| Salmonella typhimurium is a foodborne pathogen that persistently colonizes the gastrointestinal tract of livestock and poultry, and is a causative agent of gastroenteritis in humans. Understanding the molecular basis of bacterial persistence is critical for stemming zoonotic outbreaks and for the management of disease in humans. In this thesis, we use the C. elegans pathogenesis model to address the question of how S. typhimurium establishes a persistent intestinal infection.; We began our studies by characterizing the pathophysiology of infection. Using well-characterized Salmonella mutants, we found that PhoP, pSLT, and the SPI-1 and SPI-2 type III secretion systems are required for intestinal persistence. Next, we demonstrated that resistance to host induced antimicrobial peptides is a strategy used to establish stable intestinal infection. We showed that the nematode responds to Salmonella infection, in part by inducing the expression of two antimicrobial genes, abf-2 and spp-1. Reducing expression of these antimicrobials resulted in increased bacterial proliferation. Importantly, loss of spp-1 was sufficient to restore the ability of phoP, SPI-2, and pSLT mutants to persist. Encouraged by the feasibility of this host-pathogen system for discerning virulence factors, we developed an in vivo visual screen to identify additional bacterial genes required for intestinal persistence. Mutants with persistence defects fall in several functional categories including metabolism, attachment, and cell membrane stability, providing us with clues about the host environment and adaptive challenges Salmonella encounters in the nematode gut.; The work presented here provides the first in-depth descriptive and genetic analysis of proximal events of Salmonella infection in worms. Our experimental system reveals the importance of antimicrobial resistance in establishing Salmonella in the intestine. This has immediate implications, as the outcome of Salmonella infections in humans is reliant upon effective control of this pathogen in the intestinal tract. We demonstrate additional functions of SPI2 and the virulence plasmid in the context of resistance to antimicrobial peptides, and suggest new roles of these effectors during the extracellular phase of Salmonella pathogenesis in humans. My work highlights the utility of C. elegans for understanding mechanisms of intestinal persistence, and for uncovering novel bacterial factors required for mammalian pathogenesis. |
