Faulty genes and misguided antibodies underlie life-threatening COVID-19

New research has shed light on why some people develop a more severe form of COVID-19 than others.

Published today in two Science papers, the new studies reveal that at least 3.5% of patients with life-threatening COVID-19 pneumonia have known or new genetic defects, and that more than 10% of those with severe COVID-19 have misguided antibodies that attack not the virus, but the immune system itself. 

The findings help to explain why some people develop a more severe form of COVID-19 than others in their age group, for example, those in their twenties who have no underlying health conditions. They may also provide the first molecular explanation for why more men than women die from the disease. 

These are the first results to be published by the COVID Human Genetic Effort, an ongoing international project spanning over 50 sequencing hubs, including Dr Vanessa Sancho-Shimizu’s lab at Imperial College London, and hundreds of hospitals around the world. Led jointly by The Rockefeller University and the National Institute of Allergy and Infectious Diseases, the project was established to investigate the underlying causes and mechanisms of life-threatening COVID-19. 

Genetic clues 

In the first study, researchers genetically analysed blood samples from a diverse group of 659 patients who had been hospitalised for life-threatening COVID-19 pneumonia, 14% of whom had died. They also included samples from 534 people with asymptomatic or milder infection. Initially, the team searched for differences between the two groups across 13 genes known to be critical in defending the body against the influenza virus. These genes control type I interferons, a group of signalling proteins that provide first-line defence against infection by heightening our cells' anti-viral defences.

The team found that a significant number of people with severe COVID-19 carried rare variants in these 13 genes, with at least 3.5% of patients missing a functioning gene. Further experiments showed that immune cells from these patients did not produce any detectable type I interferons in response to SARS-CoV-2, the virus that causes COVID-19. 

"Our findings clearly indicate that type I interferons are critically important in SARS-CoV-2 infection and that host genetics clearly impacts disease outcome," comments Dr Sancho-Shimizu, whose team assessed the genetic variants identified in patients with severe COVID-19.

“These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19. In theory, such interferon problems could be treated with existing medications and interventions,” adds the study's co-lead Professor Jean-Laurent Casanova, Head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University.

Mistaken immunity 

Building on these findings in a second study, the team examined 987 patients with life-threatening COVID-19 pneumonia and found that at least 10% had autoantibodies against interferons at the onset of their infection. Autoantibodies are antibodies that mistakenly target a person’s own tissue or organs. 

Biochemical experiments confirmed these autoantibodies can effectively curb the activity of interferon type I. In some cases, they could be detected in blood samples taken before patients became infected; in others, they were found in the early stages of the infection, before the immune system had the time to mount a response.  

As 94% of those with autoantibodies were men, the findings could explain why more men develop life-threatening COVID-19 than women. The study also highlights certain medical interventions to consider for further investigation. For example, there are already two types of interferons available as drugs and approved for use to treat conditions such as chronic viral hepatitis.  

Commenting on the broader significance of the results, Dr Sancho-Shimizu said: "These findings very elegantly demonstrate how rare genetic investigations highlight key molecular pathways underlying disease, but can also lead to the identification of alternate but parallel mechanisms of pathogenesis, in this case, autoantibodies targeting the same pathway, that explain severity in a larger number of individuals."

Researchers working as part of the COVID Human Genetic Effort will now continue to look for genetic variations that may affect other types of interferons or additional aspects of the immune response in COVID-19 outliers. 

This article was adapted from a press release by The Rockefeller University 

'Inborn errors of type I IFN immunity in patients with life-threatening COVID-19' by Qian Zhang et al. is published in Science

'Auto-antibodies against type I IFNs in patients with life-threatening COVID-19' by Paul Bastard et al. is published in Science