Some severe COVID-19 cases linked to genetic mutations or antibodies
that attack the body

Date:
September 24, 2020
Source:
Howard Hughes Medical Institute
Summary:
Two new studies offer an explanation for why COVID-19 cases can be
so variable. A subset of patients has mutations in key immunity
genes; other patients have auto-antibodies that target the same
components of the immune system. Both circumstances could contribute
to severe forms of the disease.



FULL STORY ========================================================================== [Coronavirus illustration | Credit: (c) Production Perig /
stock.adobe.com] Coronavirus illustration (stock image).

Credit: (c) Production Perig / stock.adobe.com [Coronavirus illustration | Credit: (c) Production Perig / stock.adobe.com] Coronavirus illustration
(stock image).

Credit: (c) Production Perig / stock.adobe.com Close 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.


========================================================================== Story Source: Materials provided by Howard_Hughes_Medical_Institute. Note: Content may be edited for style and length.


========================================================================== Journal References:
1. Paul Bastard et al. Auto-antibodies against type I IFNs in
patients with
life-threatening COVID-19. Science, Sept. 24, 2010; DOI: 10.1126/
science.abd4585
2. Qian Zhang et al. Inborn errors of type I IFN immunity in patients
with
life-threatening COVID-19. Science, Sept. 24, 2020; DOI: 10.1126/
science.abd4570 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200924141529.htm

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