TY - JOUR
T1 - Recurrent rhinovirus infections in a child with inherited MDA5 deficiency
AU - Lamborn, Ian T.
AU - Jing, Huie
AU - Zhang, Yu
AU - Drutman, Scott B.
AU - Abbott, Jordan K.
AU - Munir, Shirin
AU - Bade, Sangeeta
AU - Murdock, Heardley M.
AU - Santos, Celia P.
AU - Brock, Linda G.
AU - Masutani, Evan
AU - Fordjour, Emmanuel Y.
AU - McElwee, Joshua J.
AU - Hughes, Jason D.
AU - Nichols, Dave P.
AU - Belkadi, Aziz
AU - Oler, Andrew J.
AU - Happel, Corinne S.
AU - Matthews, Helen F.
AU - Abel, Laurent
AU - Collins, Peter L.
AU - Subbarao, Kanta
AU - Gelfand, Erwin W.
AU - Ciancanelli, Michael J.
AU - Casanova, Jean Laurent
AU - Su, Helen C.
N1 - Funding Information:
We thank the following people: for technical assistance, Hyoungjun Ham and Michael Leney-Greene; for technical advice and reagents, Gary Fahle, Ronald Germain, Yong He, Wei-Ming Lee, and Charles Rice; for clinical assistance and support, Patricia Littel, Martha Marquesen, Arianne Soldatos, and Angela Wang; for helpful discussions and/or critically reading the manuscript, Avinash Bhandoola, Sara Cherry, Michael Lenardo, Pamela Schwartzberg, and Qian Zhang. We also thank the patient, her family, and National Jewish Health staff for participating in this study. The data presented in this work are presented in the main paper and the supplemental material, and are archived under dbGaP database accession no. phs001235.v1 and BioProject accession no. PRJ NA387035. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, the National Center for Research Resources, and the National Center for Advancing Sciences of the National Institutes of Health (grant 8UL1TR000043), the St. Giles Foundation, the Rockefeller University, and National Jewish Health. S.B. Drutman is supported by T32CA009207, and J.K. Abbot was supported by a fellowship from CSL Behring. I.T. Lamborn is a Medical Scientist Training Program student in the Graduate Program in Immunology at the University of Pennsylvania. The authors declare no competing financial interests.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - 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.
AB - 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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U2 - 10.1084/jem.20161759
DO - 10.1084/jem.20161759
M3 - Article
C2 - 28606988
AN - SCOPUS:85021862719
SN - 0022-1007
VL - 214
SP - 1949
EP - 1972
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -