Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
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IFN型IFN免疫的先天误差在危及生命的Covid-19。
DOI：
10.1126/science.abd4570
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发表时间：
2020-10-23
期刊：
影响因子：
--
通讯作者：
Casanova JL
中科院分区：
文献类型：
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作者：
Zhang Q;Bastard P;Liu Z;Le Pen J;Moncada-Velez M;Chen J;Ogishi M;Sabli IKD;Hodeib S;Korol C;Rosain J;Bilguvar K;Ye J;Bolze A;Bigio B;Yang R;Arias AA;Zhou Q;Zhang Y;Onodi F;Korniotis S;Karpf L;Philippot Q;Chbihi M;Bonnet-Madin L;Dorgham K;Smith N;Schneider WM;Razooky BS;Hoffmann HH;Michailidis E;Moens L;Han JE;Lorenzo L;Bizien L;Meade P;Neehus AL;Ugurbil AC;Corneau A;Kerner G;Zhang P;Rapaport F;Seeleuthner Y;Manry J;Masson C;Schmitt Y;Schlüter A;Le Voyer T;Khan T;Li J;Fellay J;Roussel L;Shahrooei M;Alosaimi MF;Mansouri D;Al-Saud H;Al-Mulla F;Almourfi F;Al-Muhsen SZ;Alsohime F;Al Turki S;Hasanato R;van de Beek D;Biondi A;Bettini LR;D'Angio' M;Bonfanti P;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Oler AJ;Tompkins MF;Alba C;Vandernoot I;Goffard JC;Smits G;Migeotte I;Haerynck F;Soler-Palacin P;Martin-Nalda A;Colobran R;Morange PE;Keles S;Çölkesen F;Ozcelik T;Yasar KK;Senoglu S;Karabela ŞN;Rodríguez-Gallego C;Novelli G;Hraiech S;Tandjaoui-Lambiotte Y;Duval X;Laouénan C;COVID-STORM Clinicians;COVID Clinicians;Imagine COVID Group;French COVID Cohort Study Group;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;NIAID-USUHS/TAGC COVID Immunity Group;Snow AL;Dalgard CL;Milner JD;Vinh DC;Mogensen TH;Marr N;Spaan AN;Boisson B;Boisson-Dupuis S;Bustamante J;Puel A;Ciancanelli MJ;Meyts I;Maniatis T;Soumelis V;Amara A;Nussenzweig M;García-Sastre A;Krammer F;Pujol A;Duffy D;Lifton RP;Zhang SY;Gorochov G;Béziat V;Jouanguy E;Sancho-Shimizu V;Rice CM;Abel L;Notarangelo LD;Cobat A;Su HC;Casanova JL
免疫系统是复杂的，涉及许多基因，包括那些编码被称为干扰素（ifn）的细胞因子的基因。缺乏特异性干扰素的个体更容易感染传染病。此外，自身抗体系统抑制IFN反应，以防止病原体引起的炎症损害。现在有两项研究调查了遗传通过该系统的组成部分影响2019年严重冠状病毒病（COVID-19）风险的可能性（见Beck和Aksentijevich的观点）。Q. Zhang等人使用候选基因方法确定了参与I型和III型IFN免疫调节的基因突变的严重COVID-19患者。他们在患者体内发现了这些基因的富集，并得出结论：基因可能决定了感染的临床病程。Bastard等人在约10%的COVID-19重症肺炎患者中发现了高滴度的针对I型IFN-α2和IFN-ω的中和性自身抗体。这些自身抗体在无症状或表型较轻的感染者或健康个体中均未发现。总之，这些研究确定了一种方法，可以通过这种方法识别危及生命的COVID-19风险最高的个体。《科学》，本期p. eabd4570, p.；另见p.一项针对COVID-19患者的大型免疫学和基因组学研究显示，I型IFN通路存在过多突变。人类严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）感染的临床结果从无声感染到致命的冠状病毒病2019 （COVID-19）不等。流行病学研究已经确定了严重疾病的三个风险因素：男性、老年人和有其他医疗条件。然而，在每个人口统计类别中，个体间的临床差异仍然很大。发现威胁生命的COVID-19的根本原因和详细的分子、细胞、组织和身体层面的机制具有最大的生物学和医学重要性。我们建立了COVID Human Genetic Effort (www.covidhge.com)，以验证一些或大多数患者中危及生命的COVID-19可能是由对SARS-CoV-2的单基因先天免疫错误引起的，具有不完全或完全外显性。我们对659名不同血统的危及生命的COVID-19肺炎患者和534名无症状或良性感染患者的外显子组或基因组进行了测序。我们验证了toll样受体3 （TLR3）和干扰素调节因子7 （IRF7）依赖性I型干扰素（IFN）免疫的先天性错误是危及生命的流感肺炎的基础，也是危及生命的COVID-19肺炎的基础。我们考虑了在危及生命的流感患者中发现的三个突变位点：TLR3、IRF7和IRF9。我们还考虑了在其他病毒性疾病患者中发生突变的10个位点，但与具有流感易感性的三个核心基因直接相关：来自tlr3依赖性I型IFN诱导途径的TICAM1/TRIF、UNC93B1、TRAF3、TBK1、IRF3和NEMO/IKBKG，以及来自IRF7和irf9依赖性I型IFN扩增途径的IFNAR1、IFNAR2、STAT1和STAT2。