Thursday, April 3, 2025
4/3/2025
Host factors in shigellosis - Abstract The intestinal pathogen Shigella flexneri is the causative agent of bacillary dysentery and is responsible for more than 250 million cases of dysentery annually, resulting in more than 200,000 deaths. The disease results from epithelial cell infection in the colon, leading to mucosal ulceration, vascular lesions and massive immune cell infiltration. Various animal models have been used to model various aspects of the disease, but none of these models recapitulated the colonic symptoms of human shigellosis. We have recently shown that infant rabbits experience all the symptoms of human shigellosis, including epithelial fenestration in the colon, vascular lesions, immune cell infiltration, and bloody diarrhea. Here, we propose to use the infant rabbit model of shigellosis to investigate the role of host factors in the disease and clarify aspects that are controversial in the field. In Aim1, we will determine the route of intestinal cell infection in the colon. The prevalent view is that S. flexneri invades the epithelium via M cells, a notion that was derived from studies conducted in the small intestine of adult rabbits. Our preliminary data however suggest that in the colon, S. flexneri directly invade epithelial cells. In Aim2, we will clarify the exact role of neutrophils in shigellosis. We will determine if they are the cause of extensive damage inflicted to the colonic tissue, as previously suggested, or if they are indeed beneficial and required for confining the infection process to the mucosa. In Aim3, we will determine the mechanisms supporting S. flexneri interaction with macrophages and dendritic cells, and their role in regulating the resolution of shigellosis.
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