Shigella species are highly infectious and important pathogens of humans. In 2016, there were an estimated 269 million cases and 212,000 deaths due to Shigella. Humans are typically infected with Shigella after oral ingestion of a minimal inoculum, consisting of as few as 10-100 bacteria. A major roadblock in Shigella research is the lack of an in vivo oral infection mouse model that recapitulates key aspects of human disease. Mice resist oral doses of Shigella as high as 100 million bacteria, but the reason for this resistance remains poorly understood. In our preliminary data, we describe our discovery that the reason mice are resistant to Shigella is because of a robust and mouse-specific innate immune inflammasome response in intestinal epithelial cells. Mice lacking inflammasomes are thus susceptible to oral Shigella infection and provide the first opportunity to use the full repertoire of mouse genetic and immunological tools and methodologies to dissect Shigella pathogenesis in a physiological infection model. Importantly, our data suggest that inflammasome-deficient mice are a highly relevant model because, in humans, we find Shigella inhibits or evades the NAIP/NLRC4 inflammasome. We propose three Specific Aims.
In Aim 1, we will characterize innate immune and bacterial factors responsible for shigellosis in vivo.
In Aim 2, we will characterize the adaptive immune responses of mice to wild-type and mutant Shigella. In, Aim 3, we will test the hypothesis that Shigella encodes effectors to inactivate the human NAIP/NLRC4 inflammasome. By exploiting the experimental tractability of our new model, we hope to identify the key factors mediating immunity and disease during Shigella infection, thereby providing a foundation of knowledge to inform the development of safer and more effective vaccines.
Shigella species are a major global cause of morbidity and mortality, estimated to be responsible for 269 million cases and 212,000 deaths annually. There is no approved vaccine and only a poor understanding of natural or vaccine-elicited immunity, in large part because of the lack of a physiological mouse model of infection. In this application, we propose to take advantage of our development of a new oral infection mouse model of shigellosis to answer fundamental questions about Shigella pathogenesis and immune responses to this important global pathogen.