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The role of natural resistance-associated macrophage protein 1 (Nramp1) in salmonellosis

University of British Columbia

Salmonellosis poses a global threat to human health. Host resistance against Salmonella enterica serovar Typhimurium (S. Typhimurium) in the murine model is mediated by Natural resistance-associated macrophage protein 1 (Nramp1/Slc11a1). Nramp1 is critical for host defense, as mice lacking Nramp1 fail to control bacterial replication and succumb to low doses of S. Typhimurium. Despite this critical role, the mechanisms underlying Nramp1’s protective effects are unclear. This thesis presents a detailed analysis of Nramp1 expression in the murine gastrointestinal tract and its impact on S. Typhimurium infection following oral infection. Dendritic cells (DCs) that sample the intestinal lumen are among the first cells encountered by S. Typhimurium and play an important role in Salmonella pathogenesis. Intestinal, splenic and bone marrow derived DCs (BMDCs) all expressed Nramp1 protein. In intestinal DCs, Nramp1 expression is restricted to a discrete subset of DCs (CD11c⁺ CD103-) that express elevated levels of pro-inflammatory cytokines in response to bacterial products. While Nramp1 expression did not affect S. Typhimurium replication in DCs, infected Nramp1⁺/⁺ DCs secreted more inflammatory cytokines (IL-6, IL-12 and TNF-α) than Nramp1-/- DCs. This suggests that Nramp1 expression promotes accelerated inflammatory responses to S. Typhimurium. This hypothesis was tested using the Salmonella-induced colitis model, where pre-treatment of mice with antibiotics enhances colonization of the cecum/colon and induces massive inflammation. We found that Nramp1⁺/⁺ mice mounted a faster and more robust inflammatory response characterized by elevated pro-inflammatory cyto/chemokines (IFN-γ, TNF-α and MIP1-α) and recruitment of neutrophils and macrophages, thereby limiting spread of S. Typhimurium to systemic sites and ultimately protecting the host. Nramp1⁺/⁺ mice also developed a chronic Salmonella infection of the gastrointestinal tract that led to severe tissue fibrosis. Intestinal fibrosis is a serious complication of Crohn’s disease, often requiring surgical intervention but the mechanisms underlying its development are poorly understood due to the lack of relevant animal models. A novel model of severe and persistent intestinal fibrosis caused by chronic bacterial induced colitis was developed. Since the pathology closely resembles human fibrosis, we present a valuable tool for investigating host and bacterial contributions to inflammatory bowel diseases, as well as infectious colitis.

Thesis/Dissertation

application/pdf

2009-04-06

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/6845

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/