The genetics underlying extreme COVID-19

The immune system is advanced and entails many genes, together with people who encode cytokines referred to as interferons (IFNs). People that lack particular IFNs might be extra prone to infectious ailments. Moreover, the autoantibody system dampens IFN response to forestall harm from pathogen-induced irritation. Two research now study the probability that genetics impacts the danger of extreme coronavirus illness 2019 (COVID-19) by parts of this technique (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene strategy and recognized sufferers with extreme COVID-19 who’ve mutations in genes concerned within the regulation of kind I and III IFN immunity. They discovered enrichment of those genes in sufferers and conclude that genetics could decide the scientific course of the an infection. Bastard et al. recognized people with excessive titers of neutralizing autoantibodies in opposition to kind I IFN-α2 and IFN-ω in about 10% of sufferers with extreme COVID-19 pneumonia. These autoantibodies weren’t discovered both in contaminated individuals who had been asymptomatic or had milder phenotype or in wholesome people. Collectively, these research establish a method by which people at highest threat of life-threatening COVID-19 might be recognized.

Science, this situation p. eabd4570, p. eabd4585; see additionally p. 404

Structured Summary

INTRODUCTION

Scientific outcomes of human extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2) an infection vary from silent an infection to deadly coronavirus illness 2019 (COVID-19). Epidemiological research have recognized three threat elements for extreme illness: being male, being aged, and having different medical situations. Nonetheless, interindividual scientific variability stays large in every demographic class. Discovering the basis trigger and detailed molecular, mobile, and tissue- and body-level mechanisms underlying life-threatening COVID-19 is of the utmost organic and medical significance.

RATIONALE

We established the COVID Human Genetic Effort (www.covidhge.com) to check the overall speculation that life-threatening COVID-19 in some or most sufferers could also be brought on by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or full penetrance. We sequenced the exome or genome of 659 sufferers of assorted ancestries with life-threatening COVID-19 pneumonia and 534 topics with asymptomatic or benign an infection. We examined the precise speculation that inborn errors of Toll-like receptor 3 (TLR3)– and interferon regulatory issue 7 (IRF7)–dependent kind I interferon (IFN) immunity that underlie life-threatening influenza pneumonia additionally underlie life-threatening COVID-19 pneumonia. We thought of three loci recognized as mutated in sufferers with life-threatening influenza: TLR3, IRF7, and IRF9. We additionally thought of 10 loci mutated in sufferers with different viral sicknesses however straight linked to the three core genes conferring influenza susceptibility: TICAM1/TRIF, UNC93B1, TRAF3, TBK1, IRF3, and NEMO/IKBKG from the TLR3-dependent kind I IFN induction pathway, and IFNAR1, IFNAR2, STAT1, and STAT2 from the IRF7- and IRF9-dependent kind I IFN amplification pathway. Lastly, we thought of numerous modes of inheritance at these 13 loci.

RESULTS

We discovered an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001, on the 13 candidate loci within the 659 sufferers with life-threatening COVID-19 pneumonia relative to the 534 topics with asymptomatic or benign an infection (P = 0.01). Experimental assessments for all 118 uncommon nonsynonymous variants (together with each pLOF and different variants) of those 13 genes present in sufferers with vital illness recognized 23 sufferers (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 4 and 19 sufferers, respectively. These sufferers had by no means been hospitalized for different life-threatening viral sickness. Plasmacytoid dendritic cells from IRF7-deficient sufferers produced no kind I IFN on an infection with SARS-CoV-2, and TLR3−/−, TLR3+/−, IRF7−/−, and IFNAR1−/− fibroblasts had been prone to SARS-CoV-2 an infection in vitro.

CONCLUSION

At the least 3.5% of sufferers with life-threatening COVID-19 pneumonia had identified (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 concerned within the TLR3- and IRF7-dependent induction and amplification of kind I IFNs. This discovery reveals important roles for each the double-stranded RNA sensor TLR3 and sort I IFN cell-intrinsic immunity within the management of SARS-CoV-2 an infection. Sort I IFN administration could also be of therapeutic profit in chosen sufferers, not less than early in the midst of SARS-CoV-2 an infection.

Inborn errors of TLR3- and IRF7-dependent kind I IFN manufacturing and amplification underlie life-threatening COVID-19 pneumonia.

Molecules in pink are encoded by core genes, deleterious variants of which underlie vital influenza pneumonia with incomplete penetrance, and deleterious variants of genes encoding biochemically associated molecules in blue underlie different viral sicknesses. Molecules represented in daring are encoded by genes with variants that additionally underlie vital COVID-19 pneumonia.

Summary

Scientific end result upon an infection with extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent an infection to deadly coronavirus illness 2019 (COVID-19). We’ve got discovered an enrichment in uncommon variants predicted to be loss-of-function (LOF) on the 13 human loci identified to manipulate Toll-like receptor 3 (TLR3)– and interferon regulatory issue 7 (IRF7)–dependent kind I interferon (IFN) immunity to influenza virus in 659 sufferers with life-threatening COVID-19 pneumonia relative to 534 topics with asymptomatic or benign an infection. By testing these and different uncommon variants at these 13 loci, we experimentally outlined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 sufferers (3.5%) 17 to 77 years of age. We present that human fibroblasts with mutations affecting this circuit are susceptible to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent kind I IFN immunity can underlie life-threatening COVID-19 pneumonia in sufferers with no prior extreme an infection.

Extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already claimed not less than 1 million lives, has been detected in not less than 20 million folks, and has in all probability contaminated not less than one other 200 million. The scientific manifestations vary from silent an infection to deadly illness, with an an infection fatality price of 0.1 to 0.9%. Three epidemiological elements enhance the danger of severity: (i) rising age, decade by decade, after the age of fifty, (ii) being male, and (iii) having numerous underlying medical situations (1). Nonetheless, even taking these elements into consideration, there may be immense interindividual scientific variability in every demographic class thought of. Following on from our human genetic research of different extreme infectious ailments (2, 3), we established the COVID Human Genetic Effort (https://www.covidhge.com) to check the overall speculation that in some sufferers, life-threatening coronavirus illness 2019 (COVID-19) could also be brought on by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or full penetrance (4). We enrolled 659 sufferers (74.5% males and 25.5% girls, 13.9% of whom died) of assorted ancestries between 1 month and 99 years of age (Fig. 1A). These sufferers had been hospitalized for life-threatening pneumonia brought on by SARS-CoV-2 (vital COVID-19). We sequenced their complete genome (N = 364) or exome (N = 295), and principal element evaluation (PCA) on these information confirmed their ancestries (Fig. 1B).

