Immunodeficiency determines the severity of COVID-19

Disease and treatment 28. okt 2020 3 min Professor Trine Mogensen Written by Kristian Sjøgren

Researchers have identified the role played by genes and specific type 1 interferon deficiencies in the immune response when even young people develop life-threatening COVID-19.

According to two recently published studies in Science (here and here), a relatively large group of people who have severe COVID-19 lack some very specific components of the immune response that would normally protect them against viruses.

The two studies indicate that, when people lack 17 essential type 1 interferons, then SARS-CoV-2 has virtually free rein in the body and can make both young and old people seriously ill by spreading to the lungs and other places.

At least 10% of thousands of otherwise healthy and fit people with life-threatening COVID-19 pneumonia had autoantibodies that, instead of attacking the virus, neutralize the body’s own interferons by attacking them. A total of 3.5% had specific mutations in the genes that produce and regulate type 1 interferons.

“This is basic research, but there is clearly a clinical perspective, because screening for both autoantibodies that attack the body’s own interferons and genetic variants that result in dysfunctional interferons can identify who is at high risk of experiencing severe COVID-19, even if they are young,” explains Trine Mogensen, Professor, Department of Biomedicine, Aarhus University and Department of Infectious Diseases, Aarhus University Hospital.

Collaboration between countries

The two new studies both stem from the COVID Human Genetic Effort project, a consortium of laboratories in various countries to identify the genetic aspect of human COVID-19.

The project has included thousands of participants with COVID-19 from Asia, Europe, Latin America and the Middle East since February 2020.

Genetics determine the type 1 interferon response

In one study, the researchers sequenced blood samples from 650 people hospitalized with life-threatening COVID-19 pneumonia, of which 14% died.

The researchers initially investigated genetic variants in 13 genes that are critical to the immune response to viruses and specifically control how the type 1 interferons respond.

The study showed that 3.5% of those who experienced life-threatening COVID-19 symptoms lacked at least one functional gene required for a measurable type 1 interferon response.

Type 1 interferons work by inhibiting viruses from dividing, preventing them from entering the cells and being able to spread to other cells. If people lack interferons, a viral infection quickly becomes severe and can spread to the lungs and other organs.

“We also know that defects in some of these 13 genes influence people who develop severe complications associated with influenza. However, some of the other genes we found are completely new and specific to COVID-19,” says Trine Mogensen.

Men have a higher risk of having autoantibodies

In the second study, the researchers examined blood samples for the presence of autoantibodies: the antibodies that attack the body’s own cells.

The researchers took samples of blood from 987 people to determine the presence of autoantibodies against type 1 interferons, and 10% of those severely ill with COVID-19, 95% of them men, had this type of autoantibodies.

Further experiments with the autoantibodies in cell cultures confirmed that they neutralized the activity of the type 1 interferons so that the body could not achieve a proper immune response to COVID-19.

These autoantibodies are generally very rare in the general population. The researchers found only four of 1,227 controls had them.

“This indicates that the presence of autoantibodies may be the underlying reason why some people become severely ill with COVID-19,” says Trine Mogensen.

Generally screening risk factors for severe disease may be relevant

Trine Mogensen explains that the discoveries have several clinical perspectives, which are already being investigated in several trials.

According to Trine Mogensen, the autoantibodies may be removed from the blood if they can be detected early enough in the trajectory of COVID-19 by plasmapheresis, in which the blood is centrifuged to remove the unwanted components.

“Patients can also be given various types of medicine that prevent the production of more autoantibodies, and we are investigating this in clinical trials right now,” explains Trine Mogensen.

People at risk of becoming severely ill due to genetic defects cannot be given medication in the same way. However, according to Trine Mogensen, people may be screened to identify an inadequate type 1 interferon response.

“Various clinical trials are underway, and some clinical trials are also being planned. We need to use this new knowledge to test people early for the presence of autoantibodies or genetic variants that produce a poor interferon response. This will enable especially vulnerable people to be treated intensively at an early stage of the disease. In the long term, we can envision screening the population to identify in advance who has a high risk of severe COVID-19,” says Trine Mogensen.

“Auto-antibodies against type I IFNs in patients with life-threatening COVID-19” has been published in Science. In 2015, the Novo Nordisk Foundation awarded a Tandem Programme grant to Trine Mogensen for the project Identification of Novel Primary Immunodeficiencies Conferring Susceptibility to Viral Infections.

Trine H. Mogensen obtained her medical degree from Aarhus University (AU) in 2002, a PhD degree in 2003, and a Doctor of Medical Sciences degree (DMSc...

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