期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 7, 页码 1949-1972出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161759
关键词
-
资金
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health
- National Center for Research Resources
- National Center for Advancing Sciences of the National Institutes of Health [8UL1TR000043]
- St. Giles Foundation
- Rockefeller University
- National Jewish Health
- CSL Behring
- [T32CA009207]
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-kappa B 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-beta/lambda. 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据