Clostridium difficile is one of the most important, resurging nosocomial enteric pathogens. Incidence and mortality rates for C. difficile infection (CDI) have increased dramatically over the past decade making CDI by far the most common cause of fatal infectious diarrhea in the United States and in Europe. Patients with fulminant or severe complicated CDI (SCCDI) often develop systemic disease which is a prelude to fatality. The causes for the development of systemic complications remain poorly understood, but clinical observations by us and by others and studies using animal models suggest that C. difficile exotoxins TcdA and TcdB are likely contributing factors. Our central hypothesis is that systemic dissemination of TcdA and/or TcdB is a major factor leading to systemic complications and SCCDI is preventable by neutralizing antibodies against the two toxins. To test this hypothesis, we will exploit an ultrasensitive immunocytotoxicity assay developed at this lab to measure circulating toxins and determine their association with systemic complications in CDI patients. In addition, we will investigate the time and sequence of events leading to systemic dissemination of TcdA and/or TcdB, the tissue and organ tropism and abnormalities associated with the individual toxins. Finally, we propose to develop a novel therapeutics against SCCDI by generating multivalent single-domain (or VHH) antibodies with enhanced neutralizing activity against each of the two toxins. Upon completion of our proposed studies, we expect to gain more understandings of the pathogenesis of SCCDI and potentially lead to a development of much needed treatments against the disease. To accomplish these objectives we will use clinical specimens of CDI patients from several hospitals, as well as unique research tools/methods and animal models we have developed at this laboratory.

Public Health Relevance

Substantial evidence demonstrates that the infection of Clostridium difficile, an enteric bacterium, also causes systemic and life-threatening disease by liberating toxins. The goal of this project is to understand how the toxins cause systemic disease and to design strategies to target the toxins for preventing the systemic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI099458-01A1
Application #
8664002
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Ranallo, Ryan
Project Start
2013-06-15
Project End
2014-05-31
Budget Start
2013-06-15
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$387,995
Indirect Cost
$117,767
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Yang, Zhiyong; Schmidt, Diane; Liu, Weilong et al. (2014) A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice. J Infect Dis 210:964-72
Huang, Tuxiong; Li, Shan; Li, Guangchao et al. (2014) Utility of Clostridium difficile toxin B for inducing anti-tumor immunity. PLoS One 9:e110826