Genetic mechanism behind some children falling extremely ill found

WASHINGTON DC: Scientists have discovered details about the genetic predispositions of children who tended to fall ill suddenly and dramatically during the Covid pandemic.

''The patients are sick not because of the virus,'' said Jean-Laurent Casanova, a geneticist at Rockefeller University, US.

''They're sick because they excessively respond to the virus.'' Rockefeller scientists and affiliates of the COVID Human Genetic Effort (CHGE) described 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 multisystem inflammatory syndrome in children, or MIS-C.

Children with MIS-C, who end up in the hospital, are characterised by inflamed hearts, lungs, kidneys, and brains, spiked temperatures, skin rashes, and abdominal pain.

The CHGE is an international consortium of researchers seeking the human genetic and immunological bases of all the different ways a SARS-CoV-2 infection can manifest.

The study said that the findings constituted the first mechanistic explanation of any Kawasaki disease and that they were reported in a paper published in the journal Science.

According to the study, in February 2020, Casanova and his collaborators in the CHGE began searching for inborn errors, or genetic mutations, of immunity among healthy people who had severe forms of COVID. Among their targets were children with MIS-C, the study said.

Casanova and his team 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, the study said.

They have since made several discoveries about the genetic predispositions of individuals who develop severe COVID, the study said.

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, said Casanova.

To find out, they analyzed the genomes of 558 children who had had MIS-C, the study said.

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, the study said.

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 cannot 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 study said.

According to the study, 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,'' said Casanova.

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.

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 and land in the hospital with what researchers call MIS-C.

Why this reaction only takes place about a month after infection remains unknown, the study said.

''We now understand the molecular and cellular basis of the disease, but we don't understand the timing,'' said Casanova.