Covid-19: Toulouse researchers discover a receptor capable of sabotaging the multiplication of the virus

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Toulouse researchers have just made a key discovery in understanding the spread of Covid-19 in the body. They show that, in the immune system, a receptor acts as a decoy against the virus and sabotages its multiplication action by causing the death of the infected cell. This work is published in the journal Molecular Cell.

What happens once cells in the nose, throat and lung are infected with the SARS-CoV-2 virus that induces Covid-19? This is what researchers from IPBS, the Institute of Pharmacology and Structural Biology in Toulouse, wanted to know. “When the Covid-19 epidemic started, in 2020, everyone was afraid of ‘sepsis’, this over-inflammation of one or more organs which can lead to death. Our team, which works on bacteria and sepsis, decided to position itself on the virus because the mechanisms involved seemed similar to us”, explains Etienne Meunier, director of the “Detection and elimination of pathogens” team.

After the first confinement, when researchers are finally allowed to return to work in CNRS laboratories, the team tackles this problem directly.

“When a cell is infected, it dies, and therefore prevents the virus from spreading, but if too many cells die, over-inflammation appears in parallel with the organ’s inability to repair itself properly, which can lead to to its destruction. It is therefore necessary to understand the mechanisms of cell death in the infection in order to target them effectively, either by activating them or by inhibiting them, summarizes the biologist. We sought to find out what, in the cells of the lung, can cause cell death in response to SARS-CoV-2. And we found, totally by chance, the NLRP1 receptor.”

When the receptor activates, the cell dies and prevents the virus from multiplying

NRP1 is an inflammasome, a complex of immunity proteins in humans, which reacts when it detects danger. According to the work of the Toulouse team, during the infection of respiratory cells by SARS-CoV-2, the NLRP1 receptor behaves like a trap. “The SARS-CoV-2 virus develops in the body by hiding and attacking cellular defenses: thanks to the protease NSP5, a viral scissor, it creates new infectious viral cells which spread and infect new cells. At the same time, SARS-CoV-2 defuses the defenses that the cell has put in place, allowing it to multiply without too much pressure.But, by cutting off the NLRP1 receptor which behaved like a decoy by mimicking the proteins of the SARS-CoV-2 virus, the opposite effect occurs: NLRP1 is activated and becomes toxic for the cell.

In other words, this receptor “sabotages” the cell to counter the virus: “The cell dies and thus prevents the virus from multiplying (this is the case for 85% of people affected by the Covid-19 virus). However, this cell death becomes problematic when, instead of controlling infection, it leads to hyperinflammation in people susceptible to SARS-CoV-2, likely due to their inability to effectively utilize their body’s entire antiviral arsenal “, details the researcher.

The “cellular saboteur” NLRP1 is therefore a key molecule for the protection of the body against the virus which triggers Covid-19, while also being the element which can trigger the inflammatory storm and therefore the destruction of the lungs.

The same receptor involved in skin diseases, allergies

Étienne Meunier and his team will continue their research on human cells to target NLRP1. Molecule libraries are also screened to see if any can inhibit NLRP1. “This NLRP1 receptor is not expressed on the rodent models we are studying, we had to find it! We came across it by chance but it opens up unimaginable fields of research… There was an elephant in a corridor and we were looking at the walls!” enthuses the researcher, citing the pathologies in which NLRP1 is involved: skin diseases, skin tumours, asthma, allergies, neurodegenerative diseases.

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