Genetic defects in patients' immune system may underlie severe COVID-19

Reviewed by Emily Henderson, B.Sc.Sep 29 2020

Worldwide, otherwise healthy adolescents and young people without underlying conditions are sometimes severely affected by COVID-19, with the viral infection in the worst cases quickly becoming life-threatening. But why is this happening?

A world-wide consortium of researchers is determined to investigate this - and they have now made so much progress that Science has just published two scientific articles describing some of their results.

Professor Trine Mogensen from the Department of Biomedicine at Aarhus University is co-author on the two research articles in Science. She conducts research into rare immunodeficiencies that lead to increased susceptibility to viral infections and, together with her research group, participates in the steering committee of the research consortium Covid human genetic effort (covidhge) as the only Danish representativ.

She explains that in the vast majority of people, infection with the COVID-19 causing coronavirus leads to an anti-viral response in which interferon plays a crucial role. Interferon is an importantimmune signaling hormone that slows the division of the virus and prevents it from penetrating the surrounding cells. In the event of a viral infection, the body normally quickly begins producing interferon, and the virus can be brought under control withing a few hours. In popular terms, interferon is our first safeguard against an infection.

However, if there are defects in the interferon signalling pathways, there is nothing to inhibit the virus dividing, and while the coronavirus usually remains in the cells in the throat, it can in this case also infect other parts of the body such as the lungs, kidneys and perhaps even the brain."

Trine Mogensen, Medical Specialist at the Department of Infectious Diseases, Aarhus University Hospital, Denmark

Genetic and immunological analyses of blood samples from 650 patients from all over the world with severe COVID-19 show that some of these patients have an inherited immunodeficiency which leads to the anti-viral interferon either not being produced or not working on the body's cells. Blood samples from 1,226 healthy individuals have functioned as a control group - with all of the samples being taken prior to the COVID-19 pandemic.

The researchers have obtained consent to collect blood samples and carry out a genetic analysis from hospitalized and severely ill COVID-19 patients. From the blood samples, the researchers have purified immune cells from the 650 patients and subsequently infected these immune cells with coronavirus, which enabled them to ascertain that the immune system was not properly activated. In addition, a genetic sequencing of DNA from the 650 patients has been carried out, with some of this work being carried out at Aarhus University Hospital.

"Our DNA consists of approximately 20,000 genes, and we have found defects in thirteen different genes. This means that the proteins which the genes encode become defective and therefore cannot perform their role in the immune system. We're already aware of some of these genetic defects from patients affected by severe influenza, but some are new and specific to COVID-19," says Trine Mogensen.

The next task for the international research consortium is to translate - i.e. transfer - the basic immunological findings to the treatment of patients, and the first clinical trials are on the way. Medical doctors will be able to measure whether the patients have autoantibodies in their blood as these are relatively easy to measure, and if they are, they can be filtered from the blood. It will also be possible to screen for the thirteen critical genes identified and in this way have the ability to identify particularly vulnerable individuals. This group will then be able to receive preventative medical treatment and a vaccine once this is available.

"The goal is to prevent the very severe cases of COVID-19 with high mortality rates," summarizes Trine Mogensen, who is optimistic and hopes that the clinical trials will demonstrate positive results - perhaps already within a year.

She does not only base her optimism on the unique international collaboration which exists in the COVID Human Genetic Effort, as the international research consortium is named.

"I've never experienced anything like it before in my field of immunology and infectious diseases. We share knowledge and work together in a very altruistic spirit," she adds. The consortium comprises more than 250 researchers under the overall leadership of Professor Jean-Laurent Casanova from The Rockefeller University in the United States - with the professor also serving as an Honorary Skou professor at Aarhus University since 2019.