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Research Project 3

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Human intestinal mucosal immune and functional response to S. typhi

Project Leader: Alessio Fasano, MD 

Abstract:

The intestinal epithelium presents the largest mucosal barrier between the internal host milieu and the external environment.  Under physiological circumstances antigen trafficking occurs through three non-mutually exclusive pathways: transcellular, paracellular, and dendritic cell sampling within the intestinal lumen.  When the delicate balance between controlled antigen trafficking and host immune response is lost, severe inflammation and overt clinical symptoms may develop.  This negative outcome may be influenced by host genetic makeup, virulence traits of the intestinal pathogens, or the combination of both.  The outcome of the interplay between host and intestinal microorganisms is influenced by the fact that the intestinal epithelium is extremely dynamic and exquisitely responsive to stimuli of innumerable variety. The tightness of the epithelial barrier is itself dynamic and depends on tight junctions (TJ) competency, though the mechanisms governing and affecting their permeability are poorly understood.  What is becoming increasingly clear is that modulation of epithelial permeability may affect clinical outcome, namely infection vs. immune-protection. 

Upon exposure to S. Typhi, the host displays a plethora of specific intestinal mucosal immunological effector to resist the infection.  Whereas the molecular mechanisms that determine S. Typhi and the host innate and adaptive innate immune responses have been intensively studied, less is known about the initial cross-talk between the microorganism and gut mucosa that influences downstream immune responses.

With this project, we intend to capitalize on our previous CCHI-supported data to specifically focus on human gut-S.Typhi interaction by challenging the overall specific hypothesis that gut colonization by S. Typhi causes specific mucosal responses mediated by epithelial pattern recognition receptors (PRRs) and the generation of a specific micro-milieu leading to changes in antigen trafficking through the gut mucosal barrier that strongly influence the downstream immunological events leading to either infection or protection. The outcome of this project will highly contribute to the overall objectives of the Center proposal by integrating our mucosal immunological and functional findings with the systemic immune response triggered by S.Typhi (Project 1) and the role of the gut microbiome on these responses (Project 2) with the ultimate goal to develop safe, attenuated S. Typhi vaccines.