Study reveals immune mechanism responsible for some fatal COVID-19 cases
August 24, 2022
By Maria Fernanda Ziegler | Agência FAPESP – A study conducted at the University of São Paulo (USP) in Brazil helps explain at the molecular level why some people infected by SARS-CoV-2 develop a potentially fatal systemic inflammation even after their organism has eliminated the virus. These patients typically spend days in intensive care, require mechanical ventilation, and suffer from complications such as pulmonary fibrosis and thrombosis.
According to an article on the study posted to the preprint platform medRxiv and not yet peer-reviewed, in some critical patients a mechanism known as inflammasome is both exacerbated and persistent because the immune response that causes the inflammation fails to shut down. The discovery is relevant to the development of specific treatment for such cases, the authors note.
“We confirmed that the inflammasome responsible for the excessive immune response [called a cytokine storm] that leads to death in many cases isn’t deactivated. This explains some fatal cases of COVID-19,” said Dario Zamboni, a professor at the Ribeirão Preto Medical School (FMRP-USP) and principal investigator for two projects on inflammasomes (19/11342-6 and 20/04964-8).
Zamboni explained that inflammasomes are protein complexes inside defense cells. When this cellular mechanism is activated, pro-inflammatory molecules known as cytokines are produced to warn the immune system that more defense cells need to be sent to the infection site.
The study shows that some patients hospitalized for COVID-19 have a high viral load with low inflammasome activation and why they die is unknown, whereas others have very intense inflammation with continuously activated inflammasomes and die for this reason.
Lung tissue samples were collected by minimally invasive autopsy from 47 COVID-19 patients who died in hospital in 2020, when no vaccines were available and the several SARS-CoV-2 variants of concern had not yet emerged. The researchers analyzed responses to the ancestral strain of the virus (which caused the first cases of COVID-19 in the Chinese city of Wuhan), as evidenced by these samples, and compared them with responses to the influenza virus, as evidenced by lung samples from flu patients who died between 2012 and 2020. In the COVID-19 patients, inflammasome activation occurred mainly in macrophages (the first line of defense against pathogens) and endothelial cells (which line the inside of blood vessels), while type I and type II pneumocytes (which line the alveoli, or air sacs, in the lungs) contributed more significantly in the flu patients.
“Inflammasomes were much more activated in the patients who died from COVID-19 than those who died from infection by the influenza virus. This also helps us understand why mortality was much higher among the former,” said PhD candidate Keyla de Sá, first author of the article.
The group then analyzed gene expression in the lung cells collected by autopsy. “These patients could clearly be divided into two groups: those who died with a high viral load and mild inflammation, and those who died at a later stage, with a low viral load and severe inflammation,” Sá said. “Although the second group no longer had the virus in their organism, their inflammasome hadn’t shut down, and this appears to have been a key factor in their death.”
Zamboni explained that the aim of the investigation was to understand why infection by the same virus can lead to such different outcomes. “That’s why we chose patients who died before there were any vaccines and before the emergence of viral variants,” he said. “It’s important to know how the ancestral virus behaves. The variants derive from it, after all, and it continues to circulate in bats.”
Other diseases that trigger inflammasomes, besides COVID-19 and flu, include autoimmune and neurodegenerative disorders, some kinds of cancer, and infectious diseases such as zika, chikungunya, and Mayaro fever.
In the case of COVID-19, in 2020 another CRID study led by Zamboni found that the cytokine storm typical of the disease is inflammasome-triggered (more at: agencia.fapesp.br/34732).
“This new study revealed the existence of two groups of severe COVID-19 patients, one of which is unable to deactivate the inflammasome and inflammatory process even after viral replication has stopped. It's important to understand this process in other inflammatory diseases besides COVID-19,” Zamboni said.
Why the inflammasome is not deactivated is unknown, but the discovery of this mechanism will contribute to the development of treatments for such cases. “It’s important to know whether patients belong to the type with very high inflammasome levels, as they can die from complications due to the inflammatory process, or the type with less inflammation despite intense viral replication. In other words, for future treatments we’ll need to know whether to tackle the inflammation or the virus,” he concluded.
The article “Inflammasome activation and pulmonary viral loads define two distinct clinical outcomes in COVID-19" is at: www.medrxiv.org/content/10.1101/2022.06.24.22276878v1.full.
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