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. 2020 Oct 23;370(6515):eabd4570.
doi: 10.1126/science.abd4570. Epub 2020 Sep 24.

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Qian Zhang  1 , Paul Bastard #  2   3 , Zhiyong Liu #  1 , Jérémie Le Pen #  4 , Marcela Moncada-Velez #  1 , Jie Chen #  1 , Masato Ogishi #  1 , Ira K D Sabli #  5 , Stephanie Hodeib #  5 , Cecilia Korol #  2 , Jérémie Rosain #  2   3 , Kaya Bilguvar #  6 , Junqiang Ye #  7 , Alexandre Bolze #  8 , Benedetta Bigio #  1 , Rui Yang #  1 , Andrés Augusto Arias #  1   9   10 , Qinhua Zhou #  1 , Yu Zhang #  11   12 , Fanny Onodi  13 , Sarantis Korniotis  13 , Léa Karpf  13 , Quentin Philippot  2   3 , Marwa Chbihi  2   3 , Lucie Bonnet-Madin  14 , Karim Dorgham  15 , Nikaïa Smith  16 , William M Schneider  4 , Brandon S Razooky  4 , Hans-Heinrich Hoffmann  4 , Eleftherios Michailidis  4 , Leen Moens  17 , Ji Eun Han  1 , Lazaro Lorenzo  2   3 , Lucy Bizien  2   3 , Philip Meade  18 , Anna-Lena Neehus  2   3 , Aileen Camille Ugurbil  1 , Aurélien Corneau  19 , Gaspard Kerner  2   3 , Peng Zhang  1 , Franck Rapaport  1 , Yoann Seeleuthner  2   3 , Jeremy Manry  2   3 , Cecile Masson  20 , Yohann Schmitt  20 , Agatha Schlüter  21 , Tom Le Voyer  2   3 , Taushif Khan  22 , Juan Li  1 , Jacques Fellay  23   24   25 , Lucie Roussel  26 , Mohammad Shahrooei  27   28 , Mohammed F Alosaimi  29 , Davood Mansouri  30   31   32 , Haya Al-Saud  33 , Fahd Al-Mulla  34 , Feras Almourfi  33 , Saleh Zaid Al-Muhsen  35 , Fahad Alsohime  29 , Saeed Al Turki  36   37 , Rana Hasanato  29 , Diederik van de Beek  38 , Andrea Biondi  39 , Laura Rachele Bettini  39 , Mariella D'Angio'  39 , Paolo Bonfanti  40 , Luisa Imberti  41 , Alessandra Sottini  41 , Simone Paghera  41 , Eugenia Quiros-Roldan  42 , Camillo Rossi  43 , Andrew J Oler  44 , Miranda F Tompkins  45 , Camille Alba  45 , Isabelle Vandernoot  46 , Jean-Christophe Goffard  47 , Guillaume Smits  46 , Isabelle Migeotte  48 , Filomeen Haerynck  49 , Pere Soler-Palacin  50 , Andrea Martin-Nalda  50 , Roger Colobran  51 , Pierre-Emmanuel Morange  52 , Sevgi Keles  53 , Fatma Çölkesen  54 , Tayfun Ozcelik  55 , Kadriye Kart Yasar  56 , Sevtap Senoglu  56 , Şemsi Nur Karabela  56 , Carlos Rodríguez-Gallego  57   58 , Giuseppe Novelli  59 , Sami Hraiech  60 , Yacine Tandjaoui-Lambiotte  61   62 , Xavier Duval  63   64 , Cédric Laouénan  63   64   65 ; 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; Andrew L Snow  66 , Clifton L Dalgard  45   67 , Joshua D Milner  68 , Donald C Vinh  26 , Trine H Mogensen  69   70 , Nico Marr  22   71 , András N Spaan  1   72 , Bertrand Boisson  1   2   3 , Stéphanie Boisson-Dupuis  1   2   3 , Jacinta Bustamante  1   2   3   73 , Anne Puel  1   2   3 , Michael J Ciancanelli  1   74 , Isabelle Meyts  17   75 , Tom Maniatis  7   76 , Vassili Soumelis  13   77 , Ali Amara  14 , Michel Nussenzweig  78   79 , Adolfo García-Sastre  18   80   81   82 , Florian Krammer  18 , Aurora Pujol  21 , Darragh Duffy  16 , Richard P Lifton #  83   84   85 , Shen-Ying Zhang #  1   2   3 , Guy Gorochov #  15 , Vivien Béziat #  1   2   3 , Emmanuelle Jouanguy #  1   2   3 , Vanessa Sancho-Shimizu #  5 , Charles M Rice #  4 , Laurent Abel #  1   2   3 , Luigi D Notarangelo #  11   12 , Aurélie Cobat #  1   2   3 , Helen C Su #  11   12 , Jean-Laurent Casanova #  86   2   3   79   87
Collaborators, Affiliations

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Qian Zhang et al. Science. .

