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Effects of C3 in the inflammatory response and fibrosis in the chronic leptospirosis murine model

Grant number: 22/05793-8
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): September 01, 2022
Effective date (End): May 31, 2023
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Lourdes Isaac
Grantee:Leonardo Moura Midon
Supervisor: Maria Gomes-Solecki
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: University of Tennessee Health Science Center (UTHSC), United States  
Associated to the scholarship:18/26574-7 - Complement system and Leptospirosis: understanding the role of C3 in renal fibrosis induced by chronic infection of pathogenic leptospires in murine experimental model, BP.DD


Leptospirosis is an important zoonosis caused by bacteria from the genus Leptospira. It is present in most countries of tropical and mild climates. Approximately 1 million cases are reported each year, with 10% deaths. Leptospira spp. present in contaminated urine can easily spread into water and soil. Infected individuals can be either asymptomatic or present mild or aggravated symptoms, such as jaundice, renal insufficiency, internal bleeding liver and renal failure. Leptospires can activate innate and adaptive immune responses leading to phagocytosis, production of specific antibodies and the activation of the Complement System. When activated, this system generates chemotactic factors, generates opsonins such as C3b and iC3b, which can facilitate phagocytosis, and produce anaphylatoxins C3a and C5a, that can attract and activate immune cells on the inflammation site. The Complement System is also responsible for stimulating antibody production of B cells and inducing the formation of the Membrane Attack Complex (MAC), leading to lysis and microorganism killing. It is well known that leptospirosis can cause renal fibrosis, resulting in exacerbated inflammation and destruction of the renal tissue, causing overload and irreversible damage to the remaining nephrons. This process is classified as a chronic kidney disease (CKD) and can lead to renal failure. Nonetheless, we do not completely understand the mechanism behind this process as well as the role of the Complement System during the renal fibrosis formation after chronic infection by pathogenic Leptospira. At this moment, we are studying the role of C3 during prolonged infections with pathogenic strains of Leptospira (15, 30, 60, 90 and 180 days) in C57BL/6 wild-type mice (B6.C3+/+) and C57BL/6 C3 knockout mice (B6.C3-/-). Our preliminary results show that B6.C3-/- mice, when compared to B6.C3+/+, develop more renal fibrosis after 15 and 30 days of infection by pathogenic L. interrogans. In this project, we aim to study the gene expression of some proteins associated to fibrosis [Collagen type I alpha chain I (COL1A1), alpha smooth muscle actin (±-sma) and vimentin] and inflammatory cytokines, such as interferon gamma (IFN-³), tumor growth factor beta (TGF-²), tumor necrosis factor alpha (TNF-±), and interleukines 6 and 1-beta (IL-6 and IL-1²) in the kidney of infected wild type and C3 deficient mice. In parallel, a proteomic analysis will be performed to identify some differences that may occur in the lack of C3 during Leptospira infection. (AU)

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