Pathogens and symbionts: War and Peace at mucosal surfaces and in intestinal crypts.
My previous ERC-funded grant HOMEOEPITH intended to achieve a major transition from our “classical” research focus on deciphering the molecular cross-talks between the invasive bacterial pathogen Shigella flexneri, the gut epithelium, and associated mucosal immune system, to a novel research endeavor aiming to decipher the molecular cross-talks established between the microbiota and the gut mucosa. In summary, a paradigm transition from the “cellular microbiology of pathogens” to the “cellular microbiology of symbionts”. In the proposed program, I wish to strengthen these novel orientations – particularly the most successful and promising lines emerging from the current work – while keeping a balance between the study of symbionts and pathogens, both studied at their interface with the gut mucosa, in order to further our knowledge of the homeostatic and pathogenic mechanisms that respectively characterize a healthy and diseased gut. The intestinal crypt is a key location for the dialogue established between the gut, the microbiota and the pathogens. Because it contains the stem cells, the differentiation and transit amplifying/proliferative compartments of the epithelium, the crypt is essential for epithelial regeneration at homeostasis, and restitution in case of an aggression by a pathogen. Thus the breaking nature of my project will bear on the demonstration that crypt homeostasis depends on signals “emitted” by the microbiota, thereby stressing the depth of our symbiosis with the microbial world, and on the demonstration that the crypt is also the target of enteric pathogens like Shigella, thus introducing the novel paradigm that pathogenesis is not only matter of inflammatory destruction of infected tissues, but also of altered epithelial restitution. In brief, epithelial/tissue restitution is intrinsically part of the innate immune response. An extension of this paradigm is that loss or subversion of the microbiota-crypt homeostasis may account for diseases such as inflammatory bowel diseases (IBD) and colon cancer. This basic knowledge will also be the basis for translational research, particularly the search for molecules that maintain homeostasis and boost antimicrobial defenses.