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Genetic Mutations May Underlie Severe COVID-19 Illness


More than 10% of those who develop severe COVID-19 have misguided antibodies that derail the immune response, according to new research.


More than 10% of people who develop severe COVID-19 have autoantibodies that attack the immune system rather than the SARS-CoV-2 virus that causes the disease. Another 3.5% carry a genetic mutation that impacts immunity.

New research has determined that both groups lack the effective immune response that depends on type 1 interferon (IFN-1), a group of 17 proteins crucial to the human immune response.

The findings also may provide a molecular explanation for the greater morbidity from COVID-19 observed among men than women, according to press releases from the National Institutes of Health (NIH), and Rockefeller University.

Scientists from the National Institute of Allergy and Infectious Diseases (NIAID), co-led by Helen Su, MD, PhD, a senior NIAID investigator, and Jean-Laurent Casanova, MD, PHD, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University in New York, are uncertain whether the absence of IFN-1 in these patients is the result of neutralization by autoantibodies or, because of a genetic defect, insufficient levels to being with or inadequate antiviral response.

From symptom-free to death

These findings, published in 2 papers in the journal Science, (Zhang et al, Bastard et al) are the first published results from the COVID Human Genetic Effort , an international project spanning more than 50 genetic sequencing hubs and hundreds of hospitals.

The COVID Human Genetic Effort is an international consortium aiming to discover:

(i) Monogenic inborn errors of immunity (IEI), rare or common,
underlying severe forms of COVID-19 in previously healthy individuals.

(ii) Monogenic variations, rare or common, which make certain individuals
resistant to the infection by the SARS-CoV2 itself, despite repeated exposure.

“These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19,” said Casanova in the press release from Rockefeller University. And, at least in theory, such interferon problems could be treated with existing medications and interventions.”

The wide variation in disease severity among those with COVID-19—from symptom-free infection to death and myriad outcomes in between—has been puzzling to scientists. To investigate whether the disparate outcomes have a genetic underpinning, Drs Su and Casanova and their collaborators have since February enrolled thousands of CVOID-19 patients.

Dire illness, rare etiologies

Among nearly 660 people with severe COVID-19, they found a significant number carried rare genetic variants in 13 genes known to be critical in the body’s response to influenza virus, and more than 3.5% were completely missing a functioning gene. Further experiments showed that immune cells from those 3.5% did not produce any detectable IFN-1 in response to SARS-CoV-2.

Examination of approximately 1,000 patients with life-threatening COVID-19 pneumonia revealed that >10% had autoantibodies against interferons at the onset of their infection, and 95% of those patients were men. Biochemical experiments confirmed that the autoantibodies block the activity of IFN-1.

The autoantibodies were detected in blood samples of some patients before they were infected with the SARS-CoV-2 virus and in others found in very early in the infection—before the immune system was able to mount a response.

Out of 1,227 randomly selected healthy people, the autoantibodies were detected in only 4, underscoring the rarity of the condition, according to the Rockefeller University release.

“All of these findings strongly indicate that these auto-antibodies are actually the underlying reason some people get very sick, and not the consequence of the infection,” said Casanova in the same release.

Research among the international team members will continue, focused on identifying genetic variations affecting other types of interferons or other aspects of the immune response observed in COVID-19 outliers.


Globally, as of September 24, 2020, there have been 32 284 038 confirmed cases of COVID-19, 983 952 related deaths, and 22 268 309 recoveries.

For more COVID-19 coverage for primary care, visit our COVID-19 Resource Page.

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