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. Epub 2017 Jun 12.

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.

Publication types

  • Case Reports

MeSH terms

  • Antiviral Agents / pharmacology
  • Base Sequence
  • Cells, Cultured
  • Child, Preschool
  • DNA Mutational Analysis / methods
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • Gene Expression / drug effects
  • Genes, Recessive / genetics
  • Heterozygote
  • Homozygote
  • Host-Pathogen Interactions
  • Humans
  • Interferon-Induced Helicase, IFIH1 / deficiency
  • Interferon-Induced Helicase, IFIH1 / genetics*
  • Interferons / pharmacology
  • Male
  • Mutation*
  • Pedigree
  • Picornaviridae Infections / genetics*
  • Picornaviridae Infections / virology*
  • Rhinovirus / physiology*

Substances

  • Antiviral Agents
  • Interferons
  • IFIH1 protein, human
  • Interferon-Induced Helicase, IFIH1