Covid-19: inborn errors responsible for multisystemic inflammatory syndrome in children

A team from the Human Genetics of Infectious Diseases Laboratory of the Necker-Enfants malades AP-HP Hospital, Inserm, Université Paris Cité within Institut Imagine, leading the international consortium COVID Human Genetic Effort ( coordinated by Prof. Jean-Laurent Casanova and Prof. Laurent Abel, has discovered genetic defects responsible for the multisystemic inflammatory syndrome of children (MIS-C), following an infection with SARS-CoV-2. The results of this study were published on December 20, 2022 in the journal Science.

Published on 18.01.2023

Research Acceleration

Childhood multisystemic inflammatory syndrome is a new systemic inflammatory entity in children that has emerged in the epidemic setting of SARS-Cov-2 infection. It is a rare and severe condition that strongly resembles Kawasaki disease. This syndrome is misunderstood and the suggestive symptoms (fever, altered general condition and digestive disorders) are not very specific, which may lead to a delay in diagnosis, especially since SARS-CoV-2 infection is often not very symptomatic, or even asymptomatic, in children.

It is estimated to affect approximately 1 in 10,000 children infected with SARS-CoV-2. This syndrome usually occurs four weeks after infection.

The objective of this study was to identify a cause of MIS-C following SARS-CoV-2 infection.

558 patients with MIS-C, aged three months to 19 years, from 16 different countries (60.4% boys and 39.6% girls) were analyzed. The study focused on five of these patients, aged between three months and 14 years, because of their specific genetic characteristics. Indeed, these patients had mutations responsible for a loss of function in a zone of their genome (affecting the OAS1, OAS2 and RNASEL genes). As these mutations were recessive, the children had to have two copies inherited from each of their parents for them to be expressed. This specificity suggested that these genetic mutations were probably responsible for the development of MIS-C.

They were compared immunologically to healthy children and to children with SARS-CoV-2 infection. In children with a mutation in the OAS-RNase L pathway, an excess response to the virus was observed in certain immune cells: phagocytes.

It is now known that the body's response to SARS-Cov2 must be finely regulated in order to defend itself properly. An under-activation of the immune system prevents the body from fighting SARS-CoV-2 correctly, but conversely, an over-activation of the immune system can also lead to serious dysfunctions.

The study therefore identified genetic deficiencies that explain MIS-C. These deficiencies excessively increase the inflammatory response triggered by SARS-CoV-2 in phagocytic cells (monocytes, dendritic cells etc).

More generally, the data of this work demonstrate that the OAS1, OAS2 and RNASEL pathway is essential for the correct regulation of immunity against SARS-CoV-2, by limiting the inflammation produced by phagocytes in contact with the virus.

Reference : 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, CoV-Contact Cohort, COVID Human Genetic Effort,  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, Rick 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. Science.

Université Paris Cité is a multidisciplinary research-intensive university in the heart of the capital, which has reached the highest international level thanks to its research, the diversity of its training courses, its support for innovation, and its active participation in the construction of the European research and training area. Université Paris Cité is made up of three faculties (Health, Sciences and Societies, and Humanities), a component institution, the Institut de Physique du Globe de Paris, and a partner research organization, the Institut Pasteur. Université Paris Cité has 63,000 students, 7,500 teacher-researchers and researchers, 2,700 administrative and technical staff, 21 doctoral schools and 119 research units.

About Inserm: Created in 1964, Inserm is a public scientific and technological institution under the dual supervision of the Ministry of Health and the Ministry of Research. Dedicated to biological, medical and human health research, it is involved in the entire process from the research laboratory to the patient's bed. On the international scene, it is the partner of the largest institutions involved in the challenges and scientific progress in these fields

About AP-HP: As Europe's leading university hospital center (CHU), AP-HP and its 38 hospitals are organized into six university hospital groups (AP-HP. Center - Université Paris Cité; AP-HP. Sorbonne University; AP-HP. Nord - Université Paris Cité; AP-HP. Université Paris Saclay; AP-HP. Henri Mondor University Hospitals and AP-HP. Hôpitaux Universitaires Paris Seine-Saint-Denis) and are structured around five Ile-de-France universities. Closely linked to major research organizations, AP-HP has four world-class university hospital institutes (ICM, ICAN, IMAGINE, FOReSIGHT) and the largest French health data warehouse (EDS). As a major player in applied research and innovation in healthcare, the AP-HP holds a portfolio of 650 active patents, its clinical researchers sign more than 10,000 scientific publications each year and more than 4,000 research projects are currently under development, all sponsors included. In 2020, the AP-HP obtained the Carnot Institute label, which rewards the quality of its partnership research: the Carnot@AP-HP offers industrial players applied and clinical research solutions in the field of health. In 2015, the AP-HP also created the AP-HP Foundation, which works directly with caregivers to support the organization of care, hospital staff and research within the AP-HP.