Share This Article Facebook twitter Email You are free to share this article under the Attribution 4.0 International license. University Rockefeller University Unable to curb the immune system's all-out attack on SARS-CoV-2, the triple faulty gene may help explain some severe cases of COVID in children. One of the most terrifying aspects of the COVID pandemic has had an unimaginably severe impact on some children. While most infected children have few or no symptoms, one in 10,000 children become suddenly and dramatically ill about a month after a mild infection and are hospitalized with inflammation of the heart, lungs, kidneys and brain, sudden fever, skin rashes and abdominal pain. . Researchers call this MIS-C—multisystem inflammatory syndrome in children. Some suspect that MIS-C is a SARS-CoV-2-specific form of Kawasaki disease, a rare childhood inflammatory condition that has long puzzled clinicians and appears to be triggered by many different viruses. The new findings in Science constitute the first mechanistic explanation of any Kawasaki disease. "Patients are not sick because of the virus," says Jean-Laurent Casanova, a Rockefeller University geneticist. "They are sick because they are overreacting to the virus." An enduring mystery of COVID has been its wildly variable impact on individuals, with one person suffering from a sore throat and the other being on a ventilator, or worse. In February 2020, Casanova and his collaborators at CHGE, an international consortium of researchers investigating the human genetic and immunological underpinnings of all the different ways a SARS-CoV-2 infection can manifest, began looking for innate immune errors . among healthy people with severe forms of COVID. Among their targets were children with MIS-C. Casanova and her CHGE colleagues have put together an ever-growing database of hundreds of fully sequenced COVID victim genomes from hospitals in North America, Asia, Europe, Latin America, Oceania and the Middle East. Since then, they have made several discoveries about the genetic predispositions of individuals who develop severe COVID. Professor Casanova said for the current study, researchers hypothesized that MIS-C in some children may be caused by a gene defect that makes them vulnerable to an inflammatory condition caused by SARS-CoV-2 infection. Rockefeller's St. Giles Human Genetics Laboratory of Infectious Diseases. To find out, they analyzed the genomes of 558 children with MIS-C. Five unrelated children from four countries carried common mutations in three closely related genes that control the OAS-RNase L pathway involved in the viral response. Normally, this pathway is induced by type 1 interferons and activated by viral infection inducing molecules OAS1, OAS2 and OAS3. These, in turn, activate RNase L, an antiviral enzyme that breaks down single-stranded viral and cellular RNA by shutting down the cell. Once a cell turns black, the virus cannot hijack the replication mechanism to spread disease. However, in five children with these mutations, the pathway was not activated in response to the presence of SARS-CoV-2. The cell instead sensed the viral RNA using another pathway known as MAVS, which incites an army of dendritic cells, phagocytes, monocytes, and macrophages to attack viral invaders en masse. The MAVS pathway functions as a kind of accelerator of the immunological response. The OAS-RNase L pathway needs to act as a brake. But in MIS-C the brake fails and the response gets out of control. “Phagocytes produce excessive levels of inflammatory cytokines and chemokines and growth factors and interferons – you name it,” Casanova says. Massive inflammation occurs. Because MIS-C is clinically and immunologically very compatible with other examples of Kawasaki disease, researchers believe MIS-C is a variant of the disease driven by a SARS-CoV-2 infection - the first such Kawasaki provocateur to be definitively identified. It is unknown why this reaction occurs approximately one month after infection. "We now understand the molecular and cellular basis of the disease, but we don't understand the timing," says Casanova. While the findings may shed light on how problematic genes may trigger MIS-C in some populations, they only accounted for 1% of the children in the study. As for the remaining children with COVID who were hospitalized weeks later—the vast majority of whom recover quickly with treatment—the researchers plan to look for further mutations in the OAS-RNase L pathway or related pathways. “We now have only one pathway that causes disease when interrupted,” he says. “There is every good reason to believe that there will be many other patients with MIS-C who have genes mutated in this pathway. Will it be 5%, 10%, 50%, 100%? I don't know. But surely there are mutations in other genes controlling this pathway? it will be.” Source: Rockefeller University