Scientists from EPFL and CHUV Lausanne have found the biological mechanism behind severe forms of Covid-19. They discovered a signaling pathway involved in the hyper-inflammation observed in some patients.
During a viral infection, the host produces proteins called type I interferons (IFN) to defend itself. Patients infected with SARS-CoV-2 who fail to quickly put in place this first defense progress to a severe form of the disease, with pulmonary complications.
Strangely, in these patients, there is then a late IFN response which leads to destructive hyper-inflammation, said Thursday the Federal Polytechnic School of Lausanne (EPFL) and the Vaud University Hospital Center (CHUV) in a press release.
The teams of Michel Gilliet, head of the Department of Dermatology at CHUV, and Andrea Ablasser, head of the Innate Immunity laboratory at EPFL, shed new light on this paradox in the journal Nature.
Signaling molecules
The teams discovered that the late IFN response leading to hyper-inflammation is not triggered by the virus itself, but by the tissue damage it induces, through signaling molecules called cGAS-STING.
These molecules detect the DNA – dropped by dying cells – which enters the interior of the cells and then triggers the IFN response leading to hyper-inflammation: a “cytokine storm” which ends up generating more tissue destruction. healthy.
This is a reaction identical to that occurring during injuries and in the context of certain autoimmune diseases. This same research team had already identified it during work on skin healing and psoriasis.
Disabled in bat
“We were intrigued that bats, which have evolved the STING gene disabled to avoid inflammatory responses during flight, are resistant to SARS-CoV-2-induced disease and constitute thus a viral reservoir”, explains Professor Gilliet, quoted in the press release.
“This prompted us to investigate whether STING is activated in the manifestations of Covid-19 and could be responsible for the severe disease in patients”, adds the researcher.
Andrea Ablasser has studied the STING pathway for years, elucidating the cascade of molecular reactions it entails: “As STING drives the expression of type I IFNs and other inflammatory mediators, it made sense to test its involvement in the hyper-inflammation process induced by SARS-CoV-2,” she says.
Skin and lung lesions
The CHUV dermatology research team started by studying the skin lesions of patients with severe forms of Covid-19 and found that they showed significant vascular destruction, with production of IFN by the surrounding macrophages which detect DNA from dying endothelial cells via the STING pathway.
The researchers then examined lung samples from patients who died of pneumonia due to SARS-CoV-2 and also found STING activity there. Using lung modelling, EPFL scientists have confirmed that infection with the SARS-CoV-2 virus also activates STING signaling in lung endothelial cells, as well as in macrophages.
Finally, they conducted an in vivo study to determine the pharmacological implications of their findings. By giving mice infected with SARS-CoV-2 drugs that block the STING pathway, they found a reduction in lung inflammation and a less severe form of the disease.
According to the authors, the cGAS-STING pathway acts as a key driver explaining aberrant responses to IFN in Covid-19. This study paves the way for new developments of therapies that specifically block this pathological inflammatory process.
This work was funded by the Swiss National Science Foundation as part of the National Research Program “Covid-19” ( NRP 78). Launched in the fall of 2020, it should last two years and includes 28 research projects.
This article has been published automatically. Source: ats