Multi-Layered Host-Pathogen Interactions in Salmonella Typhimurium

Abstract

Every organism faces threats from pathogens and relies on different defense mechanisms to survive. Since the early study of bacteriology, the interactions between bacteria and bacterial viruses (bacteriophages or phages), have been investigated and used as tools for understanding many fundamental processes of cell biology. Recently, the study of bacteria and phage interactions has been reinvigorated by the discovery of multitudes of different anti-phage defense systems that reveal that bacterial immunity has many parallels to the building blocks of the eukaryotic immune system. Many bacteria are lysogens, meaning that they coexist with dormant bacterial viruses (prophages). Specific signals induce prophages to enter a lytic, or replicative, phase; thus, bacteria must protect themselves against invading phages and activated prophages. Many anti-phage defense elements are encoded on prophages raising intriguing questions regarding how the prophages and their encoded defense systems interact. Prophages also influence the interactions of bacteria with eukaryotic host cells during infection. Prophage-encoded virulence factors can facilitate bacterial survival and proliferation in the face of the eukaryotic host immune response. However, as bacteria face many stresses during conflict with the eukaryotic immune system that are stimuli to induce lytic replication of prophages, prophages are also a risk to bacterial pathogens. This thesis describes my efforts to understand several layers of host-pathogen interactions in Salmonella Typhimurium encompassing its interactions with its prophages, external phages and mammalian host. Specifically, I initiated this work studying intramacrophage Salmonella persisters, a subpopulation of Salmonella that are growth arrested when stressed by macrophages during infection. I focused first on the phenomenon in which persisters continue chromosomal DNA synthesis despite bacterial growth arrest. Through that, I discovered that intramacrophage persisters experience lytic prophage activation but avoid lysis. I then identified anti-phage defense elements that are encoded in Salmonella prophages and found that prophages and their anti-phage defense elements influence the interaction of Salmonella with macrophages and the interactions between prophages within Salmonella. Characterizing these prophage-encoded anti-phage defense elements, I uncovered multiple ways in which prophages benefit from and cooperate with their encoded anti-phage defense systems. Altogether this work furthers our understanding of both bacterial immunity and its effect on prophages and the interaction of Salmonella with the host immune system during infection.