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Two weeks later, when a second pair of Covid-affected siblings, both in their 20s, also turned up in the Netherlands, geneticists were called in to investigate. What they discovered was a path that led to serious cases, genetic variationsand gender differences to a loss of immune function that may ultimately lead to a new approach to treating thousands of coronavirus patients.
The common thread of the investigation is the lack of a substance called interferon It helps orchestrate the body’s defense against viral pathogens and can be infused to treat conditions such as infectious hepatitis. Now increasing evidence suggests that a significant minority of Covid-19 patients become seriously ill due to a interferon answer. Benchmark studies of twins published Thursday in the journal Science showed that insufficient Interferon may lurk at a dangerous tipping point in SARS-CoV-2 infections.
“It seems this virus has a great trick,” he said. Shane crotty, a professor at the Center for Vaccine and Infectious Disease Research at the La Jolla Institute for Immunology in California. “That big trick is to avoid the initial innate immune response for a significant period of time and, in particular, to avoid an early type 1 interferon response.”
The work highlights the potential of therapies to expand a range of slowly accumulating Covid-19 treatments. These include remdesivir and convalescent plasma from Gilead Sciences Inc., a component of the blood of recovered patients that may contain beneficial immune factors.
These treatments provide limited benefit and are typically used in very sick hospital patients. the possibility The fact that interferon can help some people is attractive because it appears most effective in the early stages of infection, when life-threatening respiratory failure can still be avoided. Dozens of studies are currently being conducted on interferon treatment. recruitment Patients with Covid-19.
“We believe that time may be of the essence because only in the initial phase can one fight the virus particles and defend against infection,” he said. Alexander Hoischen, head of the genomic and immunogenic technologies group at Radboud University Medical Center in Nijmegen, who analyzed the DNA of the two groups of siblings.
Being male, elderly, and having underlying medical conditions can increase patients’ risk of life-threatening Covid-19. But even within these groups, the severity of the disease varies widely. Scientists have speculated that other factors influence susceptibility, including pre-existing levels of inflammation and immunity, the amount of virus that initiates an infection, and the ability of patients. genetic makeup.
New nexus
The role of interferon represents a new nexus in the complex interaction of Covid-19 with the human immune system. Many patients suffer their worst complications due to an exaggerated immune reaction sometimes called a cytokine storm, and they can benefit from dexamethasone, a cheap generic that calms these storms.
“It’s a very interesting disease because too little immunity is not good,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said Sept. 10 in an online information session for Massachusetts General Hospital staff. “Too much immunity is really bad.”
Whether enough interferon is available early or late in Covid-19 cases has a major influence on the severity of the disease, according to Yuen Kwok-Yung, chair of infectious diseases in the department of microbiology at the University of Hong Kong. Ideally, production of the antiviral substance will kick in when immune cells encounter SARS-CoV-2 genetic material, stopping rapid viral reproduction within the body and preventing complications, he said.
“But the SARS-CoV-2 virus has anti-interferon genes that can stop or antagonize the production or effect of interferon,” said Yuen, who measured the effects in human lung tissue. If the response to interferon is delayed and the amount of virus in the body reaches a high level, other parts of the immune system will “wake up.”
‘Really disastrous’
That can trigger inflammation that damages the lungs – collateral damage from an excessive immune reaction to the virus. “This is really disastrous,” he said.
Some people are known to have trouble fighting infections because they produce antibodies that deactivate their own interferon. On Thursday, a global consortium of researchers said such immune reactions to the protein could explain life-threatening Covid-19 pneumonia in at least 2.6% of women and 12.5% of men.
Interferon-blocking antibodies appeared in 101 of 987 patients with severe disease, but none of 663 people with an asymptomatic or mild case, according to the study in science. Patients older than 65 were also more likely than younger ones to have the autoimmune abnormality, which was “clinically silent until the patients were infected with SARS-CoV-2,” the group of more than 100 scientists said.
‘First explanation’
“These findings provide a first explanation for the excess of males among patients with life-threatening Covid-19 and the increased risk with age,” the researchers led by Jean-Laurent Casanovasaid the director of the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller University in New York. “They also provide a means of identifying people at risk of developing life-threatening Covid-19.”
Genetic analysis of Covid-19 patients published in the same journal revealed two dozen genetic mutations that had remained “silent” until the patients were infected with SARS-CoV-2. The researchers, many of them also involved in the study of antibodies, sequenced the genomes of 659 patients with life-threatening cases of the disease; 3.5% carried genetic variations that inhibit interferon production.
Those genetic defects were similar to those Hoischen and his colleagues from a dozen Dutch centers described in the Journal of the American Medical Association two months ago. The two groups of siblings had inherited a genetic mutation that affected the interferon response, preventing their immune systems from fighting the coronavirus until it had replicated for days.
On the Dutch, the effects were cruel. The first, a young father from a village in the southern Netherlands, suffered from shortness of breath, cough and fever at home for eight days before being admitted to intensive care. He would spend 33 days in the hospital, 10 of them with a ventilator.
Raging fever
His 29-year-old brother succumbed to Covid-19 in an intensive care unit in Rotterdam, after being treated for shock and a fever that soared to 44 degrees Celsius (111 degrees Fahrenheit). When Radboud’s doctors learned of his younger brother’s case, as well as a second pair (21 and 23-year-old brothers also with respiratory failure), they went looking for a genetic cause.
They found a mutation that was carried on the X chromosome. Defects in this chromosome they are more likely to affect men, who only have one copy, while women have two.
Male mutations are rare (occurring in 1 in 10,000 people) and an unlikely explanation for the vast majority of severe Covid-19 cases. But studies in Science indicate that various forms of interferon dysfunction can be the cause of up to 14% of critically ill patients, and that detection and targeted treatment could prevent serious illness and death.
“If we can get them to our university medical center early enough,” Hoischen said, “our doctors could treat them with interferons.”
Other ways to overcome autoimmunity, such as removing antibodies to interferon from the blood, called plasmapheresis, may also help patients. On the other hand, patients who produce antibodies against interferon should not donate blood products to treat other patients.
“Rare diseases and the most common forms of the same disease can converge and we can learn from each other,” said Hoischen. “That is the hope.”
