Integration of mucosal immune responses through the enteric nervous system

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DESCRIPTION (provided by applicant): Inflammatory responses play a key pathogenic role in the main causes of mortality in Western societies. Lack of proper protective inflammation is also directly linked to susceptibility to infection, a major concern in developing countries. Nowhere is the balance between protective inflammation against pathogens and tolerance towards innocuous substances more challenging than at the intestinal surface, which represents the largest surface of the body exposed to the environment. The human intestine absorbs roughly 80g of proteins daily and deals with about 1014 bacteria. Although most of its microbes are represented by non- invasive commensals, the intestine is also a target for parasites, viruses, fungi and pathogenic bacteria. Not surprisingly, the immune system associated with the intestine accounts for the majority of B and T lymphocytes in the body. Apart from containing the largest lymphoid organ in the body, the digestive tract is recognized as "a second brain", with as many neurons as the spinal cord. The enteric nervous system (ENS) is organized in several plexuses throughout the intestinal wall. The mucosal layer contains nerve networks known as the mucosal plexus, which contains nerve endings that are potentially in contact with mucosal immune cells, although the exact nature of such associations is to be determined. Our preliminary characterization shows that antigen-presenting cells (APCs) are in close proximity to neuronal axons within the intestinal lamina propria. These axons extend towards the myenteric plexus, where they are also surrounded by a previously unappreciated population of APCs. This population of APCs quickly responds to inflammatory stimuli from pathogenic bacteria from the mucosal region, even before any detectable bacteria can be found at deeper regions of the intestinal wall. We hypothesize that intestinal neurons may integrate inflammatory signals received at one region of the mucosal surface, preparing the intestinal tissue for a quick response, avoiding systemic invasion. The experiments aim to characterize this interaction using a sophisticated multi-photon intravital microscopy and novel mouse strains in which visualization of this communication in vivo is enabled by genetic labeling. The investigation of the dynamics of APC behavior in the two regions at steady state and under intestinal infection conditions will be followed by the analysis of functional implications of altered neuronal activity in the recruitment and activity of these innate immune cells. Using my expertise in mucosal immunology, combined with the rich environment of neuroscientists at the Rockefeller University, I expect to expand our understanding of the functional repercussions of neuroimmune interactions. The knowledge gained from this highly innovative study will shed light on previously unappreciated multidirectional interactions between the immune system and the nervous system, enhancing our comprehension of gut immunity, opening new avenues for the design of alternative treatment for intestinal infections and inflammatory diseases.