Severe COVID-19 cases may be explained by genetic defects

A proportion of the most severe novel coronavirus (COVID-19) cases can be explained by genetic defects in the patients' immune system, according to a new study published in the journal Science.

In most people, infection with COVID-19 leads to an anti-viral response in which the hormone interferon plays a crucial role. Interferon is an immune 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 begins producing interferon, and the virus can be brought under control withing a few hours. However, if there are defects in the interferon signaling pathways, there is nothing to inhibit the virus dividing. While COVID-19 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 the brain, the researchers said.

In the study, genetic and immunological analyses of blood samples from 650 patients with severe COVID-19 showed that some of the 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 functioned as a control group, with all the samples being taken prior to the COVID-19 pandemic.

The researchers 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 purified immune cells from the 650 patients and subsequently infected these immune cells with COVID-19, which enabled them to ascertain that the immune system was not properly activated. In addition, the researchers carried out a genetic sequencing of DNA from the 650 patients, according to the study.

The DNA consisted of approximately 20,000 genes, and the researchers found defects in thirteen different genes. The researchers said this means that the proteins the genes encode become defective and therefore cannot perform their role in the immune system. Similar genetic defects have been observed in patients with severe influenza, though some are new and specific to COVID-19, the researchers said.

The next task for the researchers is to translate 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 identify vulnerable individuals. This group will then be able to receive preventative medical treatment and a vaccine once this is available, the researchers said,

“The goal is to prevent the very severe cases of COVID-19 with high mortality rates,” said Trine Mogensen, MD, DMSc, PhD, co-author of the study and professor from the Department of Biomedicine at Aarhus University, in a statement. “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.”

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