Modulator effect of TORID on the pathological activation of inflammasome: a genetic-based approach

• Grant number: 19/06363-4
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2019
• End date: October 31, 2021
• Field of knowledge: Biological Sciences - Immunology - Immunogenetics
• Principal Investigator: Alessandra Pontillo
• Grantee: Alessandra Pontillo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Fernanda Pereira Fernandes ; Iohanã Gabriely Costa Oliveira ; Marcelo Rafael Hill Mongabure ; Vinícius Nunes Cordeiro Leal

Abstract

Inflammasome is a cytosolic complex responsible for the release of inflammatory cytokines IL-1ß and IL-18 in response to microbial and/or cellular stress stimuli. Although it plays a central role in the first line of defense and in the induction of inflammation and adaptive immunity, it may also be involved in chronic inflammation and tissue damage and thus contribute to most common diseases in the general population such as cancer, autoimmune, neurological, cardiovascular and metabolic diseases. Specific genetic variants in inflammatory components or regulators have been associated with these diseases as susceptibility/protection factors, emphasizing the contribution of the complex in their pathogenesis, and suggesting the therapeutic use of commercially available inflammatory inhibitors. Recent findings have shown that the intracellular cation channel TORID is a key regulator of inflammasome activation, and its inhibition or absence would optimize a CD8 + T cell mediated immune response, by favoring inflammasome activation. In this project we propose to describe the regulatory function of TORID in the activation of inflammasome, through a genetic approach. Therefore, we will: (1) evaluate the contribution of variants of the TORID gene in the predisposition and / or prognosis of diseases mediated by CD8 + T cells; (2) characterize the impact of TORID variants on inflammatory activation; (3) to verify the effect of BayK8644, a newly described TORID inhibitor, on inflammatory activation in cells of patients with CD8 + T cell mediated diseases. In this way we hope to identify functional genetic variants in the TORID with modulatory effect on the activation of the inflammassoma and relate them with the incidence and/or severity of specific diseases, infectious or sterile. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GOMES DOS SANTOS, ALEXANDRA; WATANABE, ELIESER HITOSHI; FERREIRA, DAIANE TOMOMI; OLIVEIRA, JAMILLE; NAKANISHI, ERIKA SHIMODA; OLIVEIRA, CLAUDIA SILVA; BOCCHI, EDIMAR; NOVAES, CRISTINA TERRA GALLAFRIO; CRUZ, FATIMA; CARVALHO, NOEMIA BARBOSA; et al. A Specific IL6 Polymorphic Genotype Modulates the Risk of Trypanosoma cruzi Parasitemia While IL18, IL17A, and IL1B Variant Profiles and HIV Infection Protect Against Cardiomyopathy in Chagas Disease. FRONTIERS IN IMMUNOLOGY, v. 11, OCT 22 2020. (19/06363-4, 12/50273-0)

GONCALVES CAMBUI, RAYLANE ADRIELLE; FERNANDES, FERNANDA PEREIRA; CORDEIRO LEAL, VINICIUS NUNES; REIS, EDIONE CRISTINA; DE LIMA, DHEMERSON SOUZA; DO ESPIRITO SANTO, GILMAR FERREIRA; ELIAS, ROSA MARIA; PONTILLO, ALESSANDRA. The Ala134Thr variant in TMEM176B exerts a beneficial role in colorectal cancer prognosis by increasing NLRP3 inflammasome activation. JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, v. N/A, p. 10-pg., 2022-08-18. (19/06363-4)

MENDONCA, LEONARDO OLIVEIRA; MARAGNA TOLEDO-BARROS, MYRTHES ANNA; CORDEIRO LEAL, VINICIUS NUNES; GISLENE VERA ROA, MARIELA ESTEFANY; GONCALVES CAMBUI, RAYLANE ADRIELLE; TOLEDO, ELIANA; BARROS, SAMAR FRESCHI; DE OLIVEIRA, AMANDA MELATO; RIVITTI-MACHADO, MARIA CECILIA; MEDEIROS FRANCESCANTONIO, ISADORA CARVALHO; et al. In-vitro NLRP3 functional test assists the diagnosis of cryopyrin-associated periodic syndrome (CAPS) patients: A Brazilian cooperation. Clinical Immunology, v. 245, p. 8-pg., 2022-10-25. (15/23395-6, 19/06363-4)

FERNANDES, FERNANDA PEREIRA; CAMBUI, RAYLANE ADRIELLE GONCALVES; SOARES, JAINE LIMA DA SILVA; REIS, EDIONE CRISTINA DOS; LEAL, VINICIUS NUNES CORDEIRO; PONTILLO, ALESSANDRA. Cervical carcinoma induces NLRP3 inflammasome activation and IL-1ss release in human peripheral blood monocytes affecting patients' overall survival. Clinical & Translational Oncology, v. 25, n. 11, p. 10-pg., 2023-06-16. (17/10824-1, 19/06363-4, 15/50650-7, 18/04361-1, 15/17373-0)