Interferon Disorders Increase Chance Of Severe COVID-19 – Science & Life – News

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From the first months of the COVID-19 pandemic, there has been concern about the aggressiveness of the disease and the question has been raised as to whether the vanguard against viruses (and SARS-CoV-2), a molecular messenger called interferon type I, is missing or inadequate. . Two publications in the leading journal Science confirm this suspicion. Studies show that in a significant minority of patients with severe COVID-19, the immune response through interferon is limited by genetic “defects” or by antibodies that attack and inactivate interferon itself. Type I interferons are produced by every cell in the body and are key components of the initial response to viruses.

They trigger an immediate, strong local response when a virus invades a cell, triggering the production of other proteins that attack the virus and mobilize the immune system by calling the immune cells, while “warning” uninfected neighboring cells to prepare their own . The Professors of the Therapeutic Clinic of the Medical School of the National and Kapodistrian University of Athens, Efstathios Kastritis and Thanos Dimopoulos (Rector of EKPA) summarize these data.

The researchers looked at blood samples from 987 seriously ill patients around the world. In 10.2% of patients, the researchers identified antibodies that attack and neutralize type I interferon. A subset of affected patients had extremely low or undetectable levels of this interferon in the blood. Studies have confirmed that the antibodies inactivate interferon and the cells exposed to the plasma of these patients failed to prevent the invasion of SARS-CoV-2. In contrast, none of the 663 individuals in a control group with mild or asymptomatic SARS-CoV-2 infection had these harmful antibodies.

Antibodies were also rare in the general population, and were found in only 0.33% of the more than 1,200 healthy individuals tested. This means that at least 10% of patients with severe COVID-19 experience an autoimmune attack on the immune system itself. The dominance of male patients was also a surprise, as women have higher rates of autoimmune diseases. The researchers’ hypothesis is that this is a residual trait associated with the X chromosome: women with two X chromosomes are protected, and men who have one are not protected. In support of this hypothesis, a woman with a rare condition where one X chromosome is inactivated was among the serious patients with autoantibodies. These results may also help explain the increased vulnerability of older people to severe COVID-19, as half of the patients with autoantibodies were over 65 years of age. Some researchers warn that interferon-neutralizing antibodies could be a consequence and not a cause of severe COVID-19, as they are likely to develop during the course of the disease. This would explain why patients had not experienced life-threatening viral infections before. But other researchers say there is a strong case for causation: pre-existing blood samples from patients showed they had antibodies in their blood before they became infected with SARS-CoV-2, and in response to infection, the immune system is unlikely to be able to react quickly. generate high levels of interferon antibodies.

In the second study, the researchers found genetic “defects” in patients that led to the same end result: an extremely inadequate response through interferon to SARS-CoV-2 infection. The research team sequenced DNA from 659 patients with severe COVID-19 and from 534 controls with mild or asymptomatic disease. Thirteen genes were examined, selected because their mutations affect the production or use of type I interferon. Mutations in these genes are associated with life-threatening infections from influenza virus or other viral diseases. The researchers found that 3.5% of patients with severe disease had rare mutations in eight of these genes. In patients for whom blood samples were also available, interferon levels were missing or at very low levels. In contrast, no member of the control group carried any of the mutations. This is the first work that unequivocally proves the presence of mutations associated with severe COVID-19, but it is probably the tip of the iceberg, as many other destructive mutations, whether interferon-related or not, can affect the onset of severe COVID-19 . None of the patients who developed antibodies to interferon or had the mutations had a history of life-threatening viral illnesses that required hospitalization, suggesting that type I interferons may be critical for protection against SARS-CoV-2.

These data explain almost 14% of severe COVID-19 cases and highlight the critical role of type I interferons in SARS-CoV-2 infection and the development of potentially fatal COVID-19. Another important finding was that 94% of patients with antibodies that attack and inactivate interferon were men, and this may significantly explain why men have a higher risk of serious disease. These studies have direct practical implications.

It is important to try therapies that aim to enhance responses through type I interferon. Dozens of randomized clinical trials are now developing interferons against SARS-CoV-2. One of them reported promising findings in a small group of COVID-19 patients. But synthetic interferons will not help patients who have mutations that block the action of interferons or those with antibodies that neutralize them. The fact is that given the millions of COVIOD-19 cases worldwide, 10% is so high that the effects are very significant, so creating an antibody test to detect them is particularly important.

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