The overall goal of this proposal is to significantly expand on findings from our ongoing Merit award-supported work to further interrogate gastrointestinal tract colonization and disease establishment of the diarrheagenic pathogen Clostridium difficile. To enable this project, we have identified unique bacterial factors that mediate C. difficile interaction(s) with the host intestine.
Three Specific Aims are proposed. First, we will expand on our studies defining C. difficile response to, and tolerance of, reactive oxygen species and redox stress. This response severely impacts GI tract colonization of the pathogen, and highly attenuated, potential vaccine strains were generated for these studies during the current award period. Second, we will continue studies to interrogate infectious mechanism(s) of the low-toxin/high-virulence C. difficile strains we recovered from our active disease surveillance of the Southern Arizona veteran and non-veteran population. The wealth of proteomic data we have garnered will be exploited for genetic studies to define virulence and colonization mechanisms of these strains. Third, and with the goal of translating our research into an immediately clinically-relevant context, we will validate and test our newly-engineered recombinant probiotic bacterium which is a targeted C. difficile colonization inhibitor. All studies in this proposal will use existing or t-be-collected specimens from the veteran population, and utilize both hamster and mouse models of acute C. difficile infection and colonization respectively. We will also incorporate state-of-the-at methodologies including next-generation omics and sequencing, and live-animal bioluminescence imaging to interrogate various aspects of C. difficile colonization and disease establishment.

Public Health Relevance

Over 400,000 cases of Clostridium difficile infection (CDI) occur annually in the USA, imposing a burden of >$3 billion on the healthcare system. Risk factors for CDI include hospitalization, age >65, co-morbid conditions, and antibiotic use - all of which are immediately relevant to patients treated in VA hospitals. CDI rates have consistently increased in the VA healthcare system, and up to 11% of veterans relapse with multiple recurrences of the disease. Severity of initial infection as well as relapses are now also much higher with the newly emerged 'epidemic-associated' strains of C. difficile that are common in VA hospitals. The studies proposed in this application are focused on understanding how C. difficile colonizes the human gut, and to validate a safe, cost-effective and easily tolerated intervention to prevent this establishment. The proposed work specifically utilizes C. difficile strains obtained from veterans, and is thus directly relevant to veterans' health.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001183-08
Application #
9605188
Study Section
Gastroenterology (GAST)
Project Start
2011-04-01
Project End
2019-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Southern Arizona VA Health Care System
Department
Type
DUNS #
084471531
City
Tucson
State
AZ
Country
United States
Zip Code
85723
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Soavelomandroso, Anna P; Gaudin, Fran├žoise; Hoys, Sandra et al. (2017) Biofilm Structures in a Mono-Associated Mouse Model of Clostridium difficile Infection. Front Microbiol 8:2086
Merrigan, Michelle M; Venugopal, Anilrudh; Roxas, Jennifer L et al. (2013) Surface-layer protein A (SlpA) is a major contributor to host-cell adherence of Clostridium difficile. PLoS One 8:e78404
Roxas, Jennifer Lising; Wilbur, John Scott; Zhang, Xiangfeng et al. (2012) The enteropathogenic Escherichia coli-secreted protein EspZ inhibits host cell apoptosis. Infect Immun 80:3850-7
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