最后，我们考虑了这13个位点的各种遗传模式。我们发现，在659例危及生命的COVID-19肺炎患者中，相对于534例无症状或良性感染患者，13个候选基因座中预测功能丧失（pLOF）的变异频率<0.001 （P = 0.01）。在危重症患者中发现的这13种基因的所有118种罕见非同义变体（包括pLOF和其他变体）的实验测试确定了23名患者（3.5%），年龄在17至77岁之间，携带8种基因的24种有害变体。这些变异分别是4例和19例常染色体隐性（AR）缺陷（IRF7和IFNAR1）和常染色体显性（AD）缺陷（TLR3、UNC93B1、TICAM1、TBK1、IRF3、IRF7、IFNAR1和IFNAR2）的基础。这些患者从未因其他威胁生命的病毒性疾病而住院。IRF7缺陷患者的浆细胞样树突状细胞对SARS-CoV-2感染不产生I型IFN， TLR3−/−、TLR3+/−、IRF7−/−和IFNAR1−/−成纤维细胞对SARS-CoV-2感染敏感。至少3.5%的危及生命的COVID-19肺炎患者在参与TLR3和IRF7依赖性诱导和扩增I型IFNs的13个候选位点中的8个存在已知（AR IRF7和IFNAR1缺陷或AD TLR3、TICAM1、TBK1和IRF3缺陷）或新的（AD UNC93B1、IRF7、IFNAR1和IFNAR2缺陷）遗传缺陷。这一发现揭示了双链RNA传感器TLR3和I型IFN细胞内在免疫在控制SARS-CoV-2感染中的重要作用。在某些患者中，至少在SARS-CoV-2感染过程的早期，使用I型干扰素可能具有治疗益处。红色的分子是由核心基因编码的，核心基因的有害变异是具有不完全外显率的重症流感肺炎的基础，而蓝色的编码生化相关分子的基因的有害变异是其他病毒性疾病的基础。黑体表示的分子由具有变异的基因编码，这些变异也是COVID-19重症肺炎的基础。感染严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的临床结果从无声感染到致命的冠状病毒病2019 （COVID-19）不等。我们发现，在659例危及生命的COVID-19肺炎患者中，相对于534例无症状或良性感染患者，在13个已知控制toll样受体3 （TLR3）和干扰素调节因子7 （IRF7）依赖性I型干扰素（IFN）对流感病毒免疫的人类基因座中，预测功能丧失（LOF）的罕见变异富集。通过在这13个位点检测这些和其他罕见变异，我们实验确定了23例（3.5%）17 - 77岁患者常染色体隐性或常染色体显性缺陷的LOF变异。我们发现，具有影响该回路的突变的人类成纤维细胞易受SARS-CoV-2的影响。TLR3-和irf7依赖性I型IFN免疫的先天错误可能是先前没有严重感染的患者危及生命的COVID-19肺炎的基础。
The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. ; see also p. A large immunological and genomics study of COVID-19 patients reveals excess mutations in the type I IFN pathway. Clinical outcomes of human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection range from silent infection to lethal coronavirus disease 2019 (COVID-19). Epidemiological studies have identified three risk factors for severe disease: being male, being elderly, and having other medical conditions. However, interindividual clinical variability remains huge in each demographic category. Discovering the root cause and detailed molecular, cellular, and tissue- and body-level mechanisms underlying life-threatening COVID-19 is of the utmost biological and medical importance. We established the COVID Human Genetic Effort (www.covidhge.com) to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance. We sequenced the exome or genome of 659 patients of various ancestries with life-threatening COVID-19 pneumonia and 534 subjects with asymptomatic or benign infection. We tested the specific hypothesis that inborn errors of Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity that underlie life-threatening influenza pneumonia also underlie life-threatening COVID-19 pneumonia. We considered three loci identified as mutated in patients with life-threatening influenza: TLR3, IRF7, and IRF9. We also considered 10 loci mutated in patients with other viral illnesses but directly connected to the three core genes conferring influenza susceptibility: TICAM1/TRIF, UNC93B1, TRAF3, TBK1, IRF3, and NEMO/IKBKG from the TLR3-dependent type I IFN induction pathway, and IFNAR1, IFNAR2, STAT1, and STAT2 from the IRF7- and IRF9-dependent type I IFN amplification pathway. Finally, we considered various modes of inheritance at these 13 loci. We found