B CDC/USDA overlap toxin and a major virulence factor in natural veterinary infections caused by ETX-producing C. perfingens isolates. Currently there are no ETX therapeutics (NIH prefers ETX therapeutics over vaccines because natural ETX-related disease in humans is uncommon). Early steps in ETX action on host cells are poorly understood, which has negatively impacted the development of ETX therapeutics. To remedy the limited understanding of early steps in ETX action and begin exploring the development of ETX therapeutics, the following specific aims will be pursued in this MARGE project (part of Program V, interactions between toxins and host cells): i) Aim 1 will identify the ETX receptor in kidney, brain and lung by expression cloning approaches;ii) Aim 2 will immunolocalize the distribution of the identified receptor in animal and human tissues;iii) Aim 3 will evaluate the pathogenic importance of the identified ETX receptor using antibody blocking approaches, siRNA-mediated reduction of receptor expression, and (if available) receptor knock-out mice;iv) Aim 4 will analyze, by mass spectrometry, the protein composition of ETX complexes formed in the plasma membrane of sensitive host cells to gain further insights into ETX action;v) since previous studies have shown that sialidases can increase ETX binding/activity in MDCK cells, Aim 5 will use isogenic sialidase mutants to evaluate the hypothesis that sialidases similarly potentiate the virulence of ETX-producing isolates and vi) Aim 6 will evaluate the therapeutic potential of ETX receptor decoys. These studies are expected to produce new approaches for therapeutic inhibition of ETX activity, which is a current priority for NIH biodefense activities.

Public Health Relevance

Because of its potency, Clostridium perfringens epsilon toxin (ETX) is listed as a CDC/USDA overlap class B select toxin. Development of ETX therapeutics has been hindered by limited understanding of the early steps in ETX action. This project seeks to understand the early steps in ETX action, particularly the interactions between ETX and its receptor, and exploit this knowledge to develop ETX therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057168-09
Application #
8375163
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$268,306
Indirect Cost
$36,131
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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