Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

• Published in: The Journal of experimental medicine 2017-07, Vol.214 (7), p.1949-1972
• Main Authors: Lamborn, Ian T, Jing, Huie, Zhang, Yu, Drutman, Scott B, Abbott, Jordan K, Munir, Shirin, Bade, Sangeeta, Murdock, Heardley M, Santos, Celia P, Brock, Linda G, Masutani, Evan, Fordjour, Emmanuel Y, McElwee, Joshua J, Hughes, Jason D, Nichols, Dave P, Belkadi, Aziz, Oler, Andrew J, Happel, Corinne S, Matthews, Helen F, Abel, Laurent, Collins, Peter L, Subbarao, Kanta, Gelfand, Erwin W, Ciancanelli, Michael J, Casanova, Jean-Laurent, Su, Helen C
• Format: Article
• Language: English
• Subjects: Antiviral Agents - pharmacology; Base Sequence; Byproducts; Cells, Cultured; Child, Preschool; Common cold; DNA Mutational Analysis - methods; Double-stranded RNA; Enterovirus; Epithelial cells; Female; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - virology; Gene expression; Gene Expression - drug effects; Genes, Recessive - genetics; Genetic modification; Heterozygote; Homozygote; Host-Pathogen Interactions; Humans; Immunity; Infections; Influenza; Interferon; Interferon-Induced Helicase, IFIH1 - deficiency; Interferon-Induced Helicase, IFIH1 - genetics; Interferons - pharmacology; Intermediates; Male; Missense mutation; Mutation; NF-κB protein; Orthomyxoviridae; Pedigree; Picornaviridae; Picornaviridae Infections - genetics; Picornaviridae Infections - virology; Polyinosinic:polycytidylic acid; Replication; Respiratory syncytial virus; Respiratory tract; Respiratory tract diseases; Rhinovirus; Rhinovirus - physiology; Ribonucleic acid; RNA; Signaling; Viruses
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20161759

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 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 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.