Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children - Repository

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: https://doi.org/10.1126/science.abo3627

Abstract

INTRODUCTION

Multisystem inflammatory syndrome in children (MIS-C) is a severe, unexplained complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with an estimated prevalence of ~1 per 10,000 infected children. It typically occurs 4 weeks after infection, without hypoxemic pneumonia. Affected children present with fever, rash, abdominal pain, myocarditis, and other clinical features reminiscent of Kawasaki disease, including lymphadenopathy, coronary aneurysm, and high levels of biological markers of acute inflammation. Sustained monocyte activation is consistently reported as a key immunological feature of MIS-C. A more specific immunological abnormality is the polyclonal expansion of CD4⁺ and CD8⁺ T cells bearing the T cell receptor Vβ21.3. The root cause of MIS-C and its immunological and clinical features remains unknown.

RATIONALE

We hypothesized that monogenic inborn errors of immunity to SARS-CoV-2 may underlie MIS-C in some children. We further hypothesized that the identification of these inborn errors would provide insights into the molecular and cellular mechanisms underlying its immunological and clinical phenotypes. Finally, we hypothesized that a genetic and mechanistic understanding of a few patients would provide a proof of principle that would facilitate studies in other patients. We performed whole-exome or whole-genome sequencing on 558 internationally recruited patients with MIS-C (aged 3 months to 19 years). We searched for rare nonsynonymous biallelic variants of protein-coding genes, testing a hypothesis of genetic homogeneity.

RESULTS

We found autosomal recessive deficiencies of OAS1 (2′-5′-oligoadenylate synthetase 1), OAS2, or RNase L (ribonuclease L) in five unrelated children of four different ancestries with MIS-C (~1% of our cohort). There were no similar defects in a cohort of 1288 individuals (aged 6 months to 99 years) with asymptomatic or mild infection (P = 0.001) or 334 young patients (aged 0 to 21 years) with asymptomatic or mild infection or COVID-19 pneumonia (P = 0.046). The estimated cumulative frequency of these defects in the general population was ~0.00013. The type I interferon (IFN)–inducible double-stranded RNA (dsRNA)–sensing proteins OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A), which activate the antiviral single-stranded RNA (ssRNA)–degrading RNase L, particularly in mononuclear phagocytes. Consistent with the absence of pneumonia in these patients, epithelial cells and fibroblasts defective for this pathway restricted SARS-CoV-2 normally. This contrasted with interferon alpha and beta receptor subunit 1 (IFNAR1)–deficient cells from patients prone to hypoxemic pneumonia without MIS-C. Monocytic cell lines with genetic deficiencies of OAS1, OAS2, or RNase L displayed excessive inflammatory cytokine production in response to intracellular dsRNA. Cytokine production by RNase L–deficient cells was impaired by melanoma differentiation-associated protein 5 (MDA5) or retinoic acid–inducible gene I (RIG-I) deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Exogenous 2-5A suppressed inflammatory responses to these stimuli in control and OAS1-deficient cells but not in RNase L–deficient cells. Finally, monocytic cell lines, primary monocytes, and monocyte-derived dendritic cells with genetic deficiencies of OAS1, OAS2, or RNase L displayed exaggerated inflammatory responses to SARS-CoV-2 as well as SARS-CoV-2–infected cells and their RNA.

CONCLUSION

We report autosomal recessive deficiencies of OAS1, OAS2, or RNase L in ∼1% of an international cohort of MIS-C patients. The cytosolic OAS–RNase L pathway suppresses RIG-I/MDA5–MAVS–mediated inflammation in dsRNA-stimulated mononuclear phagocytes. Single-gene recessive inborn errors of the OAS–RNase L pathway unleash the production of SARS-CoV-2–triggered inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

Rights

This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

Cite as

Lee, D., Le Pen, J., Yatim, A., Dong, B., Aquino, Y., Ogishi, M., Pescarmona, R., Talouarn, E., Rinchai, D., Zhang, P., Perret, M., Liu, Z., Jordan, I., Elmas Bozdemir, S., Bayhan, G., Beaufils, C., Bizien, L., Bisiaux, A., Lei, W., Hasan, M., Chen, J., Gaughan, C., Asthana, A., Libri, V., Luna, J., Jaffré, F., Hoffmann, H., Michailidis, E., Moreews, M., Seeleuthner, Y., Bilguvar, K., Mane, S., Flores, C., Zhang, Y., Arias, A., Bailey, R., Schlüter, A., Milisavljevic, B., Bigio, B., Le Voyer, T., Materna, M., Gervais, A., Moncada-Velez, M., Pala, F., Lazarov, T., Levy, R., Neehus, A., Rosain, J., Peel, J., Chan, Y., Morin, M., Pino-Ramirez, R., Belkaya, S., Lorenzo, L., Anton, J., Delafontaine, S., Toubiana, J., Bajolle, F., Fumadó, V., DeDiego, M., Fidouh, N., Rozenberg, F., Pérez-Tur, J., Chen, S., Evans, T., Geissmann, F., Lebon, P., Weiss, S., Bonnet, D., Duval, X., Pan-Hammarström, Q., Planas, A., Meyts, I., Haerynck, F., Pujol, A., Sancho-Shimizu, V., Dalgard, C., Bustamante, J., Puel, A., Boisson-Dupuis, S., Boisson, B., Maniatis, T., Zhang, Q., Bastard, P., Notarangelo, L., Béziat, V., Perez de Diego, R., Rodriguez-Gallego, C., Su, H., Lifton, R., Jouanguy, E., Cobat, A., Alsina, L., Keles, S., Haddad, E., Abel, L., Belot, A., Quintana-Murci, L., Rice, C., Silverman, R., Zhang, S., Casanova, J., COV-Contact-Cohort & Covid Human Genetic Effort 2022, 'Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children', Science, 379(6632), article no: eabo3627. https://doi.org/10.1126/science.abo3627

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DOI: https://doi.org/10.1126/science.abo3627

Repository URI: https://www.research.ed.ac.uk/en/publications/d57ceaf9-0e0e-4459-8df9-48edf1f0a89a