Neutrophil extracelular traps (NETs): role in the pathophysiology and potential as a therapeutic target on COVID-19

• Grant number: 20/05601-6
• Support Opportunities: Regular Research Grants
• Duration: May 01, 2020 - April 30, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Fernando de Queiroz Cunha
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Alexandre Todorovic Fabro ; Eurico de Arruda Neto ; José Carlos Farias Alves Filho ; Paulo Louzada Junior ; Renê Donizeti Ribeiro de Oliveira ; Thiago Mattar Cunha
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID
• Associated scholarship(s): 21/09539-6 - Neutrophil Extracelular Traps (NETs): role in the pathophysiology and potential as a therapeutic target on COVID--19, BP.PD; 20/07645-0 - Neutrophil extracelular traps (NETs): role in the pathophysiology and potential as a therapeutic target on COVID-19, BP.PD

Abstract

The disease caused by coronavirus in 2019 (Covid-19) is caused by coronavirus-2 of severe acute respiratory syndrome (SARS-CoV-2) and has become an important health problem worldwide. The pulmonary changes observed in patients with Covid-19 are characterized by intense damage to epithelial and endothelial cells, viral replication in pulmonary tissue and extensive inflammatory process characterized by edema, infiltration of inflammatory cells, including neutrophils and increased tissue concentrations of inflammatory cytokines , such as TNF-±, IL-1 and IL-6. In addition to pulmonary changes, there is also a systemic inflammatory response with important lesions in other organs such as kidneys, heart and intestines. Recent studies suggest that neutrophils participate in lung injuries and possibly in other organs, but it is not yet clear what mechanisms are involved. Among the cytotoxic mediators released by this cell type are free radicals, enzymes and NETs (from Neutrophil Extracellular Traps) or, simply, extracellular traps of neutrophils, which are networks of DNA conjugated with antimicrobial enzymes such as myeloperoxidase (MPO), elastase and citrullinated histones. NETs are described as one of the main mediators responsible for injuries seen in several autoimmune diseases and also in vital organs during sepsis. However, the involvement of NETs in the injuries observed at Covid-19 remains unknown. Therefore, the objective of the present project is to identify the participation of NETs in the pathogenesis of Covid-19. The possible involvement of NETs in the pathogenesis of Covid-19 will allow us to propose new therapeutic approaches for this disease, that is, drugs that degrade this mediator and / or inhibit its synthesis. In this sense, we are also proposing to conduct an open clinical trial treating patients with Covid-19 with Pulmozyme. Pulmozyme is used in the clinic to treat cystic fibrosis and its active ingredient is DNAs that degrade NETs. Confirming the feasibility of the project, in a preliminary experiment, we observed an exacerbated production of NETs by isolated neutrophils and in the plasma of patients affected with Covid-19. (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)

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)

VERAS, FLAVIO P.; GOMES, GIOVANNI F.; SILVA, BRUNA M. S.; CAETITE, DIEGO B.; ALMEIDA, CICERO J. L. R.; SILVA, CAMILA MEIRELLES S.; SCHNEIDER, AYDA H.; CORNEO, EMILY S.; BONILHA, CAIO S.; BATAH, SABRINA S.; et al. Targeting neutrophils extracellular traps (NETs) reduces multiple organ injury in a COVID-19 mouse model. RESPIRATORY RESEARCH, v. 24, n. 1, p. 11-pg., 2023-03-02. (13/08216-2, 20/05601-6)

VERAS, FLAVIO PROTASIO; PONTELLI, MARJORIE CORNEJO; SILVA, CAMILA MEIRELLES; TOLLER-KAWAHISA, JULIANA E.; DE LIMA, MIKHAEL; NASCIMENTO, DANIELE CARVALHO; SCHNEIDER, AYDA HENRIQUES; CAETITE, DIEGO; TAVARES, LUCAS ALVES; PAIVA, ISADORA M.; et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. JOURNAL OF EXPERIMENTAL MEDICINE, v. 217, n. 12, DEC 2020. (13/08216-2, 20/05601-6)

BONILHA, CAIO SANTOS; VERAS, FLAVIO PROTASIO; CUNHA, FERNANDO DE QUEIROZ. NET-targeted therapy: effects, limitations, and potential strategies to enhance treatment efficacy. TRENDS IN PHARMACOLOGICAL SCIENCES, v. 44, n. 9, p. 13-pg., 2023-09-01. (13/08216-2, 21/09539-6, 20/05601-6)