Clostridium difficile is a leading cause of hospital-acquired illness in developed countries. Treating C. difficile infection (CDI) is complicated by antibiotic resistance, recurrence (RCDI), and hypervirulence of emerging strains that produce a highly toxic variant of TcdB. TcdB is a major C. difficile virulence factor that contributes to gastrointestinal damage, inflammation, and systemic damage. In these studies experiments will characterize the differences between the historical and milder form of TcdB (TcdB1) and the hypertoxic TcdB2. Published and preliminary data from our group shows that TcdB2 has a broader tropism and is more cytotoxic than TcdB1. In addition, antibodies to TcdB1 do not cross-neutralize TcdB2, suggesting that current vaccines and therapeutic antibodies targeting TcdB may not provide broad protection against multiple strains of C. difficile. The study will examine molecular differences between TcdB1 and TcdB2 to determine how these impact cellular intoxication, antigenicity, and influence RCDI.
Aim 1 will characterize the differences in dual-receptor interactions between TcdB1 and TcdB2, assess how this impacts endocytosis, and identify key residues that influence these events.
Aim 2 will explore a mechanism through which TcdB2 cloaks neutralizing epitopes which are otherwise exposed in TcdB1. Experiments in aim 3 of this project will determine how the differences in TcdB1 and TcdB2 predispose patients to RCDI. The results from this project will provide the first insights into the differentil effects of TcdB1 and TcdB2 and the impact of TcdB2's heightened toxicity and altered antigenicity on the emergence of hypervirulent strains of C. difficile.

Public Health Relevance

Clostridium difficile infection (CDI) and recurrent CDI (RCDI) are major human health problems and difficult to treat. Patients infected by hypervirulent strains of C. difficile are subject to a higher mortality rate and increased likelihood of experiencing RCDI. This research investigates the underlying reasons for the increase in mortality, by studying the differences in a major toxin (TcdB) produced by historical and hypervirulent strains of this pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI119048-02
Application #
9122306
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Ranallo, Ryan
Project Start
2015-08-07
Project End
2020-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104