Fig. 1 Demographic and genetic information for the COVID-19 cohort.

(A) Age and intercourse distribution of sufferers with life-threatening COVID-19. (B) PCA of affected person (with or with out LOF variants within the 13 candidate genes) and management cohorts (sufferers with delicate or asymptomatic illness and people from the 1000 Genomes Mission).

Candidate variants at 13 human loci that govern immunity to influenza virus

We first examined the precise speculation that inborn errors of Toll-like receptor 3 (TLR3)– and interferon regulatory issue 7 (IRF7)–dependent kind I interferon (IFN) immunity, which underlie life-threatening influenza pneumonia, may additionally underlie life-threatening COVID-19 pneumonia (5) (Fig. 2). We thought of three loci beforehand proven to be mutated in sufferers with vital influenza pneumonia: TLR3 (6), IRF7 (7), and IRF9 (8). We additionally thought of 10 loci mutated in sufferers with different viral sicknesses however straight linked to the three core genes conferring influenza susceptibility: TICAM1/TRIF (9), UNC93B1 (10), TRAF3 (11), TBK1 (12), IRF3 (13), and NEMO/IKBKG (14) within the TLR3-dependent kind I IFN induction pathway, and IFNAR1 (15), IFNAR2 (16), STAT1 (17), and STAT2 (18) within the IRF7- and IRF9-dependent kind I IFN amplification pathway. We collected each monoallelic and biallelic nonsynonymous variants with a minor allele frequency (MAF) <0.001 in any respect 13 loci. Twelve of the 13 candidate loci are autosomal, whereas NEMO is X-linked. For the latter gene, we thought of solely a recessive mannequin (19). Autosomal-dominant (AD) inheritance has not been confirmed for six of the 12 autosomal loci (UNC93B1, IRF7, IFNAR1, IFNAR2, STAT2, and IRF9). However, we thought of heterozygous variants as a result of not one of the sufferers enrolled had been hospitalized for vital viral infections earlier than COVID-19, elevating the likelihood that any underlying genetic defects that they could have show a decrease penetrance for influenza and different viral sicknesses than for COVID-19, which is triggered by a extra virulent virus.

Fig. 2 Illustration of TLR3- and IRF7-dependent kind I IFN manufacturing and amplification circuit.

Molecules in pink are encoded by core genes, deleterious variants of which underlie vital influenza pneumonia with incomplete penetrance; deleterious variants of genes encoding biochemically associated molecules in blue underlie different viral sicknesses. Sort I IFNs additionally induce themselves. ISGs, interferon-stimulated genes.

Enrichment of variants predicted to be LOF on the influenza susceptibility loci

We discovered 4 unrelated sufferers with biallelic variants of IRF7 or IFNAR1 (Table 1 and desk S1). We additionally discovered 113 sufferers carrying 113 monoallelic variants at 12 loci: TLR3 (N = 7 sufferers/7 variants), UNC93B1 (N = 10/9), TICAM1 (N = 17/15), TRAF3 (N = 6/6), TBK1 (N = 12/11), IRF3 (N = 5/5), IRF7 (N = 20/13), IFNAR1 (N = 14/13), IFNAR2 (N = 17/15), STAT1 (N = 4/4), STAT2 (N = 11/11), and IRF9 (N = 4/4). We detected no copy quantity variation for these 13 genes. Unexpectedly, considered one of these variants has been reported in sufferers with life-threatening influenza pneumonia (TLR3 p.Pro554Ser) (6, 20) and one other was proven to be each deleterious and dominant-negative (IFNAR1 p.Pro335del) (21). 9 of the 118 biallelic or monoallelic variants had been predicted to be LOF (pLOF), whereas the remaining 109 had been missense or in-frame indels (desk S1). In a pattern of 534 controls with asymptomatic or delicate SARS-CoV-2 an infection, we discovered just one heterozygous pLOF variation with a MAF <0.001 on the 13 loci (IRF7 p.Leu99fs). A PCA-adjusted burden check on the 12 autosomal loci revealed vital enrichment in pLOF variants in sufferers relative to controls [P = 0.01; odds ratio (OR) = 8.28; 95% confidence interval (CI) = 1.04 to 65.64] beneath an AD mode of inheritance. The identical evaluation carried out on synonymous variants with a MAF <0.001 was not vital (P = 0.19), indicating that our ethnicity-adjusted burden check was properly calibrated.

Desk 1 Illness-causing variants recognized in sufferers with life-threatening COVID-19.

Experimentally deleterious alleles on the influenza susceptibility loci in 3.5% of sufferers

We examined these 118 variants experimentally in advert hoc overexpression techniques. We discovered that 24 variants of eight genes had been deleterious (together with all of the pLOF variants) as a result of they had been loss-of-expression, LOF, or severely hypomorphic: TLR3 (N = 4 variants), UNC93B1 (N = 1), TICAM1 (N = 3), TBK1 (N = 2), IRF3 (N = 2), IRF7 (N = 8), IFNAR1 (N = 3), and IFNAR2 (N = 1) (desk S1, Fig. 3, and figs. S1 to S8). Constantly, heterozygous LOF variants of IRF3 and IRF7 had been reported in single sufferers with life-threatening influenza pneumonia (22, 23). The remaining 94 variants had been biochemically impartial. Twenty-three sufferers carried these 24 deleterious variants, leading to 4 autosomal-recessive (AR) deficiencies (homozygosity or compound heterozygosity for IRF7; homozygosity for IFNAR1) and 19 AD deficiencies. These 23 sufferers didn’t carry candidate variants on the different 417 loci identified to underlie inborn errors of immunity (desk S2) (2426). These findings counsel that not less than 23 (3.5%) unrelated sufferers of the 659 sufferers examined suffered from a deficiency at considered one of eight loci among the many 13 examined: 4 sufferers with a identified AR dysfunction (IRF7 or IFNAR1) (7, 15), 11 with a identified AD dysfunction (TLR3, TICAM1, TBK1, or IRF3) (6, 9, 12, 13, 20), and eight with a beforehand unknown AD genetic dysfunction (UNC93B1, IRF7, IFNAR1, or IFNAR2).

Fig. 3 Impression of TLR3, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2 variants on kind I IFN signaling.

