Signaling through intestinal MUC receptors by bacterial Serine Proteases of Enterobacteriaceae

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Abstract Both, Enteroaggregative Escherichia coli (EAEC) and Adherent-Invasive E. coli (AIEC) are associated with clinical and subclinical inflammation. EAEC is an important pathogen of traveler's diarrhea, diarrhea in industrialized countries and growth faltering in developing countries. Clinical findings suggest that the host inflammatory responses play a substantial role in EAEC pathology given that elevated levels of pro- inflammatory markers, including interleukin (IL)-8, IL-1β, fecal lactoferrin and leukocyte infiltrates are often found in EAEC-infected individuals. Most importantly, even asymptomatic patients infected with EAEC were found to exhibit growth retardation and intestinal inflammation. On the other hand, AIEC has been implicated in the pathogenesis of the Inflammatory Bowel Disease (IBD) and it is often found adhered to the inflamed intestinal mucosa. Persistent infection with AIEC leads to chronic inflammation and intestinal fibrosis. Nevertheless, the culprits associated with the inflammatory response during infection with these pathogens are not entirely understood. Increasing evidence suggests that bacterial luminal protease activity and activation of protease receptors ultimately results in increased intestinal permeability and exacerbation of colitis in animal models and in human. In this regard, our data suggest that proteases belonging to the serine protease autotransporter of Enterobacteriaceae (SPATEs) family are associated with inflammatory processes by binding and cleaving transmembrane signaling mucins (MUC). Our overall hypothesis is that SPATEs with mucinolytic activity trigger intestinal inflammation by targeting intestinal MUC receptors during bacterial infections. This project is comprised by three specific Aims. In Aim 1, we will characterize the signaling pathways activated by C2S through intestinal MUC receptors using human colonoids. In Aim 2, we will investigate if mammalian lectin, sheddases and SPATEs use the same mechanism to activate MUC receptors and if they trigger similar signaling pathways. In Aim 3, we will investigate the role of SPATEs in the pathogenesis of EAEC and AIEC in the context of MUC receptor signaling. We will leverage the experimental systems and collaborations developed under current projects to take this understanding to an actionable level and identify promising lead interventions.