Heterogeneity of inflammation and host metabolism in a typhoid fever model

Abstract

Systemic infections can lead to severe inflammation and altered host metabolism. These host responses are being extensively studied, but their spatial relationships in infected tissues remain largely unknown. The goal of this thesis was to investigate the spatial organization of metabolic and inflammatory patterns in Salmonella-infected tissues and to elucidate the impact of host heterogeneity on host-Salmonella interactions in a murine typhoid fever model. We showed that antimicrobial effector mechanisms such as generation of ROS and RNS occurred predominantly in granulomatous lesions. However, a substantial fraction of Salmonella resided outside of these lesions and was therefore not covered by these antimicrobial regions. Heterogeneous exposure to RNS induced distinct, locally adapting Salmonella subpopulations (see chapter 2.1). We also investigated host metabolic enzyme activities in various tissue regions. Using a novel combination of immunostaining with enzyme histochemistry, we showed that granulomas had a distinct metabolic profile with a high capacity for generation of NADPH, an essential substrate for local generation of bacteriostatic/bactericidal ROS and RNS. Indeed, adaptation of GFP-based live/dead discrimination revealed extensive Salmonella killing that predominantly occurred in granulomas (see chapter 2.2). The spatial segregation of live Salmonella from regions with massive killing also offered a potential explanation why surface-associated Salmonella antigens, but not internal antigens that are inaccessible in live Salmonella, were required for protective immunity (see chapter 2.3). In conclusion, this thesis revealed markedly heterogeneous conditions in Salmonella-infected host tissues that had profound impact on disease mechanisms, infection control, and immunity.