Dissertation/Thesis Abstract

The Role of Neutrophils in Salmonella Colitis
by Kingsbury, Dawn Denise, Ph.D., University of California, Davis, 2015, 85; 3737025
Abstract (Summary)

Neutrophils are important in host defense and have a large potential to expand during infection. The goal of this thesis was to understand the role neutrophils play when inflammation modulates the interface of the host intestinal mucosa and the gut-associated microbes, particularly in the face of Salmonella Typhimurium-induced colitis. Interferongamma (IFN-γ) is an important molecular driver of intestinal inflammation during colitis. Individuals deficient in IFN-γ signaling are predisposed to recurrent, systemic infections most notably nontyphoidal Salmonella and atypical Mycobacteria. The hypothesis was that neutrophils would be a major source of IFN-γ in infectious colitis. The streptomycintreated mouse model was used to investigate the cellular sources of IFN-γ production in the cecal mucosa during the acute phase of enteric S. Typhimurium infection. The neutrophil fraction significantly increased in the live cecal cell population and was the most prominent cellular source of IFN-γ. Neutrophil depletion decreased neutrophil numbers, blunted mucosal Ifng expression, reduced the severity of histopathological damage to the cecal mucosa and increased systemic spread of S. Typhimurium to the liver and spleen.

Interestingly, streptomycin treatment alone mildly increased neutrophil numbers and expression of inducible nitric oxide synthase. The hypothesis was that host-mediated proinflammatory changes caused by streptomycin treatment could provide Proteobacteria electron acceptors for anaerobic respiration allowing them to successfully colonize and outcompete the resident anaerobic fermenters. In-vivo competition between the probiotic Proteobacteria, Escherichia coli Nissle 1917 and its isogenic nitrate reductase mutant revealed a wild type advantage that was host Nos2 dependent. To provide support for streptomycin-induced host-mediated effects versus antibiotic-mediated microbial alterations, a chemically induced colitis model was modified. Using a subpathological dose of dextran sodium sulfate in a colitis-enhancing model, streptomycin worsened pathology and increased neutrophils, supporting the novel theory that streptomycin reduces colonization resistance to E. coli by modifying the inflammatory tone of the host.

To summarize, this thesis has investigated the role neutrophils fulfill in infectious colitis as a major source of interferon gamma, and how neutrophils contribute to a loss of colonization resistance by antibiotic administration.

Indexing (document details)
Advisor: Baumler, Andreas J.
Commitee: McSorley, Stephen J., Mills, David A.
School: University of California, Davis
Department: Microbiology
School Location: United States -- California
Source: DAI-B 77/04(E), Dissertation Abstracts International
Subjects: Microbiology, Health sciences, Immunology
Keywords: Colonization resistance, Interferon-gamma, Mouse, Neutrophil, Salmonella typhimurium, Streptomycin
Publication Number: 3737025
ISBN: 978-1-339-26107-2
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