Inflammasome activation by SARS-CoV-2 and the role of this platform in the pathoge...
| Grant number: | 20/05430-7 |
| Support type: | Regular Research Grants |
| Duration: | July 01, 2020 - June 30, 2022 |
| Field of knowledge: | Health Sciences - Medicine - Medical Clinics |
| Principal Investigator: | Andrei Carvalho Sposito |
| Grantee: | Andrei Carvalho Sposito |
| Home Institution: | Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil |
| Assoc. researchers: | Deepak L Bhatt ; Derek Yellon ; Fabio Fernandes ; José Luiz Proença Módena ; Maria Luiza Moretti ; Mario Jose Abdalla Saad ; Maurício Wesley Perroud Júnior |
| Associated research grant: | 13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID |
Abstract
Since its report by the World Health Organization in February 2020, SARS-CoV-2 has spread rapidly at an alarming rate, becoming a pandemic on March 12, 2020. In early April, more than 1 million cases were reported. confirmed and there are no signs of slowdown in transmission. Brazil, with more than 10,000 cases as of the beginning of April 2020, is the most affected country in Latin America and its daily growth of confirmed cases is on an equal footing with the rest of the world.Pyroptosis is an inflammatory form of programmed cell death that occurs most frequently after infection by intracellular pathogens and has been described as occurring in severe coronavirus infections caused by SARS-CoV, MERS-CoV and SARS-CoV-2. Through a direct effect of viral capsule proteins such as viroporin 3a, the NLRP3 inflammasome is activated generating damage and rupture of the cell membrane. This process is further intensified with the activation of caspase-1 and the production of gasdermin D and interleukin 1B; (IL1B). In addition, cell death results in the release of DAMPs in neighboring cells and subsequent activation of the NLRP3 inflammasome, thus propagating the extent of the damage. In this context, reaching the inflammatory cascade and pyroptosis is potentially a viable way to control host injury in cases of severe COVID-19.Diacerein and its active metabolite, the reign, decreases the production of IL-1B AND cell death by pyroptosis by inhibiting caspase-1 E can also inhibit IL-6 production. The attenuation of the production of these inflammatory cytokines has the potential to decrease the severity of the disease, especially in those who are hospitalized with COVID-19. In cell models, the inflammatory response to IL-1B is completely reversed with diacerein treatment. In a rat model of acute sepsis-induced inflammation, diacerein reduced caspase activity and kappa nuclear factor B. Currently, there are no studies on the effect of diacerein on the acute inflammatory response in humans. However, by extrapolating human and in vitro animal model data to patients with severe manifestations of COVID-19, it can be postulated that the attenuation of pyroptosis and inflammatory activation may be a clinical benefit for these patients. Diacerein has been on the market for approximately 20 years and has been approved for use in osteoarthritis and other inflammatory conditions like Epidermolysis Bullosa. It is accessible and well tolerated by patients with rare cases of gastrointestinal disorder.For this, 300 patients will be enrolled in a double-blind, randomized, placebo-controlled study in which diacerein treatment will be tested. The primary outcome will be time to clinical worsening, defined as the time from randomization to mortality or worsening of the World Health Organization (WHO) progression scale. Secondary and tertiary outcomes will be aimed at understanding disease mechanisms and investigating risk predictors. (AU)