EXPERT REACTION: The reason some people develop life-threatening COVID-19 may have been found

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Australian researchers have helped uncover why some otherwise healthy people develop life-threatening COVID-19 symptoms. The two papers show that these severe symptoms can develop in people lacking type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. The first study found that in around 1 in 10 people with life-threatening COVID-19 pneumonia, their bodies produce antibodies which target and neutralise their own type 1 interferon. In most cases this occurred in men  - which may explain why men are more likely to develop severe disease. The second paper describes a group of people who carry a specific genetic mutation which stops their immune cells producing type I interferons in response to SARS-CoV-2. In both cases the lack of type 1 interferon appears to be a common theme among a group of COVID-19 sufferers whose severe disease has thus far been a mystery.

Journal/conference: Science

Organisation/s: Garvan Institute of Medical Research, Murdoch Children's Research Institute (MCRI), The Rockefeller University, USA

Funder: N/A

Media release

From: Murdoch Children's Research Institute (MCRI)

Scientists discover common genetic and immunological causes of severe COVID-19

More than 10 per cent of healthy people who develop severe COVID-19 produce misguided antibodies that attack the patient’s own immune system, rather than the invading virus, new research shows. Another 3.5 per cent, at least, carry genetic mutations that impair their immune response to the virus.

The international research found that in some patients who lacked type I interferon mutations in a set of 13 proteins crucial for protecting cells and the body from viruses were associated with severe COVID-19 infections.

Published in two papers in Science, the findings help explain why some people develop much more severe COVID-19 disease than others in their age group. These patients include those who required admission to the intensive care unit despite being in their 20s and otherwise healthy. They may also provide the first molecular explanation for why more men than women die from the disease.

“These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19,” said Professor Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University and a Howard Hughes Medical Institute investigator. “And at least in theory, such interferon problems could be treated with existing medications and interventions.”

The findings are the first results being published out of the COVID Human Genetic Effort, an ongoing international project spanning over 50 sequencing hubs and hundreds of hospitals around the world including the Murdoch Children’s Research Institute (MCRI) and co-led by Professor Casanova and Dr Helen Su at the National Institute of Allergy and Infectious Diseases. The study participants included various nationalities from Asia, Europe, Latin America, and the Middle East.

MCRI Professor John Christodoulou, co-leading the Australian arm of the COVID Human Genetic Effort, said these two papers provide a potential explanation for the severe COVID-19 infection seen in up to 15 per cent of cases.

“The way SARS-CoV-2 affects people differently has been puzzling. The virus can cause a symptom-free infection and go away quietly, or it can kill in a few days,” he said.

“The researchers sequenced genes for 13 proteins that are very important for protecting against viral infections and in 3.5 per cent of individuals with severe COVID-19 pneumonia, changes in a number of these genes were identified. The changes compromised their ability to protect against COVID-19 infection by impairing patients’ ability to make type I interferon.

“Also 10 per cent of individuals with severe COVID-19 infection had auto-antibodies to type I interferon, neutralising the early protective effect of innate immunity. Importantly, 95 per cent of these individuals were men, which might explain at least some of the sex differences we see in COVID-19 infection, which tends to affect males more severely.”

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Dr Joanna Groom is Laboratory Head in the immunology department at the Walter and Eliza Hall Institute

Type I interferon (IFN-I) cytokines are a family of proteins that help co-ordinate very early immune responses. IFN-I can be released by all cells when they are infected by a virus. This acts as an alert system for the immune system to activate and send powerful effector cells to the infection site. Two recent studies have highlighted that IFN-I responses are impaired in a subset of severe COVID-19 patients. The first study identified patients with genetic variants that damage either IFN-I production or response. The second found patients that have antibodies that bind to IFN-I and suppress its function. When IFN-I responses are suppressed, this can lead to an increase in un-coordinated attacks against the virus, resulting in prolonged disease and immune pathology.

Together, the identified deficiencies in IFN-I responses account for a significant portion (~14%) of severe COVID-19 cases. Early IFN-I treatments are actively being trialled in SARS-CoV-2 infections. These studies will help to identify the patients who would benefit the most from this therapy. This work will also allow the multiple pathogenic pathways leading to severe disease to be untangled, and therefore help identify other underlying risk factors.

Last updated: 29 Sep 2020 11:58am
Declared conflicts of interest:
None declared.

Professor Paul Hertzog is Associate Director at the Hudson Institute of Medical Research where he is Research Group Head, Regulation of Interferon and Innate Signalling and the Centre Head, Centre for Innate Immunity and Infectious Diseases.

