Mechanisms involved in protection against Metabolic Syndrome after infection with Yersinia pseudotuberculosis

• Grant number: 24/14290-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2025
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Denise Morais da Fonseca
• Grantee: Bernardo de Castro Oliveira
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 21/06881-5 - Gut-lung axis: understanding the immune dialogue between barrier tissues in the development of disease, AP.JP2

Abstract

The 21st century emerged with a high prevalence of Chronic Non-Communicable Diseases(NCDs), such as hypertension, neurodegenerative diseases and chronic inflammatory diseases. Agroup of these diseases, called Metabolic Syndrome, encompasses conditions that are intrinsicallyrelated, such as diabetes, obesity and dyslipidemia. An often forgotten condition in this spectrum isNon-Alcoholic Fatty Liver Disease, characterized by the accumulation of fat within hepatocytes,which can later progress to steatohepatitis, cirrhosis and even liver cancer. NASH (non-alcoholicsteatohepatitis) is one of the leading causes of liver cancer and leads to liver transplants. Dietaryfactors such as the consumption of foods rich in lipids and sugars may be related to thedevelopment of type 2 diabetes and obesity. One of these factors is the excessive consumption offructose, present in foods such as fast foods. Through several mechanisms, fructose exerts apro-steatotic and pro-inflammatory effect on the liver, which may lead to NASH. As NASH is achronic stressor, cells of the immune system, which were previously found in the vascular system,are unable to return to homeostasis. CD8 T lymphocytes and pro-inflammatory monocytes havebeen linked to the development of this condition. Through the intrinsic connection between theintestine and liver, it is possible that changes in one of these tissues can reverberate in the otherand vice versa. Impairment of canonical intestinal responses, for example, can lead to failures ofthe immune response in the liver. Furthermore, fructose as an ingested food leads to increasedintestinal permeability, which is a critical factor in the development of NASH. Other factors such aschanges in the microbiota can also affect the course of this disease. At the Mucosal ImmunologyLaboratory, we developed a model of acute gastrointestinal infection caused by the bacteriaYersinia pseudotuberculosis (Yp), which causes permanent failure of intestinal canonicalresponses after elimination of the infection, in addition to prominent inflammation in the mesenteryalso characterized by lymphatic dysfunction with chylomicron extravasation. In previous workdeveloped during the scientific initiation project of the proposing scholarship holder (Oliveira et. al,unpublished data) we found that previous Yp infection promotes resistance to a high-fathigh-fructose model of Metabolic Syndrome. We also found that this was related to the protectionof hepatocytes from steatosis and the presence of an infiltrate of regulatory T lymphocytes in theliver parenchyma. Therefore, the objective of this project is to investigate these and othermechanisms involved in resistance to metabolic syndrome caused by previous YP infection.