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.