Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

被引：112

作者：

Asgari, Samira ^{[1
,2
]}

Schlapbach, Luregn J. ^{[3
,4
,5
,6
]}

Anchisi, Stephanie ^{[7
]}

Hammer, Christian ^{[1
,2
]}

Bartha, Istvan ^{[1
,2
]}

Junier, Thomas ^{[1
,2
]}

Mottet-Osman, Genevieve ^{[7
]}

Posfay-Barbe, Klara M. ^{[8
]}

Longchamp, David ^{[9
]}

Stocker, Martin ^{[10
]}

Cordey, Samuel ^{[11
]}

Kaiser, Laurent ^{[11
]}

Riedel, Thomas ^{[5
,6
]}

Kenna, Tony ^{[12
]}

Long, Deborah ^{[3
,4
]}

Schibler, Andreas ^{[3
,4
]}

Telenti, Amalio ^{[13
]}

Tapparel, Caroline ^{[7
]}

McLaren, Paul J. ^{[14
,15
]}

Garcin, Dominique ^{[7
]}

Fellay, Jacques ^{[1
,2
]}

机构：

[1] Ecole Polytech Fed Lausanne, Sch Life Sci, Global Hlth Inst, CH-1015 Lausanne, Switzerland

[2] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[3] Univ Queensland, Mater Res Inst, Paediat Crit Care Res Grp, Brisbane, Qld 4101, Australia

[4] Lady Cilento Childrens Hosp, Paediat Intens Care Unit, Brisbane, Qld 4101, Australia

[5] Univ Childrens Hosp, Inselspital, Dept Pediat, Pediat Intens Care Unit, CH-3010 Bern, Switzerland

[6] Univ Bern, CH-3010 Bern, Switzerland

[7] Univ Geneva, Fac Med, Dept Microbiol & Mol Med, CH-1205 Geneva, Switzerland

[8] Geneva Univ Hosp, Pediat Infect Dis Unit, CH-1205 Geneva, Switzerland

[9] Lausanne Univ Hosp, Pediat Intens Care Unit, CH-1011 Lausanne, Switzerland

[10] Childrens Hosp, Neonatal & Pediat Intens Care Unit, CH-6000 Luzern, Switzerland

[11] Univ Geneva, Geneva Univ Hosp, Sch Med, Lab Virol,Div Infect Dis, CH-1205 Geneva, Switzerland

[12] Queensland Univ Technol, Translat Res Inst, Inst Hlth & Biomed Innovat, Brisbane, Qld 4000, Australia

[13] J Craig Venter Inst, La Jolla, CA 92037 USA

[14] Publ Hlth Agcy Canada, JC Wilt Infect Dis Res Ctr, Natl Lab HIV Genet, Winnipeg, MB R3E 0W3, Canada

[15] Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB R3T 2N2, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 31期

基金：

瑞士国家科学基金会;

关键词：

respiratory syncytial virus; rhinovirus; IFIH1; RIG-I-like receptor family; severe pediatric infectious disease; HERPES-SIMPLEX ENCEPHALITIS; RIG-I; ANTIVIRAL RESPONSES; VIRUS-INFECTION; RNA VIRUSES; MDA5; RECOGNITION; ASSOCIATION; LOCUS; CELLS;

D O I：

10.1073/pnas.1704259114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-beta, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.

引用

页码：8342 / 8347

页数：6

共 43 条

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