New research findings have revealed an underlying genetic reason why some children who have had a COVID-19 infection develop multisystem inflammatory syndrome in children (MIS-C), a rare but potentially life-threatening condition. There is a disease.
The findings are the first possible genetic cause identified for MIS-C, an illness that usually occurs about four weeks after COVID-19 infection and has widespread symptoms such as fever, vomiting and inflammation of the heart muscle that may lead to hospitalization. According to the most recent Centers for Disease Control and Prevention, states have reported nearly 9,000 MIS-C cases, with 71 deaths.
OAS proteins are induced by interferons as a first line of defense against viruses. After sensing the viral double-stranded RNA, the OAS protein activates RNase L to prevent the virus from growing and spreading.
“RNase L acts like scissors to cut messenger RNA that gets translated into proteins, including proteins known as cytokines that cause inflammation,” Dr. Silverman said. “Autosomal recessive mutations in MIS-C either prevent scissor from operating (OAS mutation) or prevent scissor from being formed at all (RNase L mutation). These findings provide important insights into how the OAS-RNase L can protect against this serious unexplained complication of COVID-19.
Dr. Silverman’s lab, which studies the role of interferons in the immune response with a focus on the OAS-RNase L pathway, collaborated with a team led by Rockefeller University Jean-Laurent Casanova, MD, Ph.D. Dr. Casanova’s team found the mutation by analyzing DNA sequence data from MIS-C patients compared to other children who were infected with COVID-19 but not MIS-C.
“Our findings improve the understanding of MIS-C by elucidating the molecular, cellular and immunological basis of the disease,” said Dr Casanova. “We identified the mutation by analyzing DNA sequence data from MIS-C patients in comparison to other children infected with COVID-19 but not contracting MIS-C. One of the key research questions was whether increased virus multiplication or an exaggerated inflammatory response led to MIS-C in cases with the mutation. Our results support the latter interpretation.”
As part of an international collaboration, Dr. Silverman’s team determined what the specific effects of the mutations were on the pathway. This involved examining dozens of mutated genes, identifying the effects on RNA, and then correlating the results with disease.
Doctor. “Our team took what they had learned about these enzymes over the years to obtain the functional data they needed for the study,” Silverman said. “Essentially, it validated the effects these mutations could have on function.”
Dr. Silverman’s lab also contributed reagents not commercially available, synthesizing a small molecule that switches on RNase L and causes it to cleave RNA. The study determined that these mutations led to a heightened inflammatory response at the molecular level, according to the paper.
Knowledge about these mutations and how they affect the immune system may provide more information about other diseases that cause chronic inflammation, such as Kawasaki disease, which presents similarly to MIS-C.
Funding to the Cleveland Clinic: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award R01AI104887.
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article title
Inborn errors of OAS-RNase L in SARS-CoV-2-associated multisystem inflammatory syndrome in children
article publication date
20-December-2022
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