Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

The Journal of Experimental Medicine
Ian T LambornHelen C Su

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.

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Datasets Mentioned

BETA
BC111750

Methods Mentioned

BETA
exome sequencing
transfection
RNA-seq
ELISA
scrapings
electrophoresis
PCR
chips
genotyping
biopsy

Clinical Trials Mentioned

NCT00246857
NCT00128973
NCT00895271

Software Mentioned

PolyPhen2
siNeg
Statistical R package DESeq2
PyMol Molecular Graphics System
GraphPad
PLINK
PyMol
DESeq2
Assisted Model Building with Energy Refinement ( AMBER14 )
Genome Analysis Toolkit

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