One-seventh of disastrous COVID cases may be due to a defective immune response

Perhaps the most annoying aspect of COVID-19 is its incredible range of severity, from completely asymptomatic to deadly.Since the early days of the pandemic, researchers have Factors that put people at risk for serious cases of illness, Elderly, suffering from certain chronic illnesses, being a man, etc. However, these vital trends have not reached the biological mechanisms that actually cause life-threatening infections. It also does not explain why young, healthy and healthy people get fatal illnesses from the SARS-CoV-2 virus.

Two related papers published in Science On September 24th, we will begin to tackle these mysteries. They may also partially explain men’s greater vulnerability to the virus and show the way to possible treatments and safeguards. Both studies highlight an important role in a class of immune system proteins called interferons. Interferon is so named because it prevents the virus from replicating.

New paper was created by Human genetic endeavors of COVIDA huge international consortium of researchers looking for genetic mutations that make individuals abnormally sensitive to SARS-CoV-2 or confer extraordinary resistance. The consortium is co-led by Jean-Laurent Casanova of The Rockefeller University and Helen Su of the National Institute of Allergy and Infectious Diseases, and is the co-author of both studies.

In their first paper, the researchers Compare DNA from 659 seriously ill COVID-19 patients From around the world using DNA from a control group of 534 infected individuals with mild or asymptomatic effects of the novel coronavirus. Scientists have specifically searched for mutations that impair the production of type I interferon, a set of proteins made by all cells in the body that make up the first-line defense against the virus.Previous work by Casanova and others showed that Such mutations left people very vulnerable to influenza and other viruses.. After all, some of the same life-threatening influenza-related mutations were also present in 3.5 percent of patients with life-threatening COVID-19.None of the controls in the new study had these mutation..

The second paper focuses on another mechanism that nullifies the interferon response in patients with severe COVID-19.In this series of studies, researchers examined blood samples from 987 such individuals, with 13.7 percent It contained an antibody called an “autoantibody” against the patient’s own type I interferon... In 10.2% of subjects, autoantibodies completely blocked the behavior of these important virus fighters.

In laboratory experiments, exposure of human cells to plasma (the liquid portion of blood) collected from patients with these self-attack antibodies failed to protect the cells from SARS-CoV-2. Shown. Antibodies were found in 12.5% ​​of severely ill men, but only in 2.6% of women with similar illnesses, so COVID-19 may be high. Male mortality rate.. They were also more common in patients over the age of 65.

Antibodies to cytokines in the body itself, which are cell signaling proteins of the immune system, including interferon, Exacerbate other types of infections.. Its effect is the same as having a mutation that interferes with the production of that cytokine. “For example, if you have a mutation in gamma interferon, or if you have autoantibodies to the type II interferon, gamma interferon, you are more susceptible to tuberculosis and associated mycobacterial disease,” says Casanova.

Still, he was surprised to discover that autoantibodies are desperately widespread among sick COVID-19 patients, as they appear to be rarely seen, especially in the general population. The researchers screened the blood of 1,227 healthy individuals, and only 4 (0.3 percent) had autoantibodies.

The discovery that more than 10% of COVID-19 patients in intensive care units around the world may have these antibodies “far beyond my expectations,” says Casanova. In summary, genetic and immunological disorders of type I interferon can account for nearly 14 percent of life-threatening cases.

“The two papers are noteworthy at multiple levels,” says Eleanor Fish, a professor of immunology at the University of Toronto who studied interferon and was not involved in those new studies. “One is that they very quickly identified what was happening in a life-threatening case in the context of the interferon response.” She already has evidence that interferon is important for virus removal. Although it says it is increasing, the data also show that SARS-CoV-2 is particularly good. Block the body’s interferon response..

“These papers show that interferon may be suppressed. [by SARS-CoV-2], It still provides protection against viruses, “says Elina Zúñiga, a professor of molecular biology at the University of California, San Diego, who was not involved in the study. Zuniga, who is investigating the immune response to the virus, finds the discovery of antibodies to interferon in so many patients particularly “amazing.” “Who thought this was one of the reasons patients could be infected with the more severe COVID-19?” She says.

A study by Dutch scientists, published in July JAMA, Supports the discovery of new genetics.. Researchers found two previously healthy young brothers with an average age of 26 years who were desperately ill with COVID-19 and found to have a genetic mutation on the X chromosome that impaired the interferon response. Describes unrelated pairs.

If confirmed by further studies, the new paper, along with previous studies on interferon, will have many implications for patient screening and treatment of severe COVID-19. The authors suggest that newly infected patients can be screened for autoantibodies with inexpensive blood tests to determine if they are at risk for life-threatening cases.

Most of these antibodies appear to be directed to a type of interferon called interferon alpha, so Fish suggests that such patients may respond well to treatment with interferon beta. The latter protein plays a similar role in the fight against viral infections, but may not be the target of antibodies.

Screening for these antibodies across the population may be possible in countries that have the resources to control them, Zúñiga suggests. “For young people who think they are less at risk, having these autoantibodies can change their behavior,” she says. When the vaccine becomes available, Zuniga adds, “There is a reasonable argument to prioritize those who have these autoantibodies.”

Perhaps the most direct implication of the new study is on the use of plasma during the convalescent period. This is an treatment made from the blood of people who have recovered from COVID-19. In August, the US Food and Drug Administration issued a controversial “emergency license” for blood products. Zúñiga points out that it is important to screen plasma donors for autoantibodies. “If you are infected with severe COVID-19, do you want to receive antibodies that neutralize the antiviral response?” She asks. “No, thanks.”

Given the growing evidence that interferon plays an important role in stopping severe infections, Fish can treat COVID-19 patients with interferon, regardless of antibody or genetic status. We believe it will be a winning tactic, especially in the early stages of infection. She pointed to an exploratory study of interferon in Cuba and Wuhan, China, with promising effects on mortality and early removal of the virus.

However, it is very important to determine the timing and other details of such treatment. “Interferon can be a double-edged sword in many infections,” says Zúñiga. “It activates many immune cells, but it can also enhance inflammation, which has a negative immune regulatory role and may activate factors that suppress the immune response.”

Experts seem to agree That interferon will have to be given early Helps shut down the infection. Interferon is likely to be useless if the patient develops an extreme immune response, sometimes referred to as a “sitekine storm,” Fish said.

Dozens of COVID-19 clinical trials are already underway to test the effectiveness of various types of interferon therapy that can be given as a nasal spray or injection. One large study conducted by the National Institute of Allergy and Infectious Diseases, Comparing antiviral remdesivir alone and combination therapy Of drugs and interferon beta. And Fish is participating in a study in Santiago, Chile. Investigate whether to give interferon You can prevent someone from getting sick by members of a household infected with the coronavirus. We’re still not sure if any of these treatments will work, but new discoveries will unleash at least another piece of the COVID-19 puzzle.

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