Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

被引：45

作者：

Smith, Nikaia ^{[1
]}

Posseme, Celine ^{[1
]}

Bondet, Vincent ^{[1
]}

Sugrue, Jamie ^{[2
]}

Townsend, Liam ^{[3
,4
]}

Charbit, Bruno ^{[5
]}

Rouilly, Vincent ^{[6
]}

Saint-Andre, Violaine ^{[1
,7
]}

Dott, Tom ^{[5
]}

Pozo, Andre Rodriguez ^{[1
]}

Yatim, Nader ^{[1
]}

Schwartz, Olivier ^{[8
]}

Cervantes-Gonzalez, Minerva ^{[9
,10
,11
]}

Ghosn, Jade ^{[9
,11
]}

Bastard, Paul ^{[12
,13
,14
,15
]}

Casanova, Jean Laurent ^{[12
,13
,14
,15
,16
]}

Szwebel, Tali-Anne ^{[17
]}

Terrier, Benjamin ^{[17
]}

Conlon, Niall ^{[18
,19
]}

O'Farrelly, Cliona ^{[2
,19
]}

Cheallaigh, Cliona Ni ^{[3
,4
]}

Bourke, Nollaig M. ^{[20
]}

Duffy, Darragh ^{[1
,5
]}

机构：

[1] Univ Paris Cite, Inst Pasteur, Translat Immunol Unit, Paris, France

[2] Trinity Coll Dublin, Sch Biochem & Med, Trinity Biomed Sci Inst, Dublin, Ireland

[3] Trinity Coll Dublin, Discipline Clin Med, Sch Med, Trinity Translat Med Inst, Dublin, Ireland

[4] St James Hosp, Dept Infect Dis, Dublin, Ireland

[5] Univ Paris Cite, Inst Pasteur, CBUTechS, Ctr Translat Res, Paris, France

[6] Datactix, Bordeaux, France

[7] Univ Paris Cite, Dept Computat Biol, Bioinformat & Biostat Hub, Inst Pasteur, Paris, France

[8] Inst Pasteur, Dept Virol, Virus & Immun Unit, Paris, France

[9] Hop Bichat Claude Bernard, AP HP, Infect & Trop Dis Dept, Paris, France

[10] Hop Bichat Claude Bernard, AP HP, Epidemiol Biostat & Clin Res Dept, Paris, France

[11] Univ Paris, INSERM, IAME, UMR 1137 Paris, Paris, France

[12] Necker Hosp Sick Children, AP HP, Dept Pediat, Paris, France

[13] Necker Hosp Sick Children, Lab Human Genet Infect Dis, Necker Branch, INSERM U1163, Paris, France

[14] Univ Paris Cite, Imagine Inst, Paris, France

[15] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USA

[16] Howard Hughes Med Inst, New York, NY USA

[17] Inst Cochin, AP HP, Paris, France

[18] St James Hosp, Dept Immunol, Dublin, Ireland

[19] Trinity Coll Dublin, Sch Med, Discipline Immunol, Dublin, Ireland

[20] Trinity Coll Dublin, Discipline Med Gerontol, Sch Med, Trinity Translat Med Inst, Dublin, Ireland

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

英国惠康基金; 欧盟地平线“2020”; 爱尔兰科学基金会; 美国国家卫生研究院;

关键词：

INFECTION; RESPONSES;

D O I：

10.1038/s41467-022-34895-1

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：

The interferon response has been shown to be linked to severity of SARS-CoV-2 infection and is an essential component of the immune response to COVID-19. Here the authors stratify patients according to COVID-19 severity and asses the interferon response showing defective responses in severe infection and highlight the importance of assay variables and confounding factors that impact the detection of interferon. Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon alpha measures differ according to the immunoassay used, timing of sampling, the interferon alpha subtype measured, and the presence of autoantibodies. We also show a consistently reduced induction of interferon-I proteins in hospitalized COVID-19 patients upon immune stimulation, that is not associated with detectable neutralizing autoantibodies against interferon alpha or interferon omega. Intracellular proteomic analysis shows increased monocyte numbers in hospitalized COVID-19 patients but impaired interferon-I response after stimulation. We confirm this by ex vivo whole blood stimulation with interferon-I which induces transcriptomic responses associated with inflammation in hospitalized COVID-19 patients, that is not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies.

引用

页数：14

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