Faulty Genes May Cause Multisystem Inflammatory Syndrome in Children

A trio of faulty genes negatively affect the immune system’s ability to fight SARS-CoV-2, which can cause inflammatory overload characteristics of multisystem inflammatory syndrome in children (MIS-C), according to the results of a study published in Science.

The findings are the first to explain the mechanisms of any Kawasaki disease, a rare childhood inflammatory condition that is triggered by different viruses.

“We clearly now have 1 pathway that is causal of disease when it’s disrupted,” Jean-Laurent Casanova, MD, PhD, professor at The Rockefeller University, said in a statement. “There’s every good reason to believe that there will be many other patients with MIS-C who have mutated genes in this pathway. . . There will be mutations in other genes controlling this pathway.”

Investigators initially aimed to discover genetic mutations of immunity among those who were healthy but had severe forms of COVID-19, which included children with MIS-C.

They analyzed genomes of 558 individuals with MIS-C, finding that 5 unrelated children from 4 countries, Canada, the Philippines, Spain, and Turkey, all shared mutations in 3 closely related genes in the OAS-RNase L pathway involved in viral response.

The pathway is typically triggered by type 1 interferons and activated by viral infections, inducing OAS1, OAS2, and OAS3 molecules. These activate RNase L, an antiviral enzyme that breakdown RNA, shutting down the cell, which prevents it from replicating and spreading disease.

In the 5 children with mutations, the pathway failed to activate the appropriate response to the SARS-CoV-2 virus. The cell reacted to the RNA using the MAVS pathway, which provokes the use of dendric cells, macrophages, monocytes, and phagocytes, that attack the viral invaders. The pathway is an accelerator to immunological response.

However, investigators found that the OAS-RNase L pathway failed, and the response careens were out of control and resulted in inflammation.

“Phagocytes produce excessive levels of inflammatory cytokines and chemokines and growth factors and interferons—you name it,” Casanova said. “We now understand the molecular and cellular basis of the disease, but we don’t understand the timing.”

Because MIS-C is clinically and immunologically similar to other Kawasaki diseases, investigators think that the MIS-C is a variety of the disease driven by SARS-CoV-2 infections.

Even though their findings shed some light on the gene mutations, this only accounted for 1% of children in the study, investigators said.

The rest of the children who had COVID-19 were hospitalized weeks later, with the vast majority recovering quickly with treatment.

Investigators plan to seek out other mutations in this pathway or in related pathways.

Reference

Homing in on the genetics of severe COVID in children. EurekAlert. News release. February 9, 2023. Accessed February 16, 2023. https://www.eurekalert.org/news-releases/979322