an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001, at the 13 candidate loci in the 659 patients with life-threatening COVID-19 pneumonia relative to the 534 subjects with asymptomatic or benign infection (P = 0.01). Experimental tests for all 118 rare nonsynonymous variants (including both pLOF and other variants) of these 13 genes found in patients with critical disease identified 23 patients (3.5%), aged 17 to 77 years, carrying 24 deleterious variants of eight genes. These variants underlie autosomal-recessive (AR) deficiencies (IRF7 and IFNAR1) and autosomal-dominant (AD) deficiencies (TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2) in four and 19 patients, respectively. These patients had never been hospitalized for other life-threatening viral illness. Plasmacytoid dendritic cells from IRF7-deficient patients produced no type I IFN on infection with SARS-CoV-2, and TLR3−/−, TLR3+/−, IRF7−/−, and IFNAR1−/− fibroblasts were susceptible to SARS-CoV-2 infection in vitro. At least 3.5% of patients with life-threatening COVID-19 pneumonia had known (AR IRF7 and IFNAR1 deficiencies or AD TLR3, TICAM1, TBK1, and IRF3 deficiencies) or new (AD UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiencies) genetic defects at eight of the 13 candidate loci involved in the TLR3- and IRF7-dependent induction and amplification of type I IFNs. This discovery reveals essential roles for both the double-stranded RNA sensor TLR3 and type I IFN cell-intrinsic immunity in the control of SARS-CoV-2 infection. Type I IFN administration may be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection. Molecules in red are encoded by core genes, deleterious variants of which underlie critical influenza pneumonia with incomplete penetrance, and deleterious variants of genes encoding biochemically related molecules in blue underlie other viral illnesses. Molecules represented in bold are encoded by genes with variants that also underlie critical COVID-19 pneumonia. Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
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影响因子：
30.8
作者：
Dupuis, S;Jouanguy, E;Casanova, JL
通讯作者：
Casanova, JL
危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
通讯作者：
Casanova JL
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1126/science.aaa1578
发表时间：
2015-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ciancanelli MJ;Huang SX;Luthra P;Garner H;Itan Y;Volpi S;Lafaille FG;Trouillet C;Schmolke M;Albrecht RA;Israelsson E;Lim HK;Casadio M;Hermesh T;Lorenzo L;Leung LW;Pedergnana V;Boisson B;Okada S;Picard C;Ringuier B;Troussier F;Chaussabel D;Abel L;Pellier I;Notarangelo LD;García-Sastre A;Basler CF;Geissmann F;Zhang SY;Snoeck HW;Casanova JL
通讯作者：
Casanova JL
影响因子：
32.4
作者：
Pérez de Diego R;Sancho-Shimizu V;Lorenzo L;Puel A;Plancoulaine S;Picard C;Herman M;Cardon A;Durandy A;Bustamante J;Vallabhapurapu S;Bravo J;Warnatz K;Chaix Y;Cascarrigny F;Lebon P;Rozenberg F;Karin M;Tardieu M;Al-Muhsen S;Jouanguy E;Zhang SY;Abel L;Casanova JL
通讯作者：
Casanova JL