University of Tartu researchers participated in a study published in Science, indicating that about 10 per cent of young and healthy people who develop severe COVID-19 have misguided antibodies that attack not the virus, but the immune system itself. Another recently published study showed that another 3.5 per cent of such patients carry a specific kind of genetic mutation. In both cases, the patients did not have type I interferons that are essential in protection against viruses.
Interferons are part of the intrinsic and innate immunity, kicking in before the adaptive immune system mounts an antibody response. They are known to play an important role in immediately heightening the cells’ defences in response to several viruses.
However, researchers found that in some patients, auto-antibodies neutralise the effect of interferons, and in others, the production of interferons has been impaired due to gene defects. The upshot is the same: some COVID-19 sufferers whose severe form of the disease has so far been a mystery lack type I interferon.
The findings of the research published in participation with medical researchers of the University of Tartu help explain why some younger people develop a disease much more severe than others and require admission to the intensive care despite being free of underlying conditions such as cardiovascular disease and type 2 diabetes. The findings may also provide the first molecular explanation for why more men than women die from the disease.
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, said the first publications of the findings of the major international project COVID Human Genetic Effort provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19. “And at least in theory, such interferon problems could be treated with existing medications and interventions,” Casanova said.
The project led by Casanova and Helen Su from the US National Institute of Allergy and Infectious Diseases spans over 50 sequencing and research hubs and hundreds of hospitals around the world. The study included patients from several continents. “Nearly 15% of critical COVID-19 cases found an explanation in this research,” said Casanova.
Genetics of COVID-19 outliers
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. Casanova’s research over the past two decades has shown that unusual susceptibility to certain infectious diseases can be traced to single-gene mutations that affect an individual’s immune response.
Since February, his team and their collaborators have been enrolling thousands of COVID-19 patients to find out whether something in their genetic make-up drives the disparate clinical outcomes the disease produces.
The research has now led to two publications. In one, the researchers studied more than 650 patients who had been hospitalized for life-threatening pneumonia due to SARS-CoV-2, 14 per cent of whom died. They also analysed samples from another group of over 530 people with asymptomatic or benign infection.
They initially searched for differences between the two groups across genes known to be related to severe influenza. These genes govern type I interferons. It soon became obvious that a significant number of people with a severe disease carried rare variants in these genes, and more than three per cent of them were, in fact, 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 cells that carried the studied gene variations were more sensitive to the virus: they died faster and in larger numbers compared to cells without the corresponding mutations.
A mysterious auto-immune condition
As it is known that susceptibility to some particular infectious agents can be caused by both a defective gene as well as auto-antibodies against the product of that gene, the team then checked for the possibility of a similar scenario.
Examining 987 patients with life-threatening COVID-19 pneumonia, they found that more than 10 per cent had auto-antibodies against interferons at the onset of their infection. The majority of them, 95%, were men.
Cell-based tests confirmed that these auto-antibodies are biologically active and neutralise the activity of type I interferons. In some cases, the team could analyse blood samples taken before patients became infected: these already had auto-antibodies. In others, auto-antibodies were found in the early stages of the infection, indicating that these auto-antibodies are actually the underlying reason some people get very sick and not the consequence of the infection. These auto-antibodies seem to be rare in the general population. Analysing the serum of 1,227 randomly selected healthy people, only four were found to have them.
“The findings point to new medical interventions to consider especially in the early stages of the infection,” Casanova said. For example, there are already interferons available as drugs and approved for use to treat certain conditions such as chronic viral hepatitis.
An important contribution to the research into auto-antibodies was made by medical researchers of the University of Tartu, led by Research Professor of Cellular Immunology Kai Kisand, who was one of the co‑authors of the research article published in Science.
“Our research group has a long experience in research on interferons and this was very much appreciated by the consortium. We proved that the auto-antibodies of COVID-19 patients block all subtypes of interferon-alpha, 13 in total. As a result of neutralised interferons, antiviral barriers are weakened, leading to a facilitated and faster spread of the virus in the body,” described Kisand.
According to Kisand, the presence of auto-antibodies should be also taken into account in convalescent plasma transfer to the risk-group patients. “Fortunately, the risk is low, as plasma donors are mostly people who had moderate symptoms and did not need hospitalisation – many thanks to all of them. In such patients, we have not detected auto-antibodies against interferons so far.”
Researchers say that research in the field continues, as the genetic variants of other immune mediators or their receptors may also have a role in the development of the severe form of the disease. In parallel, the potential role of several other auto-antibodies in the onset of severe COVID-19 is studied.