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The role of neuroimmune interactions in the development of the "immunological scar" after acute intestinal infection

Grant number: 17/14209-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): December 01, 2017
Effective date (End): April 26, 2019
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Denise Morais da Fonseca
Grantee:Marcela Davoli Ferreira
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:15/25364-0 - Impact of infection-induced immunological scarring on the long-term host metabolic homeostasis, AP.JP

Abstract

The gut barrier is in close contact with environmental antigens and beneficial microbial commensal communities ensuring efficient digestion, xenobiotic degradation and protection against pathobionts. To establish effective anatomical and functional barriers against commensals and pathogens, the mucosal wall encompasses complex cellular networks, including neural and immunological pathways that are constantly monitoring and responding against environmental challenges. Recent studies have demonstrated the crucial role of molecular interactions between the gut microbiota, enteric nervous system and the immune system for the maintenance of intestinal homeostasis. Thus, injuries causing disbiosis or microbiota translocation could induce important changes in neuronal and immune cells interactions, culminating in the development of enteropathy. Recently, our group showed that a single episode of oral infection by Yersinia pseudotuberculosis leads to microbiota translocation to mesentery, affecting mucosal homeostasis and inducing a chronic local inflammation, that persists irreversibly after bacterial clearance. Indeed, such changes in the gastrointestinal tract are common after acute infections and may persist for years after the pathogen clearance. However, the mechanisms preventing the reestablishment of local homeostasis in this scenario are unclear. We hypothesized that the oral infection by Y. pseudotuberculosis may induce structural and functional changes in the mesenteric nervous system by altering the levels of several neural mediators, which would be essential for restoring homeostasis or inducing/maintaining chronic mesenteric inflammation. Therefore, in this project, we will study whether acute episodes of infection may drive remodeling of the mesenteric nervous system in order to determine the role of such changes in the establishment of chronic inflammation. In addition, considering that individuals with chronic inflammatory bowel diseases are a group at risk for the development of colorectal cancer, we will investigate whether a single episode of acute intestinal infection increases the predisposition to the development of colorectal cancer in experimental model. Finally, by using samples obtained from patients with colorectal cancer, we will test potential candidates of biomarkers of mesentery remodeling and outcome of the disease. We believe that this study will open new perspectives for understanding how the infectious history of an individual could interfere with the breakdown of the immune homeostasis and promote the development of chronic diseases, such as cancer. The data obtained in this project will allow the identification of biomarkers for identification of important changes in the mesenteril and will also provide new tools for the development of strategies for the prophylaxis of chronic inflammatory diseases.