Two papers from the Casanova lab at the Rockefeller University, NY highlight the importance of one component of the body’s natural antiviral defence systems against SARS CoV-2 induced disease.

Together they implicate defects in the protective interferon system in a staggering 14 per cent of severely ill COVID 19 patients.

Interferons are the body’s premier antiviral compounds and it is likely that further studies will uncover even more defects that prevent the body mounting an effective antiviral response. These results carry important messages for: understanding the disease, screening tests for targeted therapy and potentially vaccination.

One paper sequenced interferon pathway genes known to protect us from other infections and found mutations in 8 genes involved in interferon signalling in 3.5 per cent of the 659 severely ill COVID 19 patients, compared to none in the 534 control subjects.

The other Casanova lab study of 987 severely ill patients found a surprising 10 per cent of them produced antibodies to interferons that would block its activity and are strongly linked to disease causation.  This frequency of these autoantibodies in 1200 apparently healthy subjects was lower at 0.3 per cent. These unexpected findings may explain why men and the elderly have a higher proportion of severe disease.

Last updated: 25 Sep 2020 12:59pm
Declared conflicts of interest:
The Hudson Institute is a Participating Centre in the COVID Human Genetic Effort, one of the international consortiums involved in this research. https://www.covidhge.com/participating-centers
Professor Stuart Tangye is Leader of the Immunity & Inflammation Theme and Head of the Immunology & Immunodeficiency Lab at the Garvan Institute of Medical research. He is also a Professor (Conjoint) at St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney

Professor Stuart Tangye is Leader of the Immunity and Inflammation Research Theme at the Garvan Institute of Medical Research and heads the Oceania node of the COVID Human Genomic Effort. He is an author on one of the papers (Bastard et al).

These findings reveal type I interferons (IFNs) as a central requirement for strong immunity against SARS-CoV-2 infection and COVID-19. IFNs are small proteins that are made by many cell types very quickly following infection by different pathogens, including viruses.

Both studies suggest that a defect in type I IFN immunity underlies life-threatening COVID-19 pneumonia.

In the first study, Zhang et al. studied possible genetic causes of life-threatening COVID-19 by performing whole exome or whole genome sequencing of 659 patients. In this cohort, 3.5 per cent of patients had known or new genetic variants that impacted the ability of the immune systems to produce or respond to type I IFNs. 

The second study, by Bastard et al., revealed that 10.2 per cent of 987 patients with life-threatening COVID-19 pneumonia had neutralising auto-antibodies against type I IFNs in their blood. This led to low or undetectable serum levels of type I IFN-α during acute disease.

Interestingly, 94 percent of patients with these neutralising auto-antibodies were male, which may explain why men are more susceptible to getting severe COVID-19.

The studies support recently published evidence that SARS-CoV-2 produced a viral antagonist of human IFNs (a common strategy for viruses to subvert the host response), and that poor production of type I IFNs was linked with severe COVID-19.

The findings raise the possibilities of exploring new potential treatment of COVID-19, such as ‘diluting’ the effects of auto-antibodies via plasmapheresis or infusing type I IFNs as anti-viral agents.

Last updated: 24 Sep 2020 5:45pm
Declared conflicts of interest:
Stuart is an author on the paper by Bastard et al. He heads the Oceania node of the COVID Human Genomic Effort, one of the international consortiums involved in this research.  
Professor John Christodoulou is from the Murdoch Children's Research Institute. He is co-leading the Australian arm of the COVID Human Genetic Effort, one of the international consortiums involved in this research

The way SARS-CoV-2 affects people differently has been puzzling. The virus can cause a symptom-free infection and go away quietly, or it can kill in a few days.

The researchers sequenced genes for 13 proteins that are very important for protecting against viral infections and in 3.5 per cent of individuals with severe COVID-19 pneumonia, changes in a number of these genes were identified. The changes compromised their ability to protect against COVID-19 infection by impairing patients’ ability to make type I interferon.
 
Also 10 per cent of individuals with severe COVID-19 infection had auto-antibodies to type I interferon, neutralising the early protective effect of innate immunity. Importantly, 95 per cent of these individuals were men, which might explain at least some of the sex differences we see in COVID-19 infection, which tends to affect males more severely.

Last updated: 24 Sep 2020 5:44pm
Declared conflicts of interest:
John is co-leading the Australian arm of the COVID Human Genetic Effort, one of the international consortiums involved in this research.

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