Dissecting host-pathogen interactions of the systemic disease-causing African salmonella typhimurium isolates [electronic resource]

Salmonella entetica serovars are important human pathogens causing disease ranging from self-limiting gastroenteritis to the systemic infection, typhoid fever. Salmonella enterica serovars vary in their host range from generalists like Salmonella Typhimurium (S. Typhimurium) to the human host restricted Salmonella Typhi (S. Typhi). While great advances have been made in understanding the pathogenesis of Salmonella, there is still much to be learned. The focus of this dissertation is to continue to understand Salmonella pathogenesis by dissecting the host-pathogen interactions of Salmonella. In Chapter 1, I introduce the foundation for what we know about Salmonella host-pathogen interactions. I discuss the disease syndromes caused by various Salmonella, the different mouse models used to study Salmonella infections, and the major virulence determinants of Salmonella. Chapter 2 builds on this foundation by exploring the interactions between Salmonella and dendritic cells. Specifically, we characterize how Salmonella is able to inhibit dendritic cell migration and what virulence factors are necessary for this inhibition. We use live imaging of Salmonella-infected dendritic cells in microfluidic devices with a stable, linear chemokine gradient to elucidate that Salmonella inhibits both chemotaxis and migration speed in dendritic cells. We find that the inhibition of dendritic cell chemotaxis is dependent on Salmonella Pathogenicity Island 2 (SPI-2) secreted effectors. We then perform a screen in the microfluidic device and identify 7 SPI-2 effectors that are required to inhibit dendritic cell chemotaxis. Salmonella Typhimurium usually causes a self-limiting gastroenteritis in developed countries. However, in sub-Saharan Africa Salmonella Typhimurium routinely cause systemic infections such as bacteremia and meningitis. Chapters 3 through 5 focus on these African Salmonella Typhimurium isolates and what differences in host-pathogen interactions might allow them to cause a more severe, systemic disease in humans. Chapter 3 gives a primer on what is known about these African isolates including the human disease syndromes they cause, the epidemiology of the infections, and that these African Salmonella Typhimurium isolates belong to a distinct sequence type (ST313) and cluster into two closely related lineages away from other Salmonella Typhimurium. In Chapter 4, I begin interrogating the host-pathogen interactions of these African ST313 Salmonella Typhimurium isolates associated with systemic disease. I find that these African S. Typhimurium isolates are occupying an intermediate phenotypic state between the classical gastroenteritis-associated Salmonella Typhimurium isolates and typhoid fever-causing Salmonella Typhi. The systemic disease-associated African Salmonella Typhimurium display intermediate levels of active host cell invasion and induce intermediate levels of inflammasome activation. These effects are driven by lower levels of expression of the genes encoding the Salmonella pathogenicity Island 1 effector SopE2 and the pathogen associated molecular pattern flagellin, respectively. In Chapter 5, I go on to dissect the host-pathogen interactions of these African Salmonella Typhimurium isolates in during mouse infections. I find that the African S. Typhimurium have a higher Salmonella loads in systemic, but not gastrointestinal organs. The higher Salmonella burden of these African isolates is driven predominantly by hyperdissemination from the gut to the systemic tissue. Migratory dendritic cells acting as Trojan horses carrying the Salmonella to the mesenteric lymph nodes are important for the hyperdissemination of these African isolates. Pseudogenization of the gene encoding the secreted effector SseI and differences in the Salmonella virulence plasmid in African isolates drives the higher burden in systemic tissues. Finally, Chapter 6 reflects on the importance of these findings and discusses interesting future directions and possibilities raised by this work.

Keywords: Microbiology and Immunology.
Advisor: Monack Denise M. primary advisor. Thesis advisor
Falkow Stanley advisor. Thesis advisor
Mudgett Mary Beth
Schneider David (David Samuel)
Sonnenburg Justin