(A) TLR3-deficient P2.1 fibrosarcoma cells had been stably transfected with plasmids expressing WT or mutant types of TLR3, and IFNL1 mRNA ranges had been decided by reverse transcription quantitative PCR. IFNL1 mRNA ranges had been expressed relative to the housekeeping gene GUS after which normalized. IFNL1 was undetectable in unstimulated cells. The variations between variants and WT had been examined utilizing one-way ANOVA (*P < 0.05). (B) TICAM1-deficient SV40-Fib cells had been transiently transfected with WT or mutant types of TICAM1, along with an IFN-β luciferase reporter and a constitutively expressed reporter. Normalized luciferase induction was measured 24 hours after transfection. The variations between variants and WT had been examined utilizing one-way ANOVA (*P < 0.05). (C) HEK293T cells had been transiently transfected with WT and mutant types of TBK1, along with an IFN-β luciferase reporter and a constitutively expressed reporter. Normalized luciferase exercise was measured 24 hours after transfection. The variations between variants and WT had been examined utilizing one-way ANOVA (*P < 0.05). (D) IRF3-deficient HEK293T cells had been transiently transfected with WT and mutant types of IRF3, along with an IFN-β luciferase reporter and a constitutively expressed reporter. Cells had been both left untreated or contaminated with Sendai virus for twenty-four hours earlier than the normalized measurement of luciferase exercise. The variations between variants and WT had been evaluated utilizing two-way ANOVA (*P < 0.05). (E) HEK293T cells had been transiently transfected with WT and mutant types of IRF7, along with an IFN-β luciferase reporter and a constitutively expressed reporter. Cells had been both left untreated or contaminated with Sendai virus for twenty-four hours earlier than the normalized measurement of luciferase exercise. The variations between variants and WT had been examined utilizing two-way ANOVA (*P < 0.05). (F and G) IFNAR1- or IFNAR2-deficient SV40-Fib cells had been transiently transfected with WT or mutant types of IFNAR1 for 36 hours, and both 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 had been assessed. Asterisks point out variants with MFI <50% of WT. Variants in pink had been recognized in COVID-19 sufferers. Variants in blue are identified deleterious variants and served as damaging controls. EV, empty vector; LT, lipofectamine. Three technical repeats had been carried out for (A) to (E). Means and SD are proven within the columns and horizontal bars when applicable.

Impaired TLR3- and IRF7-dependent kind I immunity in affected person cells in vitro

We examined cells from sufferers with chosen genotypes and confirmed that PHA-driven T cell blasts (PHA-T cells) from sufferers with AR or AD IRF7 deficiency had low ranges of IRF7 expression (Fig. 4A). We then remoted circulating plasmacytoid dendritic cells (pDCs) from a affected person with AR IRF7 deficiency (fig. S9A) (7). These cells had been current in regular proportions (fig. S9B), however they didn’t produce any detectable kind I or III IFNs in response to SARS-CoV-2, as analyzed by cytometric bead array (CBA), enzyme-linked immunosorbent assay (ELISA), and RNA sequencing (RNA-seq) (Fig. 4, B and C). We additionally confirmed that PHA-T cells from a affected person with AR IFN-α/β receptor 1 (IFNAR1) deficiency had impaired IFNAR1 expression and responses to IFN-α2 or IFN-β, and that the affected person’s SV40-transformed fibroblast (SV40-Fib) cells didn’t reply to IFN-α2 or IFN-β (Fig. 5). We then contaminated TLR3−/−, TLR3+/−, IRF7−/− SV40-Fib cells, and IRF7−/− SV40-Fib cells rescued with wild-type (WT) IRF7; IFNAR1−/− SV40-Fib cells, and IFNAR1−/− SV40-Fib cells rescued with WT IFNAR1, all of which had been beforehand transduced with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2). SARS-CoV-2 an infection ranges had been increased in mutant cells than in cells from wholesome donors, and transduction of WT IRF7 or IFNAR1 rescued their defects (Fig. 6). Collectively, these findings confirmed that AR IRF7 deficiency impaired the manufacturing of kind I IFN by pDCs stimulated with SARS-CoV-2, whereas AR and AD deficiencies of TLR3 or AR deficiency of IFNAR1 impaired fibroblast-intrinsic kind I IFN immunity to SARS-CoV2. Additionally they counsel that heterozygosity for LOF variations on the different 5 mutated loci additionally underlie life-threatening COVID-19.

Fig. 4 Sort I IFN responses in affected person cells faulty for IRF7.

(A) Ranges of the IRF7 protein in PHA-T cells from two sufferers with AR IRF7 deficiency (P1 and P3), one affected person with AD IRF7 deficiency (P2), and 4 wholesome donors (C1 to C4). Cells had been both left untreated or stimulated with IFN-α2 for twenty-four hours, and protein ranges had been measured by Western blotting. MX1 was used as a constructive management for IFN-α2 remedy. (B) pDCs remoted from an AR IRF7-deficient affected person (P1) and a wholesome donor (C1) had been both left untreated or contaminated with influenza A virus (IAV) or SARS-CoV-2, and RNA-seq was carried out. Genes with expression >2.5-fold increased or decrease in C1 after an infection are plotted because the fold change in expression. Pink dots are kind I IFN genes; blue dots are kind III IFN genes. (C) pDCs remoted from wholesome donor C and IRF7-deficient affected person (P1) had been both left untreated (Medium) or contaminated with IAV or SARS-CoV-2, and the manufacturing of IFN-α2 and IFN-λ1 was measured by CBA and ELISA, respectively, on the supernatant. ND, not detected.

Fig. 5 Sort I IFN responses in affected person cells faulty for IFNAR1.

(A) FACS staining of IFNAR1 on the floor of PHA-T cells from a affected person with AR IFNAR1 deficiency (P5) and wholesome donors (C1 and C2). (B) PHA-T cells and SV40-Fib from a affected person with AR IFNAR1 deficiency (P5) and a wholesome donor (C3) had been stimulated with IFN-α2 or IFN-β, and p-STAT1 ranges had been decided by FACS. Interleukin-27 stimulation served as a constructive management on PHA-T cells, whereas IFN-γ stimulation served as a constructive management on SV40-Fib cells.

Fig. 6 Cell-intrinsic kind 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 had been transduced with ACE2 and TMPRSS2 after which both left untreated or handled with IFN-β for 4 hours. Cells had been then contaminated with SARS-CoV-2 (MOI = 0.5). After staining, ACE2 and viral S-protein ranges had been measured by high-content microscopy with gating on ACE2+ cells. IRF7-deficient SV40-Fib cells had been beforehand transduced with both WT IRF7 or damaging management (Luc). IFNAR1-deficient cells had been beforehand transduced with both WT IFNAR1 or empty vector (EV).

