The Role of Chitinases and Fungal Siderophores in Salmonella enterica serovar Typhimurium Infection

Salmonella enterica serovar Typhimurium (S. Typhimurium) is one of the leading causes of food-borne illnesses worldwide. This thesis will cover two virulence mechanisms that S. Typhimurium exploits to promote gastrointestinal infection. The first mechanism that will be addressed is the expression of two chitinases by S. Typhimurium, STM0018 (chiA) and STM0233. The putative chitinase STM0233 has not been studied previously, and only limited data exists on ChiA. ChiA expression was detected in infection models and purified ChiA cleaved carbohydrate subunits present on mammalian surface glycoproteins, indicating a role during pathogenesis. Here, we demonstrate that that both chitinases facilitate epithelial cell adhesion and invasion in vitro. In a gastroenteritis mouse model, chitinase-deficient S. Typhimurium strains were also significantly attenuated in the invasion of small intestinal tissue. This reduced invasion resulted in significantly delayed S. Typhimurium dissemination to the spleen and the liver, but chitinases were not required for systemic survival. By analyzing N-linked surface glycans of small intestinal cells, we identified specific GlcNAc-containing glycans as potential extracellular targets of S. Typhimurium chitinases, potentially driving this adhesion and invasion defect. The second part of this thesis will describe the utilization of fungal siderophores by S. Typhimurium as a source of iron. During infection, the host limits the availability of micronutrients, like iron, to starve out pathogens. S. Typhimurium produces two iron-chelating molecules known as siderophores to acquire iron in this environment. In addition, S. Typhimurium express two receptors that are for specific for siderophores produced by fungi. Here, we show that these fungal siderophore receptors give S. Typhimurium the ability to utilize siderophores produced by commensal fungi and present in the diet. This provides S. Typhimurium a growth advantage in both in vitro cultures and in mouse models of infection. Overall, this thesis explores how the production of chitinases and the utilization of fungal siderophores promote S. Typhimurium infection.