Clostridium difficile is an emerging pathogen that causes severe and sometimes deadly colitis. Epidemiological evidence indicates that both the severity and incidence of C. difficile-associated disease (CDAD) are increasing at an alarming rate. Available treatment is inadequate and there are no licensed vaccines. Type IV pili (T4Ps), surface appendages that play important roles in infections caused by diverse bacterial pathogens, have been exploited for vaccine development. Recently, T4Ps were discovered in C. perfringens and the genes for T4Ps are present in C. difficile. Our overall hypothesis states that an immune response against the major pilin will protect against colonization and CDAD. To test this hypothesis we will first determine which pilin gene encodes the major structural subunit of the C. difficile T4P and then investigate the efficacy of immunization with purified pilin in prevention of C. difficile colonization and disease in a murine model. The proposed research is highly innovative because it will examine the potential of a novel antigen usually identified with Gram-negative bacteria to protect against colonization by a Gram-positive anaerobe. A result indicating a protective effect will have a profound effect on research and strategies for prevention and therapy for clostridial infections. The investigators have an established record of productivity studying T4P and using animal models of disease and the environment at the University of Maryland Baltimore is ideal for the proposed research. Given the indispensible role of T4Ps for other infections, the immunogenicity of pilin proteins, and the success of other T4P vaccines, we expect that a C. difficile pilin vaccine (alone or in combination with a toxoid vaccine) will generate a potent protective immune response against this potentially lethal infection. Demonstration of protection in a highly relevant animal model will pave the road to further preclinical and clinical testing.

Public Health Relevance

Clostridium difficile is a bacterium that causes severe and sometimes deadly infections of the large intestine. Both the severity and incidence of C. difficile associated disease (CDAD) are increasing at an alarming rate. Available treatment is inadequate and there are no licensed vaccines. Type IV pili (T4Ps) are surface fibers made by many important bacteria that cause disease. T4Ps play important roles in infection and have been used successfully as vaccines. We seek to determine whether vaccination with the protein that makes up the recently discovered T4P of C. difficile will protect against colonization and CDAD. Demonstration of protection in a highly relevant animal model will pave the road to further preclinical and clinical testing and potentially lead to a new weapon to prevent this letha infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
1R03AI097953-01A1
Application #
8303630
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Ranallo, Ryan
Project Start
2012-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$76,750
Indirect Cost
$26,750
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Maldarelli, Grace A; De Masi, Leon; von Rosenvinge, Erik C et al. (2014) Identification, immunogenicity, and cross-reactivity of type IV pilin and pilin-like proteins from Clostridium difficile. Pathog Dis 71:302-14
Donnenberg, Michael S; Narayanan, Shivakumar (2013) How to diagnose a foodborne illness. Infect Dis Clin North Am 27:535-54