Impaired manufacturing of kind I IFNs in sufferers in vivo

We examined whether or not these genotypes impaired the manufacturing of kind I IFN in vivo through the course of SARS-CoV-2 an infection. We measured the degrees of the 13 varieties of IFN-α within the blood of sufferers through the acute part of COVID-19. We discovered that 10 of the 23 sufferers with mutations for whom samples had been obtainable (one with AR IRF7 deficiency, 4 with AD IRF7 deficiency, one with AD TLR3 deficiency, two with AD TBK1 deficiency, one with AR IFNAR1 deficiency, and one with AD TICAM1 deficiency) had serum IFN-α ranges <1 pg/ml (Fig. 7). In contrast, beforehand revealed cohorts of sufferers hospitalized with unexplained, extreme COVID-19 had numerous serum IFN-α ranges, considerably increased than our 10 sufferers [one-way analysis of variance (ANOVA), P = 1.4 × 10−7; Fig. 7] (27, 28). One other 29 sufferers from our cohort displaying auto-antibodies (auto-Abs) in opposition to kind I IFNs, reported in an accompanying paper, had undetectable ranges of serum IFN-α (29). Furthermore, not one of the 23 sufferers with LOF mutations of the eight genes had detectable auto-Abs in opposition to kind I IFNs (29), strongly suggesting that the 2 mechanisms of illness are related however impartial. Excluding sufferers with auto-Abs in opposition to kind I IFN from the burden check of pLOF variants on the 12 autosomal loci strengthened the affiliation sign (P = 0.007; OR = 8.97; 95% CI = 1.13 to 71.09).

Fig. 7 In vivo kind I IFN responses to SARS-CoV-2 infections.

Plasma ranges of 13 IFN-α had been measured by Simoa. Auto-Ab(+) with out LOF variants signifies COVID-19 sufferers with neutralizing anti-IFN-α auto-Abs in our accompanying report (29). P values indicated had been evaluated utilizing one-way ANOVA.

Inborn errors of TLR3- and IRF7-dependent kind I immunity underlie vital COVID-19

Collectively, our information counsel that not less than 23 of the 659 sufferers with life-threatening COVID-19 pneumonia studied had identified (six issues) or new (4 issues) genetic defects at eight loci concerned within the TLR3- and IRF7-dependent induction and amplification of kind I IFNs. This discovery reveals the important position of each the double-stranded RNA sensor TLR3 and sort I IFN cell-intrinsic immunity within the management of SARS-CoV-2 an infection within the lungs, in line with their beforehand documented roles in pulmonary immunity to influenza virus (58). These genotypes had been silent till an infection with SARS-CoV-2. Essentially the most thought-provoking examples are the AR deficiencies of IRF7 and IFNAR1. AR IRF7 deficiency was recognized in two people aged 49 and 50 years, and AR IFNAR1 deficiency was recognized in two people aged 26 and 38 years, and not one of the 4 sufferers had a previous historical past of life-threatening infections (Table 1). One affected person with IRF7 deficiency was examined and was seropositive for a number of frequent viruses, together with numerous influenza A and B viruses (figs. S10 and S11). These genetic defects due to this fact show incomplete penetrance for influenza respiratory misery and solely manifested clinically upon an infection with the extra virulent SARS-CoV-2.

Conclusion

The AR type of IFNAR1 deficiency highlights the significance of kind I IFN manufacturing relative to kind III IFN manufacturing, which can also be impaired by defects of TLR3, IRF7, and IRF9 (5). This conclusion can also be supported by our accompanying report of neutralizing auto-Abs in opposition to kind I IFNs, however not kind III IFNs, in different sufferers with life-threatening COVID-19 pneumonia (29). Inborn errors of TLR3- and IRF7-dependent kind I IFN immunity at eight loci had been present in as many as 23 sufferers (3.5%) of assorted ages (17 to 77 years) and ancestries (numerous nationalities from Asia, Europe, Latin America, and the Center East) and in sufferers of each sexes (Table 1). Our findings counsel that there could also be mutations in different kind I IFN–associated genes in different sufferers with life-threatening COVID-19 pneumonia. Additionally they counsel that the administration of kind I IFN could also be of therapeutic profit in chosen sufferers, not less than early in the midst of SARS-CoV-2 an infection.

Strategies

Sufferers

We included on this research 659 sufferers with life-threatening COVID-19 pneumonia, outlined as sufferers with pneumonia who developed vital illness, whether or not pulmonary with mechanical air flow (CPAP, BIPAP, intubation, hi-flow oxygen), septic shock, or with every other organ harm requiring admission to the intensive care unit. Sufferers who developed Kawasaki-like syndrome had been excluded. The age of the sufferers ranged from 0.1 to 99 years, with a imply age of 51.8 years (SD 15.9 years), and 25.5% of the sufferers had been feminine. As controls, we enrolled 534 people contaminated with SARS-CoV-2 primarily based on a constructive polymerase chain response (PCR) and/or serological check and/or the presence of typical signs reminiscent of anosmia or ageusia after publicity to a confirmed COVID-19 case, who remained asymptomatic or developed delicate, self-healing, ambulatory illness.

Subsequent-generation sequencing

Genomic DNA was extracted from complete blood. For the 1193 sufferers and controls included, the entire exome (N = 687) or complete genome (N = 506) was sequenced. We used the Genome Evaluation Software program Package (GATK) (model 3.4-46 or 4) best-practice pipeline to investigate our whole-exome–sequencing information (30). We aligned the reads obtained with the human reference genome (hg19) utilizing the utmost actual matches algorithm in Burrows–Wheeler Aligner software program (31). PCR duplicates had been eliminated with Picard instruments (http://broadinstitute.github.io/picard/). The GATK base high quality rating recalibrator was utilized to right sequencing artifacts.

The entire variants had been manually curated utilizing Integrative Genomics Viewer (IGV) and confirmed to have an effect on the primary useful protein isoform by checking the protein sequence earlier than inclusion in additional analyzes. The primary useful protein isoforms had been TLR3 (NM_003265), UNC93B1 (NM_030930.4), TICAM1 (NM_182919), TRAF3 (NM_145725.2), TBK1 (NM_013254.4), IRF3 (NM_001571), IRF7 (NM_001572.5), IFNAR1 (NM_000629.3), IFNAR2 (NM_001289125.3), STAT1 (NM_007315.4), STAT2 (NM_005419.4), and IRF9 (NM_006084.5). The evaluation of IKBKG was custom-made to unmask the duplicated area in IKBKG utilizing a selected pipeline beforehand described (32). We searched the next-generation–sequencing information for deletions within the 13 genes of curiosity utilizing each the HMZDelFinder (33) and CANOES (34) algorithms.