Abstract

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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Figures

None
Inborn errors of TLR3- and IRF7-dependent type I IFN production and amplification underlie life-threatening COVID-19 pneumonia.
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.
Fig. 1
Fig. 1. Demographic and genetic data for the COVID-19 cohort.
(A) Age and sex distribution of patients with life-threatening COVID-19. (B) PCA of patient (with or without LOF variants in the 13 candidate genes) and control cohorts (patients with mild or asymptomatic disease and individuals from the 1000 Genomes Project).
Fig. 2
Fig. 2. Illustration of TLR3- and IRF7-dependent type I IFN production and amplification circuit.
Molecules in red are encoded by core genes, deleterious variants of which underlie critical influenza pneumonia with incomplete penetrance; deleterious variants of genes encoding biochemically related molecules in blue underlie other viral illnesses. Type I IFNs also induce themselves. ISGs, interferon-stimulated genes.
Fig. 3
Fig. 3. Impact of TLR3, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2 variants on type I IFN signaling.
(A) TLR3-deficient P2.1 fibrosarcoma cells were stably transfected with plasmids expressing WT or mutant forms of TLR3, and IFNL1 mRNA levels were determined by reverse transcription quantitative PCR. IFNL1 mRNA levels were expressed relative to the housekeeping gene GUS and then normalized. IFNL1 was undetectable in unstimulated cells. The differences between variants and WT were tested using one-way ANOVA (*P < 0.05). (B) TICAM1-deficient SV40-Fib cells were transiently transfected with WT or mutant forms of TICAM1, together with an IFN-β luciferase reporter and a constitutively expressed reporter. Normalized luciferase induction was measured 24 hours after transfection. The differences between variants and WT were tested using one-way ANOVA (*P < 0.05). (C) HEK293T cells were transiently transfected with WT and mutant forms of TBK1, together with an IFN-β luciferase reporter and a constitutively expressed reporter. Normalized luciferase activity was measured 24 hours after transfection. The differences between variants and WT were tested using one-way ANOVA (*P < 0.05). (D) IRF3-deficient HEK293T cells were transiently transfected with WT and mutant forms of IRF3, together with an IFN-β luciferase reporter and a constitutively expressed reporter. Cells were either left untreated or infected with Sendai virus for 24 hours before the normalized measurement of luciferase activity. The differences between variants and WT were evaluated using two-way ANOVA (*P < 0.05). (E) HEK293T cells were transiently transfected with WT and mutant forms of IRF7, together with an IFN-β luciferase reporter and a constitutively expressed reporter. Cells were either left untreated or infected with Sendai virus for 24 hours before the normalized measurement of luciferase activity. The differences between variants and WT were tested using two-way ANOVA (*P < 0.05). (F and G) IFNAR1- or IFNAR2-deficient SV40-Fib cells were transiently transfected with WT or mutant forms of IFNAR1 for 36 hours, and either left untreated or stimulated with IFN-α2 or IFN-γ. Fluorescence-activated cell sorting (FACS) staining with anti-p-STAT1 antibody and the z-score of the MFI were assessed. Asterisks indicate variants with MFI <50% of WT. Variants in red were identified in COVID-19 patients. Variants in blue are known deleterious variants and served as negative controls. EV, empty vector; LT, lipofectamine. Three technical repeats were performed for (A) to (E). Means and SD are shown in the columns and horizontal bars when appropriate.
Fig. 4
Fig. 4. Type I IFN responses in patient cells defective for IRF7.
(A) Levels of the IRF7 protein in PHA-T cells from two patients with AR IRF7 deficiency (P1 and P3), one patient with AD IRF7 deficiency (P2), and four healthy donors (C1 to C4). Cells were either left untreated or stimulated with IFN-α2 for 24 hours, and protein levels were measured by Western blotting. MX1 was used as a positive control for IFN-α2 treatment. (B) pDCs isolated from an AR IRF7-deficient patient (P1) and a healthy donor (C1) were either left untreated or infected with influenza A virus (IAV) or SARS-CoV-2, and RNA-seq was performed. Genes with expression >2.5-fold higher or lower in C1 after infection are plotted as the fold change in expression. Red dots are type I IFN genes; blue dots are type III IFN genes. (C) pDCs isolated from healthy donor C and IRF7-deficient patient (P1) were either left untreated (Medium) or infected with IAV or SARS-CoV-2, and the production of IFN-α2 and IFN-λ1 was measured by CBA and ELISA, respectively, on the supernatant. ND, not detected.
Fig. 5
Fig. 5. Type I IFN responses in patient cells defective for IFNAR1.
(A) FACS staining of IFNAR1 on the surface of PHA-T cells from a patient with AR IFNAR1 deficiency (P5) and healthy donors (C1 and C2). (B) PHA-T cells and SV40-Fib from a patient with AR IFNAR1 deficiency (P5) and a healthy donor (C3) were stimulated with IFN-α2 or IFN-β, and p-STAT1 levels were determined by FACS. Interleukin-27 stimulation served as a positive control on PHA-T cells, whereas IFN-γ stimulation served as a positive control on SV40-Fib cells.
Fig. 6
Fig. 6. Cell-intrinsic type I IFN response to SARS-CoV-2.
SV40-Fib cells of TLR3−/−, TLR3+/−, IRF7−/−, and IRF7−/− SV40-Fib cells rescued with WT IRF7; IFNAR1−/− SV40-Fib cells, and IFNAR1−/− SV40-Fib cells rescued with WT IFNAR1 were transduced with ACE2 and TMPRSS2 and then either left untreated or treated with IFN-β for 4 hours. Cells were then infected with SARS-CoV-2 (MOI = 0.5). After staining, ACE2 and viral S-protein levels were measured by high-content microscopy with gating on ACE2+ cells. IRF7-deficient SV40-Fib cells were previously transduced with either WT IRF7 or negative control (Luc). IFNAR1-deficient cells were previously transduced with either WT IFNAR1 or empty vector (EV).
Fig. 7
Fig. 7. In vivo type I IFN responses to SARS-CoV-2 infections.
Plasma levels of 13 IFN-α were measured by Simoa. Auto-Ab(+) without LOF variants indicates COVID-19 patients with neutralizing anti-IFN-α auto-Abs in our accompanying report (29). P values indicated were evaluated using one-way ANOVA.
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