Impact of infection-induced immunological scar for the development of colon-rectal cancer

• Grant number: 23/15980-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2023
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Denise Morais da Fonseca
• Grantee: Laura Barbosa da Conceição
• 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

During the past century, changes in population lifestyle, including better sanitization and the use of vaccines, antibiotics, and nutritional supplements, not only improved quality of life but also substantially changed the way hosts respond to pathogenic challenges. Despite the reduction in pathogen exposure, acute non-lethal infections are still common, particularly at barrier sites, such as the respiratory and gastrointestinal tracts. In the Laboratory of Mucosal Immunology (ICB/USP) studied the long-term effects of acute episodes of infection in the gut and respiratory mucosa. After certain models of acute gastrointestinal infection (Y. pseudotuberculosis, T. gondii and Citrobacter rodentium) there may be an increase in permeability and leakage of the contents of the lymphatic vessels that drain the gut, this phenomenon is called "immunological scar", that compromises tissue immunity in the long term and can be found in the form of impaired oral tolerance induction after bacterial infection. In parallel, the world has watched a substantial rise in the incidence of cancer incidence and complex inflammatory diseases, including IBD. Colorectal cancer (CRC) is the amongst the most commonly diagnosed and leading causes of cancer-related deaths worldwide. Recent advances in oncology have identified genes and environmental factors associated with oncogenesis and tumor progression during CRC, as well as immunological mediators and microbiota components involved in the disease. However, how the immune communication between mucosal tissues, particularly after the infection recovery, would interfere in tumor progression is still unknown. This work plan aim to understand how previous episodes of intestinal infection would impact anti-tumor immunity locally. We will evaluate the contribution of a previous episode of gastrointestinal (GI) infection to CRC progression. C57BL/6 mice will be orally infected with 1x107 CFU of YP via oral gavage as previously described (Fonseca et al., 2015) and, after the clearance of the infection (4 weeks), the animals will be submitted to a protocol of chemical carcinogenesis by azoxymethane (AOM - 10 mg/kg ip route) followed by 3 cycles with 2% DSS treatment in the drinking water (1 week/cycle). Animals will be euthanized after 12 or 40 weeks post-CRC induction to evaluate the local tumor growth. In addition, blood in the feces and bodyweight will be analyzed every week, and the presence of tumors will be verified by colonoscopy a week before euthanasia. In parallel, we will also analyze the curve of morbidity during the course of the experiment. At 12 and 40 weeks post CRC, we will measure tumor numbers and sizes in mesentery and gut (small and large intestine) will be collected for (1) histopathological analysis, (2) characterization of the cell infiltrate by flow cytometry, (3) characterization of the lymphoid follicles and lymphatic network by confocal microscopy.