Statistical evaluation

We carried out an enrichment evaluation on our cohort of 659 sufferers with life-threatening COVID-19 pneumonia and 534 SARS-CoV2–contaminated controls, specializing in 12 autosomal IFN-related genes. We thought of variants that had been pLOF with a MAF <0.001 (gnomAD model 2.1.1) after experimentally demonstrating that all the pLOF variants seen within the instances had been really LOF. We in contrast the proportion of people carrying not less than one pLOF variant of the 12 autosomal genes in instances and controls by the use of logistic regression with the probability ratio check. We accounted for the ethnic heterogeneity of the cohorts by together with the primary three principal parts of the PCA within the logistic regression mannequin. PC adjustment is a typical and environment friendly technique for accounting for various ancestries of sufferers and controls within the research of uncommon variants (3538). We checked that our adjusted burden check was properly calibrated by additionally performing an evaluation of enrichment in uncommon (MAF <0.001) synonymous variants of the 12 genes. PCA was carried out with Plink model 1.9 software program on whole-exome– and whole-genome–sequencing information and the 1000 Genomes (1kG) Mission part 3 public database as a reference, utilizing 27,480 exonic variants with a MAF >0.01 and a name price >0.99. The OR was additionally estimated by logistic regression and adjusted for ethnic heterogeneity.

Reporter assays

Cell strains or SV40-Fib cells with identified defects had been transiently or stably transfected with WT, mutant variants, IFN-β- or ISRE-firefly luciferase reporter, and pRL-TK-Renilla luciferase reporter. Reporter exercise was measured with the Twin-Luciferase Reporter Assay System (Promega) in keeping with the producer’s directions. Firefly luciferase exercise was normalized in opposition to Renilla luciferase exercise and expressed as a fold change. TRAF3-deficient human embryonic kidney (HEK) 293T cells had been kindly supplied by M. Romanelli (39).

pDC activation by SARS-CoV-2 and cytokine manufacturing

pDCs from an IRF7−/− affected person and a wholesome donor matched for age and intercourse had been cultured within the presence of medium alone, influenza virus (A/PR/8/34, 2 μg/ml; Charles River Laboratories), or the SARS-CoV-2 main pressure 220_95 (GISAID accession ID: EPI_ISL_469284) at a multiplicity of an infection (MOI) of two. After 12 hours of tradition, pDC supernatant was collected for cytokine quantification. IFN-α2 ranges had been measured utilizing CBA analyzis (BD Biosciences) in accordance with the producer’s protocol utilizing a 20 pg/ml detection restrict. IFN-λ1 secretion was measured in an ELISA (R&D Methods, DuoSet DY7246), in accordance with the producer’s directions.

SARS-CoV-2 an infection in affected person SV40-Fib

To make patient-derived fibroblasts permissive to SARS-CoV-2 an infection, we delivered human ACE2 and TMPRSS2 cDNA to cells by lentivirus transduction utilizing a modified SCRPSY vector (GenBank ID: KT368137.1). SARS-CoV-2 pressure USA-WA1/2020 was obtained from BEI Assets. ACE2/TMPRSS2-transduced cells had been both left untreated or handled with 500 U/ml IFN-β (11415-1, PBL Assay Science) 4 hours earlier than an infection. Cells had been contaminated with SARS-CoV-2 (MOI = 0.5) for 1 hour at 37°C. After 24 hours of an infection, cells had been mounted and brought out of the BSL3 for staining.

After fixation, cells had been stained with SARS-CoV-2 and ACE2 main antibodies (0.5 and 1 μg/ml, respectively). Main antibodies had been as follows: for SARS-CoV-2, human monoclonal anti-spike-SARS-CoV-2 C121 antibody (40), and for ACE2, mouse monoclonal Alexa Fluor 488–conjugated antibody (FAB9332G-100UG, R&D Methods). Photos had been acquired with an ImageXpress Micro XLS microscope (Molecular Units) utilizing the 4× goal. MetaXpress software program (Molecular Units) was used to acquire single-cell imply fluorescence depth (MFI) values.

Knowledge evaluation on single-cell MFI values was completed within the R surroundings (model 4.0.2). ACE2/TMPRSS2-transduced cells had been labeled as ACE2 constructive when the ACE2 log MFI was superior to the log imply MFI of mock-transduced cells plus 2.5 SDs. We excluded all wells with <150 ACE2-positive cells earlier than SARS-CoV-2 scoring. ACE2-expressing cells had been labeled SARS-CoV-2 constructive when the fluorescence depth worth was superior to the MFI of mock-infected cells plus 4 SDs. The median SARS-CoV-2 MFI and proportion SARS-CoV-2–constructive cells had been calculated for every properly (impartial an infection).

Single-molecule array (Simoa) IFN-α digital ELISA

Serum IFN-α concentrations had been decided utilizing Simoa expertise, with reagents and procedures obtained from Quanterix Company (Quanterix SimoaTM IFNα Reagent Package, Lexington, MA, USA). In keeping with the producer’s directions, the working dilutions had been 1:2 for all sera in working volumes of 170 μl.

COVID-STORM Clinicians

Giuseppe Foti1, Giacomo Bellani1, Giuseppe Citerio1, Ernesto Contro1, Alberto Pesci2, Maria Grazia Valsecchi3, Marina Cazzaniga4

1Division of Emergency, Anesthesia and Intensive Care, College of Medication and Surgical procedure, College of Milano-Bicocca, San Gerardo Hospital, Monza, Italy. 2Division of Pneumology, College of Medication and Surgical procedure, College of Milano-Bicocca, San Gerardo Hospital, Monza, Italy. 3Heart of Bioinformatics and Biostatistics, College of Medication and Surgical procedure, College of Milano-Bicocca, San Gerardo Hospital, Monza, Italy. 4Section I Analysis Heart, College of Medication and Surgical procedure, College of Milano-Bicocca, San Gerardo Hospital, Monza, Italy.

