Genetic or immune defects may impair ability to fight Covid-19
A significant proportion of patients who develop life-threatening forms of Covid-19 have genetic or immunological defects that impair their ability to fight the virus, research has found.
In papers published in the journal Science, the Covid Human Genetic Effort international consortium describes two glitches in severely ill Covid-19 patients that prevent them from making a frontline immune molecule called type 1 interferon.
The patients would have carried these glitches for years before the pandemic, or in the case of the genetic errors, all their lives. The discovery may help to explain a mystery surrounding the coronavirus: why it leaves some sufferers sick or dying in intensive care, while others remain barely affected or asymptomatic.
The consortium sequenced all or part of the genomes of 659 severely ill Covid-19 patients from around the world, as well as those of 534 people with asymptomatic or mild infection, and found that the severely ill patients were more likely to carry a type of mutation leaving them unable to make interferon. Though each such mutation is rare, collectively they occurred in 3.5% of severe cases.
In the second study, involving nearly 1,000 severe Covid-19 patients, they found at least one in 10 patients carried antibodies to their own interferon, which block its action. No such auto-antibodies were found in asymptomatic or mild patients, and they were detected in only a tiny fraction (0.3%) of healthy controls. These findings were described by one scientist as “astonishing”.
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Together, the two types of error account for about 15% of life-threatening Covid-19 cases, according to the immunologist Jean-Laurent Casanova of the Rockefeller University in New York City and the Necker Hospital for Sick Children in Paris, who co-directs the consortium.
Casanova suspects human genetics will end up explaining the majority of such cases, however, because the consortium has only looked for mutations in 13 of the 300-odd type 1 interferon-related genes so far – already a huge undertaking. Many other genes, including ones not related to interferon, could affect a person’s response to the virus.
Type 1 interferon is a molecule produced by the immune system as soon as it detects infection. It works by stopping a virus from replicating. If this first-line defence is effective, a person may not even feel unwell. Even if it is not, it buys the body time to mount an immune response that is more targeted to the virus in question, involving antibodies and immune cells.
Without interferon, severely ill Covid-19 patients rely solely on this second defence mechanism, which may take several days to reach full strength – giving the Sars-CoV-2 virus a head start on damaging the body’s tissues.
Casanova said the finding of inborn genetic errors in severe Covid-19 patients came about serendipitously: “We have a two-year-old girl from Angers in France to thank for it.”
The toddler turned up in the Necker intensive care unit in 2011 with life-threatening flu. Doctors saved her life but, wondering why she was unable to shrug off the infection like most children, Casanova sequenced her genome and found she carried two copies of a recessive genetic trait that meant she could not make interferon. Vaccinated annually against flu, she has thrived ever since because her antibodies work normally.
The auto-antibody finding is especially exciting, said the consortium member and infectious diseases physician Vanessa Sancho-Shimizu of Imperial College London, because 95% of severe patients who carry the auto-antibodies are male and over 50. “It explains the age and gender bias that we’re seeing in the severe patient population,” she says.
It is not clear why those patients have such antibodies, but the cause could also be genetic. Another mystery is why the patients with genetic errors survived earlier infections, though the researchers have a theory about this: “We propose that Sars-CoV-2 is a particularly virulent pathogen that imposes a much greater requirement for type 1 interferon than, say, flu,” said Sancho-Shimizu.
Stephen Chapman, a respiratory medicine physician at the Wellcome Centre for Human Genetics in Oxford, who was not involved in the research, said the papers made an important contribution towards explaining why disease severity varies so dramatically between individuals. Of the auto-antibody finding, he said: “If this is true it is an astonishing result.”
It should guide diagnosis and treatment, since patients arriving at hospital and testing positive for auto-antibodies could undergo plasma exchange to remove those antibodies from their blood – potentially keeping them out of intensive care. Since the auto-antibodies spare one particular form of interferon – the beta form – these patients might also benefit from the experimental treatment inhaled interferon beta.
Magnús Gottfređsson, an infectious diseases doctor at the University of Iceland, said the findings should sound a note of caution to those conducting clinical trials of convalescent plasma because if the donated plasma contains auto-antibodies to interferon it could potentially do more harm than good.