UC Berkeley

Shigella species, the causative agents of bacillary dysentery or shigellosis, infect more than 250 million people each year and are a major driver of diarrheal associated morbidity and mortality world-wide. Shigella induces severe gastrointestinal disease by colonizing and disseminating within the epithelial lining of the human colon and rectum, events that drive significant inflammation in the gut. Despite this heavy disease burden, little is known about the molecular determinants of pathogenesis during infection and the adaptive immune correlates of protection up re-infection, due largely to the lack of an inexpensive, tractable, and physiologically relevant mammalian model of shigellosis. Indeed, a detailed understanding of the immune response to this pathogen is critical for the development of vaccines to Shigella, none of which has been effective enough at eliciting protection to be licensed for use in humans. Mice are an ideal system to model human specific disease because of their short generation time, the relatively low cost and effort to maintain a mouse colony for research, and the extensive immunological and genetic tools that have been established in this organism over the past half-century. Wild-type laboratory mice, however, are intrinsically resistant to high doses of oral Shigella challenge and the genetic and mechanistic underpinnings of this resistance have remained largely unknown. My dissertation examines the host innate immune factors in mice that dictate resistance to oral Shigella infection. In the first chapter I review what is currently known about Shigella pathogenesis, discuss the animal models that have been used to establish this understanding, and provide background on innate immune pathways in humans and mice that sense Shigella. In the second chapter I describe the genetic basis of resistance to Shigella infection in mice and show that NAIP–NLRC4 inflammasome-deficient mice are susceptible to Shigella infection and serve as a physiologically relevant model of dysentery. In the third chapter, I use this model to expand our understanding of innate immune resistance to Shigella infection and show that a redundant, layered hierarchy of cell death in intestinal epithelial cells is key to this resistance. Finally, in the fourth and final chapter, I describe how our findings advance the field and comment on how our new model of Shigella infection can be leveraged to learn more about the immune response to this deadly intestinal pathogen.