Molecular and purinergic mechanisms involved in the gut-lung axis dialogue through exposure to the Escherichia coli-derived toxin - LT1

• Grant number: 21/15185-2
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): August 01, 2022
• Effective date (End): July 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Denise Morais da Fonseca
• Grantee: Caio Loureiro Salgado
• Supervisor: Henrique Borges da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Mayo Clinic, Arizona, United States
• Associated to the scholarship: 19/13916-0 - Study of the tissue-specific response during exposure of the intestinal mucosa to bacterial toxins, BP.DR

Abstract

Recent studies point to the hypothesis of communication between the intestinal and pulmonary mucosa through mediators from the gastrointestinal (GI) tract. These mediators can interfere with the homeostasis of distant tissues, such as the lung; conversely, changes in the lung microenvironment can regulate the homeostasis of the GI tract. However, the function of the mucosal-associated immune system has been studied in a compartmentalized manner, as if there were no communication between the different sites. Thus, the influence of the lung-GI tract communication in the development of mucosal immune responses remains understudied. Our objective is to use a model of exposure to the heat-labile toxin (LT) produced by enterotoxigenic Escherichia coli (ETEC) to investigate the molecular mechanisms behind the gut-lung immune communication. We have already demonstrated that the use of ETEC or ETEC-derived recombinant LT1 can result in a protection associated with decreased eosinophil function against the chronic exposure to lung allergens. We hypothesize that sensing of the "danger signal" extracellular ATP (through its receptor P2RX7 in immune cells) induced by LT exposure activates a signaling cascade mediated by IL-33 and eotaxin in the intestine, leading to inhibition of eosinophilic accumulation in response to lung allergen exposure. To test this hypothesis, we will use the fate-mapping mouse model Ubiquitin (UBC)-Cre-ERT2 to identify which immune cell populations translocate between the GI tract and the lung. We will also use Anti-IL33 blocking antibodies and P2rx7fl/villin-cre mice to verify if ablation of these pathways reverts the ETEC-mediated protection against allergen exposure. Our results, beyond defining immunological aspects of the gut-lung communication axis, may serve to put the hygiene hypothesis in a new perspective, demonstrating that gastrointestinal bacterial infections interference on the development of allergic diseases may be due to mediators other than Th1 lymphocytes and Tregs. (AU)