Drives cell to suicide

Core factor for severe corona courses discovered

Since the beginning of the coronavirus pandemic, it has been a mystery why some people struggled to survive after being infected and others were unaware of their illness because they showed no symptoms. An international team of scientists from Vienna has now identified an immune messenger as a key factor in the severe course of the disease and lung damage.

"The dysregulated immune response and inflammatory mechanisms that lead to severe Covid-19 disease progression are still not fully understood. Recently, we identified misguided cell death caused by ligands (binding proteins of receptors; note) as a cause of lethal inflammation. We hypothesized that this process could also cause or contribute to the pathological inflammation and lung failure after SARS-CoV-2 infection," Marie-Christine Albert (University of Cologne) and her co-authors, including Roman Reindl-Schwaighofer from the Department of Medicine III in Vienna (MedUni/AKH), wrote in "Cell Death & Differentiation".

Tests with mutated virus strain in mice
First of all, the scientists developed a new animal model (MA20) with mice in which the important disease processes of Covid-19 could be tracked. The experts used a SARS-Cov-2 virus strain with a mutation that caused the pathogens to have a stronger affinity for the ACE2 receptors in mice. ACE2 receptors are the entry point for SARS-CoV-2 into cells. In serial experiments with 20 infections of new animals each time, a virus was cultivated that caused severe to fatal courses of disease in the animals.

Immune messenger triggers cell suicide
Finally, young and old mice of a known laboratory strain were infected. "Simultaneously with the occurrence of cell death and inflammation, the expression of FasL (Fas ligands) increased on monocytic macrophages and NK cells ("scavenger cells" and so-called natural killer cells; note) in the mice infected with MA20," the scientists wrote. FasL is effectively an immune messenger substance. When FasL binds to cells with the corresponding receptor (Fas), it sends a signal that triggers programmed cell death (apoptosis), a kind of cell suicide. Normally, this mechanism is used in mammals and also in humans to eliminate unneeded, possibly harmful cells. In cancer cells, however, this usually does not work.

Researchers: "Blocking FasL reduces cell death"
The scientists reversed the process. They blocked FasL in mice infected with SARS-CoV-2. The result: this treatment dramatically increased the animals' survival rate, from 40 to 90 percent in older mice, for example. "Therapeutic blockade of FasL reduces cell death and inflammation in the lungs of mice infected with MA20," the scientists found. Apparently, immune cells with a particularly strong production of Fas ligands are responsible for the often fatal lung complications - caused by severe tissue damage due to cell death - in the context of Covid-19 diseases.

The highlight, according to the authors of the study: "FasL is also increasingly present in lung lavage fluid (fluid from samples taken for diagnostic purposes; note) from Covid-19 patients at a critical stage of the disease. Overall, the research results identify FasL as the determining factor (in affected individuals; note) of the pathogenic immune response that causes the severity and lethality of Covid-19. This implies that patients with severe Covid-19 disease could benefit from blocking FasL as a treatment."