Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

Ian T. Lamborn, Huie Jing, Yu Zhang, Scott B. Drutman, Jordan K. Abbott, Shirin Munir, Sangeeta Bade, Heardley M. Murdock, Celia P. Santos, Linda G. Brock, Evan Masutani, Emmanuel Y. Fordjour, Joshua J. McElwee, Jason D. Hughes, Dave P. Nichols, Abdelaziz Belkadi, Andrew J. Oler, Corinne S. Happel, Helen F. Matthews, Laurent Abel & 6 others Peter L. Collins, Kanta Subbarao, Erwin W. Gelfand, Michael J. Ciancanelli, Jean Laurent Casanova, Helen C. Su

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1949-1972
Number of pages24
JournalJournal of Experimental Medicine
Volume214
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017
Externally publishedYes

Fingerprint

Rhinovirus
Respiratory Syncytial Viruses
Double-Stranded RNA
Infection
Orthomyxoviridae
Human Influenza
Fibroblasts
Epithelial Cells
RNA
Poly I-C
Viral RNA
Missense Mutation
Virus Replication
Luciferases
Nose
Respiratory Tract Infections
Immunity
Viruses
Gene Expression
Genes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Lamborn, I. T., Jing, H., Zhang, Y., Drutman, S. B., Abbott, J. K., Munir, S., ... Su, H. C. (2017). Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. Journal of Experimental Medicine, 214(7), 1949-1972. https://doi.org/10.1084/jem.20161759

Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. / 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, Abdelaziz; 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.

In: Journal of Experimental Medicine, Vol. 214, No. 7, 01.07.2017, p. 1949-1972.

Research output: Contribution to journalArticle

Lamborn, IT, Jing, H, Zhang, Y, Drutman, SB, Abbott, JK, Munir, S, Bade, S, Murdock, HM, Santos, CP, Brock, LG, Masutani, E, Fordjour, EY, McElwee, JJ, Hughes, JD, Nichols, DP, Belkadi, A, Oler, AJ, Happel, CS, Matthews, HF, Abel, L, Collins, PL, Subbarao, K, Gelfand, EW, Ciancanelli, MJ, Casanova, JL & Su, HC 2017, 'Recurrent rhinovirus infections in a child with inherited MDA5 deficiency', Journal of Experimental Medicine, vol. 214, no. 7, pp. 1949-1972. https://doi.org/10.1084/jem.20161759
Lamborn IT, Jing H, Zhang Y, Drutman SB, Abbott JK, Munir S et al. Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. Journal of Experimental Medicine. 2017 Jul 1;214(7):1949-1972. https://doi.org/10.1084/jem.20161759
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, Abdelaziz ; 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. / Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 7. pp. 1949-1972.
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