Heterogeneous Salmonella-host encounters determine disease progression in a typhoid fever model

An infectious disease is an illness that is caused by invasion and multiplication of pathogenic microorganisms in body tissues of a host. The complex and heterogeneous tissue microenvironments provide different growth opportunities for pathogens with implications for disease outcome. However, the heterogeneous host environment has been largely neglected, because suitable methods to analyze single-cell host-pathogen encounters in vivo were largely lacking.
In this work, we addressed the implications of heterogeneous host-Salmonella encounters on disease progression in the well characterized mouse typhoid fever model. Specifically, we combined Salmonella biosensors with high resolution microscopy, flow cytometry and proteomics to reveal the fate of Salmonella in the diverse host microenvironments of spleen.
We showed that neutrophils and inflammatory monocytes are recruited to Salmonella infectious foci in spleen where they produce large amounts of reactive oxygen species (ROS), reactive nitrogen species (RNS) and lipids. We revealed that neutrophils and monocytes kill Salmonella with ROS generated through NADPH oxidase and myeloperoxidase (MPO), whereas RNS play a negligible role for infection control. However, ROS can also cause substantial collateral damage in host tissue. We showed that MPO protects the host against self-damage by converting diffusible long-lived ROS into highly reactive ROS with short reach that remain confined to the pathogen microenvironment. Some Salmonella escape to resident red pulp macrophages, which impose only sublethal oxidative bursts on Salmonella. Although macrophages are a primary niche for Salmonella survival, a specific subset of IFN activated macrophages can kill Salmonella with guanylate binding protein associated mechanisms. In addition, we showed that Salmonella growth in spleen is heterogeneous, independently of regional factors or host cell types. Overall, our analysis revealed numerous different Salmonella-host cell encounters in spleen with divergent outcomes. Local failures to control bacterial replication appear next to regions where the host successfully eradicates the pathogen.
Together, these data show that disease progression does not necessarily reflect an overall weak host immune response, but rather result from disparate host-pathogen encounters.