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Salmonella-host interactions : the interplay between Salmonella, SPI2 and eicosanoids

University of British Columbia

Salmonella are Gram-negative facultative intracellular pathogens that cross the intestinal barrier, and are taken up by phagocytes where, they can replicate and spread to systemic sites. Salmonella encode two type III secretion systems, Salmonella pathogenicity island 1 and 2 (SPI1 and SPI2), which mediate the translocation of bacterial effectors into the host cell. SPI1 facilitates bacterial uptake into non-phagocytic cells and is involved in forming a special replicative niche, called the Salmonella containing vacuole (SCV). SPI2 is required for maintenance of the SCV, macrophage replication and systemic disease. A comprehensive study of the contribution of individual SPI2 effectors to virulence had not been previously done, and was therefore performed. Strains deficient in specific SPI2 genes were tested for alterations in virulence in a mouse model of typhoid fever, and in epithelial and macrophage cell infections. These experiments showed that many SPI2 effectors are required for replication in macrophages, and that ΔspvB, ΔssaR, and ΔspiC strains were attenuated in mice. Salmonella infection causes many perturbations to the host, including changes in metabolites, specifically arachidonic acid metabolism, which leads to the production of eicosanoids. The effects of Salmonella infection of macrophages on eicosanoids were examined. Salmonella infection increased the expression of prostaglandin synthases, but decreased thromboxane and leukotriene synthases. The SPI2 deletion strains were tested to determine involvement of SPI2 in arachidonic acid metabolism. The SPI2 effectors SseF and SseG, which are largely uncharacterized in macrophage infections, were mainly responsible for the induction of prostaglandins. The effects of prostaglandins on Salmonella infection were studied. It was found that 15-deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2) significantly reduced Salmonella colonization of macrophages, but not epithelial cells. Furthermore, this occurs independently of SPI1, SPI2, and PPAR-γ. 15d-PGJ2 reduces cytokines and reactive nitrogen species produced by infected macrophages. A role for 15d-PGJ2 in Salmonella infection has not been previously demonstrated. This thesis examines the role of SPI2 in Salmonella virulence and arachidonic acid metabolism.

Text

2013-08-02

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44738

Microbiology and Immunology

University of British Columbia

UBCV

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