Study reveals immune mechanism responsible for part of fatal cases of Covid-19

A study conducted at USP (University of São Paulo) helped to understand, at a molecular level, why part of those infected with SARS-CoV-2 develop a potentially fatal systemic inflammation even after eliminating the virus from the body.

These patients usually spend days in intensive care, requiring mechanical ventilation, and have complications such as pulmonary fibrosis and thrombosis.

According to the research, published on the platform medRxiv in an article that has not yet been reviewed by peers, the condition is related to an inflammatory mechanism known as inflammasome that, in addition to being exacerbated in these critically ill patients, is never deactivated.

In this way, the immune response that causes inflammation does not cease. The discovery could help in the development of more specific treatments for these cases.

“In this study we were able to confirm that the inflammasome, responsible for the excessive immune response [tempestade de citocinas] and which results in high mortality, is not deactivated. This explains some fatal cases of Covid-19,” he says. Dario Zamboni professor at the Faculty of Medicine of Ribeirão Preto (FMRP-USP) and coordinator of two projects on the subject.

The investigation was carried out in Crid (Inflammatory Disease Research Center) –a Fapesp Research, Innovation and Dissemination Center.

As Zamboni explains, the inflammasome is a protein complex that exists inside the defense cells. When this cellular machinery is activated, pro-inflammatory molecules known as cytokines are produced to warn the immune system of the need to send more defense cells to the site of infection.

The group’s new study shows that while a portion of patients hospitalized for Covid-19 have a high viral load and low inflammasome activation — and it’s still not known exactly why they die — another part remains with activated inflammasome, continues with a very high inflammation and ends up dying because of it.

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The research was done with material collected through the lung autopsy of 47 individuals who died of Covid in 2020 – when there was still no vaccine available and several variants of SARS-CoV-2 of concern.

The USP group compared the response to the ancestral virus – which caused the first cases of Covid in the Chinese city of Wuhan – with the response to the influenza virus, which causes the flu. In patients with Covid, inflammasome activation occurs mainly in macrophages (front line of the immune system) and endothelial cells (which line blood vessels), while in influenza type 1 and type 2 pneumocytes (present in lung alveoli) contribute more significantly.

“The inflammasome was much more activated in patients who died from Covid than in patients who died from influenza infection. This helps us understand why mortality was much higher from SARS-CoV-2”, says the doctoral student keyla de safirst author of the study.

The group then analyzed gene expression in lung cells collected by autopsy. “There were clearly two groups of patients: one made up of those who died with a high viral load and little inflammation and another made up of those who died later, with low viral load and a lot of inflammation. Although the patients in the second group no longer had the virus in their body , the inflammasome was not deactivated, which seems to have contributed to the death”, says Sá.

Zamboni explains that the aim of the research was to understand why the same virus can cause such different outcomes. “That’s why we work with patients who died before the development of vaccines and the emergence of new viral strains. It is important to know how the ancestral virus behaves, even because the variants are derived from it, and it continues to circulate in bats”, he says.

In addition to Covid-19 and the flu, the inflammasome is also involved in autoimmune, neurodegenerative diseases, some cancers and other infectious diseases, including Zika and Chikungunya and Mayaro fever.

In the case of COVID-19, a study carried out by CRID researchers, also led by Zamboni, identified, in 2020, that it is the inflammasome that triggers the cytokine storm typical of Covid.

“This new study shows the existence of two groups of patients with severe cases of Covid-19, one of which is unable to deactivate the inflammasome and the inflammatory process, even after viral replication has ceased. Understanding this process is fundamental not only for Covid-19, but for various inflammatory diseases”, highlights Zamboni.

Although it is not yet known why the inflammasome is not deactivated in these cases, the discovery of this mechanism may help in treatment protocols. “It is important to know if the patient is the type that has very high rates of inflammasome, as he can die from complications caused by the inflammatory process, or if he is the type with a lot of viral replication and less inflammation. That is, for future treatments it is necessary to know what to attack: the inflammation or the virus”, he says.