New! Sign up for our free email newsletter.
Science News
from research organizations

Research identifies potential genetic cause for MIS-C complication following COVID-19 infection

Date:
December 20, 2022
Source:
Cleveland Clinic
Summary:
New research findings have revealed an underlying genetic cause for why some children who have had COVID-19 infection develop Multisystem Inflammatory Syndrome in Children (MIS-C), a rare but potentially life-threatening disease.
Share:
FULL STORY

New research findings have revealed an underlying genetic cause for why some children who have had COVID-19 infection develop Multisystem Inflammatory Syndrome in Children (MIS-C), a rare but potentially life-threatening disease.

The findings are the first potential genetic cause identified for MIS-C, a disease that typically occurs about four weeks after COVID-19 infection and has broad symptoms such as fever, vomiting and inflammation of the heart muscle that can lead to hospitalization. States have reported about 9,000 MIS-C cases, with 71 deaths, according to most recent Centers for Disease Control and Prevention numbers.

The results, published in Science, are rooted in more than 40 years of research from Robert Silverman, Ph.D., of Cleveland Clinic Lerner Research Institute's Department of Cancer Biology. The study, led by Rockefeller University, found genetic mutations to the proteins OAS and RNase L increased the inflammatory response in some immune cell types. That change can cause inflammation in multiple organs, including the heart, lungs, kidneys and gastrointestinal tract. In the study, mutations were identified in a small subset of children with MIS-C.

OAS proteins are induced by interferons, as a first line of defense against viruses. After sensing viral double-stranded RNA, OAS proteins activate RNase L to prevent the virus from multiplying and spreading.

"RNase L acts like scissors to cut up messenger RNA that gets translated into proteins, including proteins known as cytokines that cause inflammation," Dr. Silverman said. "The autosomal recessive mutations in MIS-C either prevent the scissors from operating (OAS mutations) or prevent the scissors from being made at all (RNase L mutations). These findings offer important insights about how OAS-RNase L can protect against this severe unexplained complication of COVID-19."

Dr. Silverman's lab, which studies the role of interferons in immune responses with a focus on the OAS-RNase L pathway, collaborated with a team at Rockefeller University led by Jean-Laurent Casanova, M.D., Ph.D. Dr. Casanova's team found the mutations in part through analyzing DNA sequence data from MIS-C patients in comparison to other children who were infected with COVID-19 but did not contract MIS-C.

"Our findings improve the understanding of MIS-C by clarifying the molecular, cellular and immunological basis of the disease," said Dr. Casanova. "We identified the mutations through analyzing DNA sequence data from MIS-C patients in comparison to other children who were infected with COVID-19 but did not contract MIS-C. One of the key research questions was whether increased virus multiplication or an exaggerated inflammatory response led to MIS-C in the cases with the mutations. Our results support the latter explanation."

As part of an international collaboration, Dr. Silverman's team determined what the specific effects of the mutations were on the pathway. That included screening dozens of mutant genes, identifying the effects on RNA and then correlating the results with the disease.

"Our team took what I had learned over the years about these enzymes to get the functional data that the study needed," said Dr. Silverman. "Essentially, this validated the effects these mutations had on function."

Dr. Silverman's lab also contributed reagents not commercially available, synthesizing a small molecule that switches on RNase L and makes it cleave RNA. The study determined that these mutations led to an exacerbated inflammatory response at a molecular level, according to the paper.

Knowledge about these mutations and how it affects immune mechanisms could provide more information on other diseases that cause chronic inflammation, like Kawasaki disease, which presents similarly to MIS-C.

Funding to Cleveland Clinic: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award R01AI104887.


Story Source:

Materials provided by Cleveland Clinic. Note: Content may be edited for style and length.


Journal Reference:

  1. Danyel Lee, Jérémie Le Pen, Ahmad Yatim, Beihua Dong, Yann Aquino, Masato Ogishi, Rémi Pescarmona, Estelle Talouarn, Darawan Rinchai, Peng Zhang, Magali Perret, Zhiyong Liu, Iolanda Jordan, Sefika Elmas Bozdemir, Gulsum Iclal Bayhan, Camille Beaufils, Lucy Bizien, Aurelie Bisiaux, Weite Lei, Milena Hasan, Jie Chen, Christina Gaughan, Abhishek Asthana, Valentina Libri, Joseph M. Luna, Fabrice Jaffré, H.-Heinrich Hoffmann, Eleftherios Michailidis, Marion Moreews, Yoann Seeleuthner, Kaya Bilguvar, Shrikant Mane, Carlos Flores, Yu Zhang, Andrés A. Arias, Rasheed Bailey, Agatha Schlüter, Baptiste Milisavljevic, Benedetta Bigio, Tom Le Voyer, Marie Materna, Adrian Gervais, Marcela Moncada-Velez, Francesca Pala, Tomi Lazarov, Romain Levy, Anna-Lena Neehus, Jérémie Rosain, Jessica Peel, Yi-Hao Chan, Marie-Paule Morin, Rosa Maria Pino-Ramirez, Serkan Belkaya, Lazaro Lorenzo, Jordi Anton, Selket Delafontaine, Julie Toubiana, Fanny Bajolle, Victoria Fumadó, Marta L. DeDiego, Nadhira Fidouh, Flore Rozenberg, Jordi Pérez-Tur, Shuibing Chen, Todd Evans, Frédéric Geissmann, Pierre Lebon, Susan R. Weiss, Damien Bonnet, Xavier Duval, Human Genetic Effort COVID, Qiang Pan-Hammarström, Anna M. Planas, Isabelle Meyts, Filomeen Haerynck, Aurora Pujol, Vanessa Sancho-Shimizu, Clifford Dalgard, Jacinta Bustamante, Anne Puel, Stéphanie Boisson-Dupuis, Bertrand Boisson, Tom Maniatis, Qian Zhang, Paul Bastard, Luigi Notarangelo, Vivien Béziat, Rebeca Perez de Diego, Carlos Rodriguez-Gallego, Helen C. Su, Richard P. Lifton, Emmanuelle Jouanguy, Aurélie Cobat, Laia Alsina, Sevgi Keles, Elie Haddad, Laurent Abel, Alexandre Belot, Lluis Quintana-Murci, Charles M. Rice, Robert H. Silverman, Shen-Ying Zhang, Jean-Laurent Casanova. Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children. Science, 2022; DOI: 10.1126/science.abo3627

Cite This Page:

Cleveland Clinic. "Research identifies potential genetic cause for MIS-C complication following COVID-19 infection." ScienceDaily. ScienceDaily, 20 December 2022. <www.sciencedaily.com/releases/2022/12/221220112433.htm>.
Cleveland Clinic. (2022, December 20). Research identifies potential genetic cause for MIS-C complication following COVID-19 infection. ScienceDaily. Retrieved April 21, 2024 from www.sciencedaily.com/releases/2022/12/221220112433.htm
Cleveland Clinic. "Research identifies potential genetic cause for MIS-C complication following COVID-19 infection." ScienceDaily. www.sciencedaily.com/releases/2022/12/221220112433.htm (accessed April 21, 2024).

Explore More

from ScienceDaily

RELATED STORIES