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Development of an experimental model of environmental Enteropathy

Grant number: 18/00458-0
Support type:Scholarships in Brazil - Master
Effective date (Start): June 01, 2018
Effective date (End): February 29, 2020
Field of knowledge:Biological Sciences - Immunology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Denise Morais da Fonseca
Grantee:Jaqueline Marques Santos
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

In middle-to-low income countries, problems associated to sanitization and chronic malnutrition contribute for the high prevalence of infection with pathogenic microbes through fecal-oral transmission. In particular, children living in conditions of poor sanitation and nutrition frequently develop Environmental Enteropaties. Environmental Enteropathy, or Environmental Enteric dysfunction is a subclinical chronic inflammatory condition affecting the small intestine which exerts a fundamental impact in malnutrition, persistence of stunted growth, cognitive dysfunction, and loss of productivity. The Environmental Enteropathy is characterized by the disturbance in small intestinal structure and impaired gut barrier function, enabling microbial translocation and chronic systemic and local inflammation, which may impair nutrient absorption and growth. In addition, children harboring Environmental Enteropathy do not respond properly to oral vaccines, such as Polio or Rotavirus vaccines. Infections early in life, associated with malnutrition, have been suggested as the key events for the pathogenesis of this condition. However, the etiology of the disease remains unknown and no animal model exists to date, the creation of which would aid in understanding this complex disease. We have shown that long term after the clearance oral infection with defined pathogens, e.g. Yersinia pseudotuberculosis, mice present chronic inflammation in the gut and mesentery. This inflammation is associated with a breakdown of the mucosal barrier and lymphatic system, which deviates the migration of dendritic cells from the gut to the lymph nodes and, in last instance, impair the activation of immunity against oral vaccines. Since oral infection and failure of oral vaccination have been implicated with Environmental Enteropathy, the aim of this study is to develop an experimental model of this disease. For that, we will associate the oral infection with Y. pseudotuberculosis or a disbiosis-inducing pathogen (Toxoplasma gondii) with different types of malnourished diets. Mechanistically, we will test the contribution of the microbiota and of the breakdown of mucosal barrier driven lymphatic damage for the chronic intestinal inflammation and impairment of oral vaccine immunogenicity in this model. Finally, we believe that by having an appropriate animal model and understanding the pathogenesis of of this understudied disease will allow for the the uncover of new biomarkers as well as the development of new interventions against this disease, including changes in the diet and the use of pre- or probiotics. (AU)