COVID Clinicians

Jorge Abad1, Sergio Aguilera-Albesa2, Ozge Metin Akcan3, Ilad Alavi Darazam4, Juan C. Aldave5, Miquel Alfonso Ramos6, Seyed Alireza Nadji7, Gulsum Alkan8, Jerome Allardet-Servent9, Luis M. Allende10, Laia Alsina11, Marie-Alexandra Alyanakian12, Blanca Amador-Borrero13, Zahir Amoura14, Arnau Antolí15, Sevket Arslan16, Sophie Assant17, Terese Auguet18, Axelle Azot19, Fanny Bajolle20, Aurélie Baldolli21, Maite Ballester22, Hagit Baris Feldman23, Benoit Barrou24, Alexandra Beurton25, Agurtzane Bilbao26, Geraldine Blanchard-Rohner27, Ignacio Blanco1, Adeline Blandinières28, Daniel Blazquez-Gamero29, Marketa Bloomfield30, Mireia Bolivar-Prados31, Raphael Borie32, Cédric Bosteels33, Ahmed A. Bousfiha34, Claire Bouvattier35, Oksana Boyarchuk36, Maria Rita P. Bueno37, Jacinta Bustamante20, Juan José Cáceres Agra38, Semra Calimli39, Ruggero Capra40, Maria Carrabba41, Carlos Casasnovas42, Marion Caseris43, Martin Castelle44, Francesco Castelli45, Martín Castillo de Vera46, Mateus V. Castro37, Emilie Catherinot47, Martin Chalumeau48, Bruno Charbit49, Matthew P. Cheng50, Père Clavé31, Bonaventura Clotet51, Anna Codina52, Fatih Colkesen53, Fatma Çölkesen54, Roger Colobran55, Cloé Comarmond56, David Dalmau57, David Ross Darley58, Nicolas Dauby59, Stéphane Dauger60, Loic de Pontual61, Amin Dehban62, Geoffroy Delplancq63, Alexandre Demoule64, Jean-Luc Diehl65, Stephanie Dobbelaere66, Sophie Durand67, Waleed Eldars68, Mohamed Elgamal69, Marwa H. Elnagdy70, Melike Emiroglu71, Emine Hafize Erdeniz72, Selma Erol Aytekin73, Romain Euvrard74, Recep Evcen75, Giovanna Fabio41, Laurence Faivre76, Antonin Falck43, Muriel Fartoukh77, Morgane Faure78, Miguel Fernandez Arquero79, Carlos Flores80, Bruno Francois81, Victoria Fumadó82, Francesca Fusco83, Blanca Garcia Solis84, Pascale Gaussem85, Juana Gil-Herrera86, Laurent Gilardin87, Monica Girona Alarcon88, Mònica Girona-Alarcón88, Jean-Christophe Goffard89, Funda Gok90, Rafaela González-Montelongo91, Antoine Guerder92, Yahya Gul93, Sukru Nail Guner93, Marta Intestine94, Jérôme Hadjadj95, Filomeen Haerynck96, Rabih Halwani97, Lennart Hammarström98, Nevin Hatipoglu99, Elisa Hernandez-Brito100, Cathérine Heijmans101, María Soledad Holanda-Peña102, Juan Pablo Horcajada103, Levi Hoste104, Eric Hoste105, Sami Hraiech106, Linda Humbert107, Alejandro D. Iglesias108, Antonio Íñigo-Campos91, Matthieu Jamme109, María Jesús Arranz110, Iolanda Jordan111, Philippe Jorens112, Fikret Kanat113, Hasan Kapakli114, Iskender Kara115, Adem Karbuz116, Kadriye Kart Yasar117, Sevgi Keles118, Yasemin Kendir Demirkol119, Adam Klocperk120, Zbigniew J. Król121, Paul Kuentz122, Yat Wah M. Kwan123, Jean-Christophe Lagier124, Bart N. Lambrecht33, Yu-Lung Lau125, Fleur Le Bourgeois60, Yee-Sin Leo126, Rafael Leon Lopez127, Daniel Leung125, Michael Levin128, Michael Levy60, Romain Lévy20, Zhi Li49, Agnes Linglart129, Bart Loeys130, José M. Lorenzo-Salazar91, Céline Louapre131, Catherine Lubetzki131, Charles-Edouard Luyt132, David C. Lye133, Davood Mansouri134, Majid Marjani135, Jesus Marquez Pereira136, Andrea Martin137, David Martínez Pueyo138, Javier Martinez-Picado139, Iciar Marzana140, Alexis Mathian14, Larissa R. B. Matos37, Gail V. Matthews141, Julien Mayaux142, Jean-Louis Mège143, Isabelle Melki144, Jean-François Meritet145, Ozge Metin146, Isabelle Meyts147, Mehdi Mezidi148, Isabelle Migeotte149, Maude Millereux150, Tristan Mirault151, Clotilde Mircher67, Mehdi Mirsaeidi152, Abián Montesdeoca Melián153, Antonio Morales Martinez154, Pierre Morange155, Clémence Mordacq107, Guillaume Morelle156, Stéphane Mouly13, Adrián Muñoz-Barrera91, Leslie Naesens157, Cyril Nafati158, João Farela Neves159, Lisa FP. Ng160, Yeray Novoa Medina161, Esmeralda Nuñez Cuadros162, J. Gonzalo Ocejo-Vinyals163, Zerrin Orbak164, Mehdi Oualha20, Tayfun Özçelik165, Qiang Pan-Hammarström166, Christophe Parizot142, Tiffany Pascreau167, Estela Paz-Artal168, Sandra Pellegrini49, Rebeca Pérez de Diego84, Aurélien Philippe169, Quentin Philippot77, Laura Planas-Serra170, Dominique Ploin171, Julien Poissy172, Géraldine Poncelet43, Marie Pouletty173, Paul Quentric142, Didier Raoult143, Anne-Sophie Rebillat67, Ismail Reisli174, Pilar Ricart175, Jean-Christophe Richard176, Nadia Rivet28, Jacques G. Rivière177, Gemma Rocamora Blanch15, Carlos Rodrigo1, Carlos Rodriguez-Gallego178, Agustí Rodríguez-Palmero179, Carolina Soledad Romero180, Anya Rothenbuhler181, Flore Rozenberg182, Maria Yolanda Ruiz del Prado183, Joan Sabater Riera15, Oliver Sanchez184, Silvia Sánchez-Ramón185, Agatha Schluter170, Matthieu Schmidt186, Cyril E. Schweitzer187, Francesco Scolari188, Anna Sediva189, Luis M. Seijo190, Damien Sene13, Sevtap Senoglu117, Mikko R. J. Seppänen191, Alex Serra Ilovich192, Mohammad Shahrooei62, Hans Slabbynck193, David M. Smadja194, Ali Sobh195, Xavier Solanich Moreno15, Jordi Solé-Violán196, Catherine Soler197, Pere Soler-Palacín137, Yuri Stepanovskiy198, Annabelle Stoclin199, Fabio Taccone149, Yacine Tandjaoui-Lambiotte200, Jean-Luc Taupin201, Simon J. Tavernier202, Benjamin Terrier203, Caroline Thumerelle107, Gabriele Tomasoni204, Julie Toubiana48, Josep Trenado Alvarez205, Sophie Trouillet-Assant206, Jesús Troya207, Alessandra Tucci208, Matilde Valeria Ursini‬83, Yurdagul Uzunhan209, Pierre Vabres210, Juan Valencia-Ramos211, Eva Van Braeckel33, Stijn Van de Velde212, Ana Maria Van Den Rym84, Jens Van Praet213, Isabelle Vandernoot214, Hulya Vatansev215, Valentina Vélez-Santamaria42, Sébastien Viel171, Cédric Vilain216, Marie E. Vilaire67, Audrey Vincent35, Guillaume Voiriot217, Fanny Vuotto107, Alper Yosunkaya90, Barnaby E. Younger126, Fatih Yucel218, Faiez Zannad219, Mayana Zatz37, Alexandre Belot220*

