Some severe COVID-19 cases linked to genetic mutations or antibodies that attack the body
Howard
Hughes Medical Institute
People infected by the novel coronavirus can have symptoms that range from mild to deadly. Now, two new analyses suggest that some life-threatening cases can be traced to weak spots in patients' immune systems.
At least 3.5 percent of study patients with severe COVID-19, the disease caused by the novel coronavirus, have mutations in genes involved in antiviral defense. And at least 10 percent of patients with severe disease create "auto-antibodies" that attack the immune system, instead of fighting the virus.
The results,
reported in two papers in the journal Science on September 24,
2020, identify some root causes of life-threatening COVID-19, says study leader
Jean-Laurent Casanova, a Howard Hughes Medical Institute Investigator at The
Rockefeller University.
Seeing
these harmful antibodies in so many patients -- 101 out of 987 -- was "a
stunning observation," he says. "These two papers provide the first
explanation for why COVID-19 can be so severe in some people, while most others
infected by the same virus are okay."
The
work has immediate implications for diagnostics and treatment, Casanova says.
If someone tests positive for the virus, they should "absolutely" be
tested for the auto-antibodies, too, he adds, "with medical follow-up if
those tests are positive." It's possible that removing such antibodies
from the blood could ease symptoms of the disease.
A global effort
Casanova's
team, in collaboration with clinicians around the world, first began enrolling
COVID-19 patients in their study in February. At the time, they were seeking
young people with severe forms of the disease to investigate whether these
patients might have underlying weaknesses in their immune systems that made
them especially vulnerable to the virus.
The
plan was to scan patients' genomes -- in particular, a set of 13 genes involved
in interferon immunity against influenza. In healthy people, interferon
molecules act as the body's security system. They detect invading viruses and
bacteria and sound the alarm, which brings other immune defenders to the scene.
Casanova's team has previously discovered genetic mutations that hinder interferon production and function. People with these mutations are more vulnerable to certain pathogens, including those that cause influenza.
Finding similar
mutations in people with COVID-19, the team thought, could help doctors
identify patients at risk of developing severe forms of the disease. It could
also point to new directions for treatment, he says.
In March, Casanova's team was aiming to enroll 500 patients with severe COVID-19 worldwide in their study. By August, they had more than 1,500, and they now have over 3,000.
As the researchers began analyzing patient samples, they started
to uncover harmful mutations, in people young and old. The team found that 23
out of 659 patients studied carried errors in genes involved in producing
antiviral interferons.
Without a full complement of these antiviral defenders, COVID-19 patients wouldn't be able to fend off the virus, the researchers suspected. That thought sparked a new idea. Maybe other patients with severe COVID-19 also lacked interferons -- but for a different reason. Maybe some patients' bodies were harming these molecules themselves.
As in autoimmune disorders such as type 1 diabetes and
rheumatoid arthritis, some patients might be making antibodies that target the
body. "That was the eureka moment for us," Casanova says.
The
team's analysis of 987 patients with life-threatening COVID-19 revealed just
that. At least 101 of the patients had auto-antibodies against an assortment of
interferon proteins. "We said, 'bingo'!" Casanova remembers. These
antibodies blocked interferon action and were not present in patients with mild
COVID-19 cases, the researchers discovered.
"It's
an unprecedented finding," says study co-author Isabelle Meyts, a
pediatrician at the University Hospitals KU Leuven, in Belgium, who earlier
this year helped enroll patients in the study, gather samples, and perform
experiments. By testing for the presence of these antibodies, she says,
"you can almost predict who will become severely ill."
The
vast majority -- 94 percent -- of patients with the harmful antibodies were
men, the team found. Men are more likely to develop severe forms of COVID-19,
and this work offers one explanation for that gender variability, Meyts says.
Casanova's
lab is now looking for the genetic driver behind those auto-antibodies. They
could be linked to mutations on the X chromosome, he says. Such mutations might
not affect women, because they have a second X chromosome to compensate for any
defects in the first. But for men, who carry only a single X, even small
genetic errors can be consequential.
Looking ahead clinically, the team's new work could change how doctors and health officials think about vaccination distribution strategies, and even potential treatments.
A clinical trial could examine, for instance, whether infected
people who have the auto-antibodies benefit from treatment with one of the 17
interferons not neutralized by the auto-antibodies, or with plasmapheresis, a
medical procedure that strips the antibodies from patients' blood. Either
method could potentially counteract the effect of these harmful antibodies,
Meyts says.
In addition to the current work, Meyts, Casanova, and hundreds of other scientists involved with an international consortium called the COVID Human Genetic Effort are working to understand a second piece of the coronavirus puzzle.
Instead of
hunting for factors that make patients especially vulnerable to COVID-19,
they're looking for the opposite -- genetic factors that might be protective.
They're now recruiting people from the households of patients with severe
COVID-19 -- people who were exposed to the virus but did not develop the
disease. "Our lab is currently running at full speed," Casanova says.
