One
of the most terrifying aspects of the COVID pandemic has been its
unpredictably severe impact on some children. While most infected kids
have few or no symptoms, one in 10,000 fall suddenly and dramatically
ill about a month after a mild infection, landing in the hospital with
inflamed hearts, lungs, kidneys, and brains, spiked temperatures, skin
rashes, and abdominal pain. Researchers call it MIS-C—multisystem
inflammatory syndrome in children.
Some suspected that MIS-C is a SARS-CoV-2-specific form of Kawasaki
disease, a rare childhood inflammatory condition that has long puzzled
clinicians and seems to be triggered by many different viruses. Now, in a
paper published in Science,
scientists describe how a trio of faulty genes fail to put the brakes
on the immune system’s all-out assault on SARS-CoV-2, leading to the
inflammatory overload characteristic of MIS-C. The findings constitute
the first mechanistic explanation of any Kawasaki disease.
“The patients are sick not because of the virus,” says the senior
author. “They’re sick because they excessively respond to the virus.”
An enduring mystery of COVID has been its wildly varied impact on
individuals, with one person getting a sore throat and another winding
up on a ventilator—or worse. In February 2020, Casanova and his
collaborators in the CHGE, an international consortium of researchers
seeking the human genetic and immunological bases of all the different
ways a SARS-CoV-2 infection can manifest, began searching for inborn
errors (genetic mutations) of immunity among healthy people who had
severe forms of COVID. Among their targets were children with MIS-C.
The authors assembled an ever-growing database of hundreds of fully
sequenced genomes of COVID victims from hospitals across North America,
Asia, Europe, Latin America, Oceania, and the Middle East. They have
since made several discoveries about the genetic predispositions of individuals who develop severe COVID.
For the current study, the researchers hypothesized that in some
children, MIS-C could be caused by a gene defect that rendered them
vulnerable to an inflammatory condition provoked by a SARS-CoV-2
infection, says the senior author.
To find out, they analyzed the genomes of 558 children who’d had MIS-C.
Five unrelated kids from four countries—Turkey, Spain, the Philippines,
and Canada—shared mutations in three closely related genes controlling
the OAS–RNase L pathway, which is involved in viral response.
Normally, this pathway is induced by type 1 interferons and activated by
viral infection, which induce OAS1, OAS2 and OAS3 molecules. These in
turn activate RNase L, an antiviral enzyme that chops up single-strand
viral and cellular RNA, shutting down the cell. When a cell goes dark,
the virus can’t hijack its replication machinery to spread disease.
But in the five children with these mutations, the pathway failed to
activate in response to the presence of SARS-CoV-2. The cell instead
sensed the viral RNA using another pathway known as MAVS, which provokes
an army of dendritic cells, phagocytes, monocytes, and macrophages to
attack the viral invaders en masse. The MAVS pathway acts as a sort of
accelerator of the immunological response.
The OAS-RNase L pathway, on the other hand, is supposed to act as the
brake. But in MIS-C, the brake fails, and the response careens out of
control. “Phagocytes produce excessive levels of inflammatory cytokines
and chemokines and growth factors and interferons—you name it,” the
author says. Massive inflammation ensues.
Because MIS-C is clinically and immunologically so aligned with other
examples of Kawasaki disease, the researchers believe that MIS-C is a
variety of the disease driven by a SARS-CoV-2 infection—the first such
provocateur of Kawasaki to be pinpointed.
Why this reaction only takes place about a month after infection remains
unknown. “We now understand the molecular and cellular basis of the
disease, but we don’t understand the timing,” the author says.
Although the findings shed light on how problem genes can kick off MIS-C
in some populations, it only accounts for 1 percent of the children in
the study. As for the rest of the children who had COVID only to wind up
hospitalized weeks later—the vast majority of whom recover quickly with
treatment—the researchers plan to seek out other mutations in the
OAS-RNase L pathway or in related pathways.
“We clearly now have one pathway that is causal of disease when it’s
disrupted,” the author says. “There’s every good reason to believe that
there will be many other patients with MIS-C who have mutated genes in
this pathway. Is that going to be 5 percent, 10 percent, 50 percent, 100
percent? I don’t know. But for sure, there will be mutations in other
genes controlling this pathway.”
https://www.science.org/doi/10.1126/science.abo3627
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Finborn-errors-of-oas&filter=22