Inflammasome activation by SARS-CoV-2 and the role of this platform in the pathogenesis of COVID-19: a prospective study aiming at NLRP3 inhibition for COVID-19 treatment

• Grant number: 20/04964-8
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2020
• End date: September 30, 2022
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Dario Simões Zamboni
• Grantee: Dario Simões Zamboni
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Leticia de Almeida ; Mariana Martins Chaves ; Paulo Louzada Junior ; Renan Villanova Homem de Carvalho ; Renê Donizeti Ribeiro de Oliveira
• Associated research grant: 19/11342-6 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens, AP.TEM
• Associated scholarship(s): 20/08788-0 - Activation of inflammasome by SARS-CoV-2 and the role of this platform in the pathogenesis of COVID-19: a prospective study aimed at inhibiting NLRP3 for the treatment of COVID-19, BP.PD

Abstract

COVID-19, caused by the new coronavirus (SARS-CoV-2) has become a worldwide health problem, with more than one million confirmed cases and 50,000 deaths by early April 2020. In its most severe forms, COVID-19 symptoms includes fever, cough, fatigue, headache and may progress to respiratory distress syndrome and death. The severe cases of COVID-19 are characterized by an intense inflammatory process, with recruitment of neutrophils and classically activated macrophages. High concentrations of inflammatory cytokines are also found, such as IL-6 and IL-1², which is produced in a manner dependent on the inflammasome, a complex intracellular protein that promotes inflammatory processes. The presence of high concentrations of IL-1² in patients suggests an important participation of the inflammasome in the pathogenesis of COVID-19. Thus, we intend to evaluate the inflammasome activation in response to infection by SARS-CoV-2 in cell cultures and in clinical material obtained from patients with COVID-19. We also intend to monitor the inflammasome activation in a prospective study with 60 patients hospitalized for SARS-CoV-2 at HC-FMRP who will be treated with chloroquine in combination (or not) with colchicine, a drug widely used for the treatment of mediated diseases by NLRP3 inflammasome, such as gout. Colchicine prevents the formation of tubulin dimers, inhibiting various cellular processes including the activation of the inflammasome. Thus, the development of this research project should directly contribute to the understanding of the pathophysiology of COVID-19. It will be possible to identify the mechanisms that promote the intense inflammatory process observed in patients infected with SARS-CoV-2, as well as to propose the use of colchicine as a possible treatment for COVID-19. (AU)

Scientific publications

(5)

(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)

LOPES, MARIA ISABEL; BONJORNO, LETICIA P.; GIANNINI, MARCELA C.; AMARAL, NATALIA B.; MENEZES, PAMELLA INDIRA; DIB, SAULO MUSSE; GIGANTE, SAMARA LIBICH; BENATTI, MAIRA N.; REZEK, UEBE C.; EMRICH-FILHO, LAERTE L.; et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD OPEN, v. 7, n. 1, 2021. (13/08216-2, 20/05601-6, 20/05288-6, 20/04964-8)

DE ALMEIDA, LETICIA; DA SILVA, ALEXANDRE L. N.; RODRIGUES, TAMARA S.; OLIVEIRA, SAMUEL; ISHIMOTO, ADRIENE Y.; SERIBELLI, AMANDA A.; BECERRA, AMANDA; ANDRADE, WARRISON A.; ATAIDE, MARCO A.; CAETANO, CAMILA C. S.; et al. Identification of immunomodulatory drugs that inhibit multiple inflammasomes and impair SARS-CoV-2 infection. SCIENCE ADVANCES, v. 8, n. 37, p. 15-pg., 2022-09-16. (20/04964-8, 13/08216-2, 19/11342-6)

RODRIGUES, TAMARA S.; CAETANO, CAMILA C. S.; DE SA, KEYLA S. G.; ALMEIDA, LETICIA; BECERRA, AMANDA; GONCALVES, AUGUSTO, V; LOPES, LETICIA DE SOUSA; OLIVEIRA, SAMUEL; MASCARENHAS, DANIELLE P. A.; BATAH, SABRINA S.; et al. CASP4/11 Contributes to NLRP3 Activation and COVID-19 Exacerbation. Journal of Infectious Diseases, v. 227, n. 12, p. 12-pg., 2023-02-10. (13/08216-2, 20/04964-8, 19/11342-6)

RODRIGUES, TAMARA S.; ZAMBONI, DARIO S.. Inflammasome activation by SARS-CoV-2 and its participation in COVID-19 exacerbation. CURRENT OPINION IN IMMUNOLOGY, v. 84, p. 6-pg., 2023-10-01. (13/08216-2, 20/04964-8, 19/11342-6)

RODRIGUES, TAMARA S.; DE SA, KEYLA S. G.; ISHIMOTO, ADRIENE Y.; BECERRA, AMANDA; OLIVEIRA, SAMUEL; ALMEIDA, LETICIA; GONCALVES, V, AUGUSTO; PERUCELLO, DEBORA B.; ANDRADE, WARRISON A.; CASTRO, RICARDO; et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. JOURNAL OF EXPERIMENTAL MEDICINE, v. 218, n. 3, MAR 1 2021. (20/04964-8, 13/08216-2, 19/11342-6)