1College Hospital and Analysis Institute “Germans Trias i Pujol,” Badalona, Spain. 2Navarra Well being Service Hospital, Pamplona, Spain. 3Division of Pediatric Infectious Ailments, Necmettin Erbakan College, Meram Medical College, Konya, Turkey. 4Division of Infectious Ailments, Loghman Hakim Hospital, Shahid Beheshti College of Medical Sciences, Tehran, Iran. 5Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru. 6Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain. 7Virology Analysis Heart, Nationwide Institutes of Tuberculosis and Lung Ailments, Shahid Beheshti College of Medical Sciences, Tehran, Iran. 8Division of Pediatric Infectious Ailments, College of Medication, Selcuk College, Konya, Turkey. 9Intensive Care Unit, Hôpital Européen, Marseille, France. 10Immunology Division, College Hospital 12 de Octubre, Analysis Institute imas12, and Complutense College, Madrid, Spain. 11Scientific Immuology and Main Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona, Spain. 12Division of Organic Immunology, Necker Hospital for Sick Kids, APHP and INEM, Paris, France. 13Inside Medication Division, Hôpital Lariboisière, APHP; Université de Paris, Paris, France. 14Inside Medication Division, Pitié-Salpétrière Hospital, Paris, France. 15Hospital Universitari de Bellvitge, Barcelona, Spain. 16Division of Scientific Immunology and Allergy, Necmettin Erbakan College, Meram Medical College, Konya, Turkey. 17Joint Analysis Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Lyon, France. 18Hospital U. de Tarragona Joan XXIII, Universitat Rovira i Virgili (URV), IISPV, Tarragona, Spain. 19Non-public follow, Paris, France. 20Necker Hospital for Sick Kids, AP-HP, Paris, France. 21Division of Infectious Ailments, CHU de Caen, Caen, France. 22Consorcio Hospital Basic Universitario, Valencia, Spain. 23The Genetics Institute, Tel Aviv Sourasky Medical Heart and Sackler College of Medication, Tel Aviv College, Tel Aviv, Israel. 24Division of Urology, Nephrology, and Transplantation, APHP-SU, Sorbonne Université, INSERM U 1082, Paris, France. 25Service de Médecine Intensive–Réanimation et Pneumologie, APHP Hôpital Pitié–Salpêtrière, Paris, France. 26Cruces College Hospital, Bizkaia, Spain. 27Paediatric Immunology and Vaccinology Unit, Geneva College Hospitals and College of Medication, Geneva, Switzerland. 28Hematology, Georges Pompidou Hospital, APHP, Paris, France. 29Pediatric Infectious Ailments Unit, Instituto de Investigación 12 de Octubre imas12, and Hospital Universitario 12 de Octubre, Madrid, Spain. 30Division of Immunology, Motol College Hospital, 2nd College of Medication, Charles College, Division of Pediatrics, Thomayer’s Hospital, 1st College of Medication, Charles College, Prague, Czech Republic. 31Centro de Investigación Biomédica en Pink de Enfermedades Hepàticas y Digestivas (Ciberehd), Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain. 32Service de Pneumologie, Hopital Bichat, APHP, Paris, France. 33Division of Pulmonology, Ghent College Hospital, Ghent, Belgium. 34Scientific Immunology Unit, Pediatric Infectious Illness Division, College of Medication and Pharmacy, Averroes College Hospital, LICIA Laboratoire d’Immunologie Clinique, d’Irritation et d’Allergie, Hassann Ii College, Casablanca, Morocco. 35Endocrinology Unit, APHP Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France. 36Division of Kids’s Ailments and Pediatric Surgical procedure, I. Horbachevsky Ternopil Nationwide Medical College, Ternopil, Ukraine. 37Human Genome and Stem-Cell Analysis Heart, College of São Paulo, São Paulo, Brazil. 38Hospital Insular, Las Palmas de Gran Canaria, Spain. 39Division of Important Care Medication, Division of Anesthesiology and Reanimation, Konya State Hospital, Konya, Turkey. 40MS Heart, Spedali Civili, Brescia, Italy. 41Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. 42Bellvitge College Hospital, L’Hospitalet de Llobregat, Barcelona, Spain. 43Hopital Robert Debré, Paris, France. 44Pediatric Immuno-hematology Unit, Necker Enfants Malades Hospital, AP-HP, Paris, France. 45Division of Infectious and Tropical Ailments, College of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy. 46Doctoral Well being Care Heart, Canarian Well being System, Las Palmas de Gran Canaria, Spain. 47Hôpital Foch, Suresnes, France. 48Necker Hospital for Sick Kids, Paris College, AP-HP, Paris, France. 49Pasteur Institute, Paris, France. 50McGill College Well being Centre, Montreal, Canada. 51College Hospital and Analysis Institute “Germans Trias i Pujol,” IrsiCaixa AIDS Analysis Institute, UVic-UCC, Badalona, Spain. 52Scientific Biochemistry, Pathology, Paediatric Neurology and Molecular Medication Departments and Biobank, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Esplugues, Spain. 53Division of Scientific Immunology and Allergy, Division of Inside Medication, Necmettin Erbakan College, Meram Medical College, Konya, Turkey. 54Division of Infectious Ailments and Scientific Microbiology, Konya Coaching and Analysis Hospital, Konya, Turkey. 55Hospital Universitari Vall d’Hebron, Barcelona, Spain. 56Pitié-Salpêtrière Hospital, Paris, France. 57Fundació Docència i Recerca Mútua Terrassa, Barcelona, Spain; Hospital Universitari Mutua Terrassa, Universitat de Barcelona, Terrassa, Catalonia, Spain. 58UNSW Medication, St. Vincent’s Scientific College, and Division of Thoracic Medication, St. Vincent’s Hospital Darlinghurst, Sidney, Australia. 59CHU Saint-Pierre, Université Libre de Bruxelles, Brussels, Belgium. 60Pediatric Intensive Care Unit, Robert-Debré College Hospital, APHP, Paris, France. 61Sorbonne Paris Nord, Hôpital Jean Verdier, APHP, Bondy, France. 