Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

J Exp Med. 2017 Jul 3;214(7):1949-1972. doi: 10.1084/jem.20161759.

Ian T Lamborn ¹ ², Huie Jing ¹, Yu Zhang ¹, Scott B Drutman ³ ⁴, Jordan K Abbott ⁵, Shirin Munir ⁶, Sangeeta Bade ⁷, Heardley M Murdock ¹, Celia P Santos ⁶, Linda G Brock ⁶, Evan Masutani ⁸, Emmanuel Y Fordjour ¹, Joshua J McElwee ⁹, Jason D Hughes ⁹, Dave P Nichols ¹⁰, Aziz Belkadi ¹¹ ¹², Andrew J Oler ¹³, Corinne S Happel ¹, Helen F Matthews ⁸, Laurent Abel ³ ¹¹ ¹², Peter L Collins ⁶, Kanta Subbarao ⁶, Erwin W Gelfand ⁵, Michael J Ciancanelli ³, Jean-Laurent Casanova ³ ¹¹ ¹² ¹⁴ ¹⁵, Helen C Su ¹⁶ ²

Affiliations

1 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
2 Department of Pathology and Laboratory Medicine, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
3 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
4 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
5 Immunodeficiency Diagnosis and Treatment Program, Division of Allergy and Immunology, Department of Pediatrics, National Jewish Health, Denver, CO.
6 Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
7 Medical Science & Computing, LLC, Rockville, MD.
8 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
9 Merck Research Laboratories, Merck and Co, Boston, MA.
10 Division of Pediatric Pulmonary Medicine, Department of Pediatrics, National Jewish Health, Denver, CO.
11 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR1163, Necker Hospital for Sick Children, Paris, France.
12 Paris Descartes University, Imagine Institute, Necker Hospital for Sick Children, Paris, France.
13 Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
14 Pediatric Immuno-Hematology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
15 Howard Hughes Medical Institute, New York, NY.
16 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD [email protected].

PMID: 28606988 DOI: 10.1084/jem.20161759

Abstract

MDA5 is a cytosolic sensor of double-stranded RNA (ds)RNA including viral byproducts and intermediates. We studied a child with life-threatening, recurrent respiratory tract infections, caused by viruses including human rhinovirus (HRV), Influenza Virus, and respiratory syncytial virus (RSV). We identified in her a homozygous missense mutation in IFIH1 that encodes MDA5. Mutant MDA5 was expressed but did not recognize the synthetic MDA5 agonist/(ds)RNA mimic polyinosinic-polycytidylic acid. When overexpressed, mutant MDA5 failed to drive luciferase activity from the IFNB1 promoter or promoters containing ISRE or NF-κB sequence motifs. In respiratory epithelial cells or fibroblasts, wild-type but not knockdown of MDA5 restricted HRV Infection while increasing IFN-stimulated gene expression and IFN-β/λ. However, wild-type MDA5 did not restrict Influenza Virus or RSV replication. Moreover, nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. Thus, human MDA5 deficiency is a novel inborn error of innate and/or intrinsic immunity that causes impaired (ds)RNA sensing, reduced IFN induction, and susceptibility to the common cold virus.

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