Life-threatening viral disease in a novel form of autosomal recessive <i>IFNAR2</i> deficiency in the Arctic-Reference-Cited by-同舟云学术

Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic

Published:2022-04-20 Issue:6 Volume:219 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Duncan Christopher J.A.¹²^ORCID,Skouboe Morten K.³⁴^ORCID,Howarth Sophie¹^ORCID,Hollensen Anne K.³⁴^ORCID,Chen Rui¹^ORCID,Børresen Malene L.⁵⁶^ORCID,Thompson Benjamin J.¹^ORCID,Stremenova Spegarova Jarmila¹^ORCID,Hatton Catherine F.¹^ORCID,Stæger Frederik F.⁷^ORCID,Andersen Mette K.⁸^ORCID,Whittaker John¹^ORCID,Paludan Søren R.³^ORCID,Jørgensen Sofie E.³⁴^ORCID,Thomsen Martin K.³^ORCID,Mikkelsen Jacob G.³^ORCID,Heilmann Carsten⁵⁹^ORCID,Buhas Daniela¹⁰¹¹^ORCID,Øbro Nina F.¹²^ORCID,Bay Jakob T.¹²^ORCID,Marquart Hanne V.¹²^ORCID,de la Morena M. Teresa¹³¹⁴^ORCID,Klejka Joseph A.¹⁵^ORCID,Hirschfeld Matthew¹⁶^ORCID,Borgwardt Line¹⁷^ORCID,Forss Isabel¹⁷^ORCID,Masmas Tania⁵^ORCID,Poulsen Anja⁵^ORCID,Noya Francisco¹⁸^ORCID,Rouleau Guy¹⁹^ORCID,Hansen Torben⁸^ORCID,Zhou Sirui¹¹^ORCID,Albrechtsen Anders⁷^ORCID,Alizadehfar Reza¹⁸^ORCID,Allenspach Eric J.¹²¹³²⁰²¹^ORCID,Hambleton Sophie¹²^ORCID,Mogensen Trine H.³⁴^ORCID

Affiliation:

1. Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK

2. The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

3. Department of Biomedicine, Aarhus University, Aarhus, Denmark

4. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark

5. Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

6. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

7. Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark

8. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

9. Medical Department, Pediatric Section, Dronning Ingrid Hospital, Nuuk, Greenland

10. Division of Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Quebec, Canada

11. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

12. Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark

13. Seattle Children’s Hospital, Seattle, WA

14. Department of Pediatrics, University of Washington, Seattle, WA

15. Yukon-Kuskokwim Health Corporation, Bethel, AK

16. Alaska Native Medical Center, Anchorage, AK

17. Center for Genomic Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

18. Division of Allergy & Clinical Immunology, Montreal Children’s Hospital, Montreal General Hospital, McGill University, Montreal, Quebec, Canada

19. The Neuro, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

20. Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, WA

21. Brotman Baty Institute for Precision Medicine, Seattle, WA

Abstract

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro—a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

Funder

Wellcome Trust

Medical Research Council

Independent Research Fund Denmark

NOVO Nordisk Foundation

Lundbeck Foundation

Aarhus University

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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