What lies beneath Covid inflammation

Scientists at EPFL and the University Hospital of Lausanne (CHUV) have found the biological mechanism behind the inflammation seen in COVID-19 infections that involve a rise in interferons in the lungs and skin.

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As the COVID-19 pandemic rages on, scientists across the world are looking at the pathology of the SARS-CoV-2 virus in an effort to find effective treatments for patients. In that vein of research, the groups of Andrea Ablasser at EPFL and Michel Gilliet at CHUV have discovered a signaling pathway that is involved in the inflammation seen in COVID-19 patients.

The cGAS-STING signaling pathway

The signaling pathway is known as cGAS-STING, and its role in the cell is to detect foreign DNA, e.g. from bacteria or viruses, that has entered the cell’s cytosol – the fluid inside the cell that contains all the organelles. Upon sensing DNA, the cGAS-STING signaling pathway triggers a cascade of molecular reactions that ends up activating inflammatory genes. Now active, the genes begin their own cascades to turn on defense mechanisms to fight the infection. However, the pathway can also respond to a cell’s own DNA – a process that has over the years been linked to various inflammatory diseases.

Ablasser’s group has been studying cGAS-STING for years. Given the association of inflammation in the pathogenesis of COVID-19, the team sought to look into the possibility that cGAS-STING is involved in the pathology of SARS-CoV-2 infections. Evolution provided another hint to a possible involvement of cGAS-STING to COVID-19. The cGAS-STING pathway is compromised in bats, an adaption that could explain why these animals are resistant to coronavirus disease and function as a viral reservoir” says Michel Gilliet, Chair of the Department of Dermatology at CHUV.

Andrea Ablasser © Alain Herzog / EPFL

Skin, lungs, and interferons

The researchers of the Department of Dermatology at CHUV studied skin tissue from COVID-19 patients, as the disease is known to cause cutaneous inflammation. By profiling COVID-19 skin manifestations, the team found a “STING-dependent” release of a set of molecules called “type I interferons”.

Type-I interferons (IFN) are proteins that play key roles in inflammation and immunoregulation, as well the responses of immune cells like T cells. They are also heavily involved in the pathogenesis of COVID-19, where high levels of type I interferons in the late phase of the infection can cause aberrant inflammation.

In the COVID-19 skin tissue, the study found that the release of type I interferons is mostly carried out by macrophages – another type of immune cell.

The CHUV researchers also looked into lung samples of patients, uncovering cGAS-STING activity there as well. They note “prominent tissue destruction” associated with type I IFN responses. Using a lung-on-chip model, EPFL researchers found that infection with the SARS-CoV-2 virus activates cGAS-STING signaling in lung endothelial cells just as it does in macrophages. However, the response is here triggered by releasing the cells’ mitochondrial DNA and leads to cell death and the production of type I interferons.

Finally, the researchers carried out a live study to confirm their in vitro findings. Testing mice infected with SARS-CoV-2, they administered drugs that block the cGAS-STING pathway. As a result, the mice showed a reduction of severe lung inflammation along with improved disease outcomes.

“We have identified the cGAS-STING pathway as a critical driver of aberrant type I interferon responses in COVID-19,” says Andrea Ablasser. Michel Gilliet adds: “Our study unravels novel principles for the development of therapeutics that specifically block this pathological inflammation process in severe disease.”

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