914. Role of Leptin in Modulating Inflammatory Responses During Clostridium difficile-associated Colitis
Session: Poster Abstract Session: Bacterial Pathogenesis
Saturday, October 22, 2011
Room: Poster Hall B1
Background: Clostridium difficile is a gram-positive, spore-forming bacterium that has emerged as one of the most common nosocomial infections in recent years. C. difficile infection is associated with severe neutrophilic inflammation and neutrophils play an important role in determining disease severity. In fact, neutrophil depletion reduces inflammatory responses following C. difficile Toxin A challenge. Leptin is an adipo-cytokine of the IL-6 family that acts as a pro-inflammatory molecule. Leptin receptor-deficient mice (db/db) exhibit a markedly decreased inflammatory response to C. difficile Toxin A challenge (Mykoniatis A, Gastroenterology, 2003), suggesting a role for leptin in promoting C. difficile associated colitis (CDAC). However, the interplay between neutrophilic inflammation and leptin-mediated inflammatory responses in C. difficile infection is still unclear. Our studies are aimed at defining the role of leptin in neutrophilic inflammation and colitis during C. difficile infection.

Methods: To evaluate leptin’s role in neutrophil recruitment, we injected wild type (WT), chemokine receptor-deficient and db/db bone marrow chimeric mice with 1mg/kg leptin or vehicle intra-peritoneally (i.p.). Peritoneal cells were harvested by lavage, stained with neutrophil-specific markers, and analyzed by flow cytometry. For C. difficile infection, WT and db/db mice were treated with an antibiotic cocktail for 5 days, and then challenged with 103 cfu of VPI 10643 strain of C. difficile. Mice were assessed daily for weight loss and diarrhea.

Results: We observed that i.p. injection of leptin results in chemokine-dependent neutrophil recruitment to the peritoneal cavity. Furthermore, using bone marrow transfers between WT and db/db mice, we found that the neutrophil recruiting activity of leptin was dependent on leptin receptors expressed by radioresistant cells. Infection of mice with C. difficile demonstrated that db/db mice had less severe inflammation compared to WT mice.

Conclusion: These data demonstrate that leptin can mediate neutrophil recruitment and plays an important role in CDAC. We are currently using the C. difficile infection model to explore the role of leptin in neutrophil recruitment and inflammation during CDAC. 


Subject Category: B. Bacterial pathogenesis, studies in animal models, molecular pathogenicity

Rajat Madan, MD, PhD1, Xiaoti Guo, PhD2, Glynis L. Kolling, PhD3, Margo Roberts, Ph.D.1 and William Petri, MD, PhD4, (1)Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, (2)Vaccine Research Center, Bethesda, MD, (3)Division of Infectious Disease and International Health, University of Virginia, Charlottesville, VA, (4)University of Virginia, Charlottesville, VA

Disclosures:

R. Madan, None

X. Guo, None

G. L. Kolling, None

M. Roberts, None

W. Petri, None

Previous Abstract | Next Abstract >>

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.