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SARS-CoV-2 is known as a particularly stealthy virus – one that employs several mechanisms to actively evade detection by its host’s immune system. In a recent study, a team of researchers at the Weizmann Institute of Science, together with their Australian collaborators, uncovered one such mechanism that allows the virus to escape the type I Interferon (IFN) response, which is part of the body’s primary early immune defense system.
By employing several complementary experimental setups, research associate Dr. Maya Shemesh and Senior Staff Scientist Dr. Daniel Harari, both of Prof. Gideon Schreiber’s group of the institute’s Biomolecular Sciences Department, tested which, if any, of the approximately thirty viral SARS-CoV-2 proteins have the capacity to block the IFN response. Intriguingly, six viral proteins – that is, information encoding about a fifth of the virus’s genetic machinery – were collectively responsible for this.
Although cells infected by SARS-CoV-2 lose their ability to produce IFNs, they still remain sensitive to its signaling
When a virus infects a cell, it is normally detected by biological “sensors”; these in turn trigger the production of IFNs that are then secreted from the cell. As a result, both infected and uninfected cells in the vicinity respond to the IFN signal, activating hundreds of genes with antiviral activity. The researchers discovered that the six identified proteins inactivate this “sensor” response, preventing the production of IFNs in the early stages of infection.
However, unlike the strategy of many other viruses, they found that SARS-CoV-2 does not effectively block the signaling of IFNs – which means that infected cells remain sensitive to the effects of added IFNs. “It is fascinating that this virus has evolved specifically to block IFN production,” says Harari. “We presume the virus does this so that it can remain in ‘stealth mode’ during early infection, thus staying undetected by the host for as long as possible,” he adds.
But does this mean that IFNs may be used as drugs to treat COVID-19? For years, IFNs have been produced by biopharmaceutical companies and used as drugs to treat numerous diseases – including, for example, hepatitis B and C. For COVID-19, it really depends on the stage of the disease. Although cells infected by SARS-CoV-2 lose their ability to produce IFNs, they still remain sensitive to its signaling. Therefore, at early stages of infection or as a prophylactic, IFN therapy could potentially provide protection and mitigate the severity of infection. However, evidence gathered so far shows that at later stages of the disease the body’s natural IFN production eventually kicks in, so there is little clinical sense in using IFN therapy. “This is probably why there have been conflicting results from different clinical trials,” explains Harari. “Timing is everything.”
Yet some patients with severe COVID-19 might still benefit from treatment with IFNs. It was recently revealed that in about 20 percent of COVID-19 deaths, patients had developed an abnormal production of antibodies that “neutralize” IFNs, particularly an interferon subtype called IFN-alpha, which is presumed to be produced by immune cells at more progressive stages of disease. In the new study, it was demonstrated that, at least in cultured cells infected with SARS-CoV-2, both IFN-alpha and another interferon subtype called IFN-beta can effectively combat the spread of the virus. And since IFN-alpha neutralizing antibodies won’t prevent IFN-beta from working, clinical trials should now determine whether IFN-beta therapy can be used to treat this subset of patients with life-threatening COVID-19.
About 20% of SARS-CoV-2's genome is made up of genes encoding proteins that halt the production of interferons.
Prof. Gideon Schreiber’s research is supported by the Ben B. and Joyce E. Eisenberg Foundation; the Rene and Tillie Molho Family Trust; Miel de Botton; and the Yotam Project.