New York, Sep 25: More than 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, and another 3.5 per cent may carry a specific kind of genetic mutation, according to a new study.
The research, published in the journal Science, noted that both groups of patients lack type I interferon -- a set of 17 proteins crucial for protecting cells and the body from viruses. These proteins, according to the researchers from the Rockefeller University in the US, are part of the intrinsic and innate immunity, kicking in before the body produces an antibody response, and are known to play an important role in immediately heightening the cells' defences in response to several viruses.
In the case of some patients with severe COVID-19, they said the interferons could either be neutralised by the patients' own antibodies, or may not be produced in insufficient amounts due to a faulty gene. They said the findings help explain why some people develop a disease much more severe than others in their age group including in individuals who required admission to the hospital Intensive Care Unit (ICU) despite being in their 20s and free of underlying conditions.
The study results, according to the researchers, may also provide the first molecular explanation for why more men than women die from COVID-19.
"These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19," says Jean-Laurent Casanova, a co-author of the study from the Rockefeller University. "And at least in theory, such interferon problems could be treated with existing medications and interventions," Casanova said.
The novel coronavirus can cause symptom-free infection in most people, or can kill some others in a few days.
According to the researchers, the unusual susceptibility to certain infectious diseases can be traced to single-gene mutations that affect an individual's immune response. In the current research, they genetically analysed blood samples from more than 650 COVID-19 patients who had been hospitalised for life-threatening pneumonia due to the coronavirus, of whom 14 per cent had died.
The scientists also included samples from another group of over 530 people with asymptomatic or benign infection. They initially searched for differences between the two groups across 13 genes known to govern the production of the type I interferons in the body, which are critical for defense against the influenza virus.
According to the study, a significant number of people with severe disease carried rare variants in these 13 genes, and more than three per cent of them were missing a functioning gene. From further experiments, they showed that immune cells from these patients did not produce any detectable type I interferons in response to the coronavirus.
The scientists demonstrated that human fibroblast cells with mutations affecting the interferon type I pathway were more vulnerable to the virus, and died in higher numbers, and did so at a faster rate than cells without those mutations. They said three other infectious diseases caused by mutations affecting an immune signalling protein can also be caused by auto-antibodies against that protein.
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, with a majority of them (95 per cent) being men.
The researchers confirmed these findings using biochemical experiments which showed that these auto-antibodies can effectively curb the activity of interferon type I.
In some cases the auto-antibodies could be detected in blood samples taken before patients became infected and in others, they said, these were found in the early stages of the infection, before the immune system had the time to mount a response. However, the auto-antibodies seem to be rare in the general population, the scientists said, adding that only four out of 1,227 randomly selected healthy people were found to have them.
"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," Casanova said. The scientists believe the findings could point to medical interventions that may help control the disease severity. Citing an example, they said two types of interferons available as drugs and approved for use to treat certain conditions, such as chronic viral hepatitis, could be further investigated for their effectiveness against severe COVID-19.