We propose to discover how eosinophils protect from C. difficile colitis (CDI). Hypotheses: (1) IL- 1? induced by C. difficile toxins promotes colitisby inhibiting IL-25-mediated gut eosinophilia. (2) IL-25-induced eosinophils protect by repair of the intestinal barrier. Human and murine work: Studies in the murine model of CDI and in humans undergoing fecal microbiota transplant (FMT) for CDI are proposed. Significance: C. difficile is the number one hospital-acquired infection in North America and despite antibiotic therapy has a mortality of 10-15%, with relapses in 10-35% of patients. Approach: There are three Specific Aims:
Specific Aim 1 : Define the mechanism by which C. difficile binary toxin (CDT) primes the inflammasome to induce IL-1? production.
Specific Aim 2 : Determine whether IL-1? is the mechanism by which the pathologic innate response to C. difficile infection suppresses eosinophils.
Specific Aim 3 : Explore the mechanism that colonic eosinophils induced by IL-25 protect from CDI. Successful completion will identify how CDT activates a pathologic innate response, and will delineate the mechanism of protection afforded by IL-25-induced eosinophilia. Therapeutic interventions that are complementary to or supplant fecal transplant and next generation probiotics are potential outcomes. Innovative aspects of the proposal include the exploration of a novel process by which bacterial toxins can promote virulence via activation of pathologic IL-1? and suppression of protective IL-25 induced eosinophils. The environment for the work includes the two graduate students who discovered the role of CDT and eosinophils in CDI, and the lab of the Principal Investigator where 25 years of infectious colitis research have been conducted.

Public Health Relevance

Clostridium difficile is the most common cause of hospital-acquired diarrhea in the US. The CDC in 2013 named it as one of the three 'Urgent Threats' (the highest CDC threat level). C. difficile is of increasing prevalence, and up to 15% of patients die and 20% relapse despite antibiotic therapy. We propose to identify how C. difficile toxins inhibit eosinophils that otherwise would protect the gut from damage. This could lead to new and effective approaches to the treatment or prevention of C. difficile colitis that act downstream of fecal transplants or next generation probiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI124214-04
Application #
9625739
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ranallo, Ryan
Project Start
2016-02-02
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Jose, S; Abhyankar, M M; Mukherjee, A et al. (2018) Leptin receptor q223r polymorphism influences neutrophil mobilization after Clostridium difficile infection. Mucosal Immunol 11:947-957
Buonomo, Erica L; Petri Jr, William A (2016) The microbiota and immune response during Clostridium difficile infection. Anaerobe 41:79-84
Cowardin, Carrie A; Jackman, Brianna M; Noor, Zannatun et al. (2016) Glucosylation Drives the Innate Inflammatory Response to Clostridium difficile Toxin A. Infect Immun 84:2317-2323
Steele, Shaun P; Melchor, Stephanie J; Petri Jr, William A (2016) Tuft Cells: New Players in Colitis. Trends Mol Med 22:921-924
Cowardin, Carrie A; Buonomo, Erica L; Saleh, Mahmoud M et al. (2016) The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat Microbiol 1:16108
Buonomo, Erica L; Cowardin, Carrie A; Wilson, Madeline G et al. (2016) Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection. Cell Rep 16:432-443
Buonomo, Erica L; Petri Jr, William A (2015) The Bug Stops Here: Innate Lymphoid Cells in Clostridium difficile Infection. Cell Host Microbe 18:5-6
Cowardin, Carrie A; Kuehne, Sarah A; Buonomo, Erica L et al. (2015) Inflammasome activation contributes to interleukin-23 production in response to Clostridium difficile. MBio 6:
Madan, Rajat; Petri Jr, William A (2015) Role of obesity and adipose tissue-derived cytokine leptin during Clostridium difficile infection. Anaerobe 34:182-6

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