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A new test can help explain why men, like this patient in an Italian intensive care unit, are more likely than women to expand a life-threatening COVID-19.
Science COVID-19 reports are supported by the Pulitzer Center and the Heising-Simons Foundation.
In the first months of the COVID-19 pandemic, scientists baffled by the ferocity of the disease wondered if the virus fighter is a vanguard bodyguard, a molecular messenger called type I interferon, absent in some severe cases. This week they verify this suspicion and reveal that in a significant minority of patients with severe COVID-19, the reaction to interferon has been paralyzed by genetic defects or by rogue antibodies that attack the interferon itself.
“Together, these two articles account for approximately 14% of severe COVID-19 cases. It’s quite surprising,” says Qiang Pan-Hammarstrom, an immunologist at the Karolinska Institute.
Tadatsugu Taniguchi, a pioneering interferon scientist and professor emeritus at the University of Tokyo, called the findings “remarkable. “He says they highlight the “critical” role of interferons I in SARS-CoV-2 infection and the progression of potentially fatal COVID -19.
Co-author Isabelle Meyts, a pediatric immunologist at the University Hospitals of Leuven, was impressed by the discovery of an article that found that rebellious antibodies underlie COVID-19 in 10% of critically ill patients: “There has never been an infectious disease ed at this point through one thing in the human body. And it’s not a remote cohort of Europeans. Patients come from all over the world, from all ethnicities. Another finding, that 94% of patients with anti-interferon antibodies were men, is also helping men be at increased risk of serious illness.
Twin studies have immediate practical implications. Synthetic interferons, long used to treat other diseases, can help some at-risk patients, as well as other treatments for destructive antibodies. A non-unusual type of antibody test can evolve smoothly and go back People at increased risk of developing severe COVID-19 may simply take precautions to avoid exposure or prioritize vaccination, says Elina Zuniga, an immunologist studying interferons at the University of California, San Diego.
The findings also raise a warning sign for plasma donations from cured patients. Because it may be rich in antibodies opposed to the virus, “convalescence plasma” is already given to some patients to fight the infection. But some donations would possibly harbor antibodies that neutralize, interferon. “You want those patients from the donor group,” Zúñiga says. “In fact, you don’t want to transfer those autoantibodys to someone else. “
Type I interferons are manufactured through each and every cell phone within the framework and are indispensable leaders in antiviral warfare at the onset of infection. They begin a rapid and intense local reaction when a virus invades a mobile, causing inflamed mobiles to produce proteins that attack the virus. They also summon immune mobiles on the site and alert non-swollen neighboring mobiles to prepare their own defenses.
In one study, Jean-Laurent Casanova, an infectious disease geneticist at Rockefeller University, and his team analyzed blood samples from 987 critical patients around the world. In 10. 2% of patients, researchers knew antibodies that attacked and neutralized patients’ type I interferon. A subgroup of patients with this interferon had incredibly low or undetectable blood levels. Laboratory studies showed that antibodies had deactivated interferon and that cells exposed to patients’ plasma had failed to repel the invasion through the new coronavirus.
At least 10% of COVID-19 is an autoimmune attack.
None of the other 663 people in an organization with a mild or asymptomatic SARS-CoV-2 infection had these destructive antibodies. Antibodies were also rare in the general population, appearing in only 0. 33% of the more than 1200 healthy people tested. “This means that at least 10% of critical COVID-19 is an autoimmune attack opposed to the immune formula in yes, “says Casanova.
The preponderance of male patients was a surprise, as women have higher rates of autoimmune diseases. “Our preferred speculation is that it’s a recessive trait similar to X,” Casanova says. “Women with two X chromosomes are and men, with one, are not. “To support this suspicion, a woman with a rare disease that silences an X chromosome was among critically ill patients with autoanticorps.
If these surprising effects continue, they may also contribute to the increased vulnerability of other older people to severe COVID-19: some critically ill patients with autoanticorps were over 65 years old.
At the time the paper discovered genetic failures in patients who led to the same end result: a markedly insufficient interferon reaction to SARS-CoV-2 infection, the team sequenced the DNA of 659 patients with COVID-19 in critical condition and 534 seconds with mild or asymptomatic disease. They tested thirteen genes, decided because their defects interfere with the production or use of type I interferon throughout the body; Genetic mutations underlie life-threatening influenza or other viral diseases. Researchers found that 3. 5% of critically ill patients had rare mutations in 8 of these genes. In patients for which blood samples were available, interferon grades were incredibly low. organization carried any of the mutations. ” This is the first article to identify undeniably pathogenic mutations underlying severe COVID-19,” says Pan-Hammarstrom.
But it’s “probably the tip of the iceberg,” says Paul Hertzog, interferon expert at the Hudson Medical Research Institute. Many other harmful mutations, related to interferon or not, can influence the progression of severe COVID-19. Said.
Zuniga notes that none of the patients who produced antibodies against interferon or had mutations had a history of life-threatening viral diseases that required hospitalization. ‘This suggests that we are more dependent on type I interferons than we are compared to SARS-CoV-2 compared to other viral infections,’ he says. “That’s why it’s critical to check treatments to stimulate responses to type I interferon. “
Recently, dozens of randomized clinical trials are implementing interferons opposed to SARS-CoV-2. One, led by Tom Wilkinson of the University of Southampton, reported promising effects on a small organization of patients hospitalized by COVID-19. mutations that prevent interferons from working or those whose antibodies attack them.
Some researchers warn that antibodies that neutralize interferon would possibly be a consequence, more than a cause, of severe COVID-19. “They would possibly expand during the disease,” says Miriam Merad, an immunologist at Icahn School of Medicine in Mount Sinai. This would be why patients had never faced life-threatening viral infections, he said.
But Casanova, who has made a career in finding mutations that confer susceptibility to infectious diseases, says there is a strong case of causation. He explains that pre-existing blood samples from a handful of patients showed that they had antibodies in their blood before. contract SARS-CoV-2. He argues that, in reaction to an infection, the framework is unlikely to temporarily generate the maximum levels of anti-interferon antibodies that his team has seen.
Yanick Crow, a clinical geneticist at the University of Edinburgh who studies interferon signaling, called paper antibodies “shocking” in a component because men were much more likely than women to bring rebellious antibodies. and will temporarily reveal whether the new findings are maintained. Given the tens of millions of cases worldwide, he says, “10% is such a high number and the implications are very important. “
Correction, September 25, a. m. : an earlier edition of this story mistakenly reversed the words “cause” and “consequence” when introducing a quote from Miriam Merad. This has been corrected.
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