62Specialised Immunology Laboratory of Dr. Shahrooei, Sina Medical Complicated, Ahvaz, Iran. 63Centre de Génétique Humaine, CHU Besançon, Besançon, France. 64Sorbonne Université Médecine and APHP Sorbonne Université Web site Pitié-Salpêtrière, Paris, France. 65Intensive Care Unit, Georges Pompidou Hospital, APHP, Paris, France. 66Division of Pneumology, AZ Delta, Roeselare, Belgium. 67Institut Jérôme Lejeune, Paris, France. 68Division of Microbiology and Immunology, College of Medication, Mansoura College, Mansoura, Egypt. 69Division of Chest, College of Medication, Mansoura College, Mansoura, Egypt. 70Division of Medical Biochemistry and Molecular Biology, College of Medication, Mansoura College, Mansoura, Egypt. 71College of Medication, Division of Pediatric Infectious Ailments, Selcuk College, Konya, Turkey. 72Division of Pediatric Infectious Ailments, Ondokuz Mayıs College, Samsun, Turkey. 73Necmettin Erbakan College, Meram Medical College, Division of Pediatric Allergy and Immunology, Konya, Turkey. 74Centre Hospitalier Fleyriat, Bourg-en-Bresse, France. 75Division of Scientific Immunology and Allergy, Division of Inside Medication, Necmettin Erbakan College, Meram Medical College, Konya, Turkey. 76Centre de Génétique, CHU Dijon, Dijon, France. 77APHP Tenon Hospital, Paris, France. 78Sorbonne Universités, UPMC College of Paris, Paris, France. 79Division of Scientific Immunology , Hospital Clínico San Carlos, Madrid, Spain. 80Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Analysis Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain; Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, San Cristóbal de La Laguna, Spain. 81CHU Limoges and Inserm CIC 1435 and UMR 1092, Limoges, France. 82Infectious Ailments Unit, Division of Pediatrics, Hospital Sant Joan de Déu, Barcelona, Spain; Institut de Recerca Sant Joan de Déu, Spain; Universitat de Barcelona (UB), Barcelona, Spain. 83Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” IGB-CNR, Naples, Italy. 84Laboratory of Immunogenetics of Human Ailments, IdiPAZ Institute for Well being Analysis, La Paz Hospital, Madrid, Spain. 85Hematology, APHP, Hopital Européen Georges Pompidou and Inserm UMR-S1140, Paris, France. 86Hospital Basic Universitario and Instituto de Investigación Sanitaria “Gregorio Marañón,” Madrid, Spain. 87Bégin army Hospital, Bégin, France. 88Pediatric Intensive Care Unit, Hospital Sant Joan de Déu, Barcelona, Spain. 89Division of Inside Medication, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 90Division of Important Care Medication, Division of Anesthesiology and Reanimation, Necmettin Erbakan College, Meram Medical College, Konya, Turkey. 91Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain. 92Help Publique Hôpitaux de Paris, Paris, France. 93Division of Allergy and Immunology, Necmettin Erbakan College, Meram Medical College, Konya, Turkey. 94CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Know-how (BIST); Universitat Pompeu Fabra (UPF), Barcelona, Spain. 95Division of Inside Medication, Nationwide Reference Heart for Uncommon Systemic Autoimmune Ailments, AP-HP, APHP-CUP, Hôpital Cochin, Paris, France. 96Ghent College Hospital, Ghent, Belgium. 97Sharjah Institute of Medical Analysis, Faculty of Medication, College of Sharjah, Sharjah, UAE. 98Division of Laboratory Medication, SE14186, Huddinge, Karolinska Institutet, Stockholm, Sweden. 99Pediatric Infectious Ailments Unit, Bakirkoy Dr. Sadi Konuk Coaching and Analysis Hospital, College of Well being Sciences, Istanbul, Turkey. 100Division of Immunology, Hospital Universitario de Gran Canaria Dr. Negrín, Canarian Well being System, Las Palmas de Gran Canaria, Spain. 101Division of Pediatric Hemato-Oncology, Jolimont Hospital; Division of Pediatric Hemato-Oncology, HUDERF, Brussels, Belgium. 102Intensive Care Unit, Marqués de Valdecilla Hospital, Santander, Spain. 103Hospital del Mar, Parc de Salut Mar, Barcelona, Spain. 104Division of Pediatric Pulmonology and Immunology, Ghent College Hospital, Ghent, Belgium. 105Division of Intensive Care Unit, Ghent College Hospital, Ghent, Belgium. 106Intensive Care Unit, APHM, Marseille, France. 107CHU Lille, Lille, France. 108Division of Pediatrics, Columbia College, New York, NY, USA. 109Centre Hospitalier Intercommunal Poissy Saint Germain en Laye, Poissy, France. 110Fundació Docència i Recerca Mútua Terrassa, Terrassa, Spain. 111Hospital Sant Joan de Déu, Children Corona Platfform, Barcelona, Spain. 112Division of Intensive Care Unit, College Hospital Antwerp, Antwerp, Belgium. 113Selcuk College, College of Medication, Chest Ailments Division, Konya, Turkey. 114Division of Allergy and Immunology, Balikesir Ataturk Metropolis Hospital, Balikesir, Turkey. 115Division of Important Care Medication, Selcuk College, College of Medication, Konya, Turkey. 116Division of Pediatric Infectious Ailments, Prof. Dr. Cemil Tascıoglu Metropolis Hospital, Istanbul, Turkey. 117Departments of Infectious Ailments and Scientific Microbiology, Bakirkoy Dr. Sadi Konuk Coaching and Analysis Hospital, College of Well being Sciences, Istanbul, Turkey. 118Meram Medical College, Necmettin Erbakan College, Meram Medical College, Konya, Turkey. 119Well being Sciences College, Umraniye Training and Analysis Hospital, Istanbul, Turkey. 120Division of Immunology, 2nd College of Medication, Charles College and College Hospital in Motol, Prague, Czech Republic. 121Central Scientific Hospital of Ministry of the Inside and Administration in Warsaw, Warsaw, Poland. 122Oncobiologie Génétique Bioinformatique, PC Bio, CHU Besançon, Besançon, France. 123Paediatric Infectious Illness Unit, Hospital Authority Infectious Illness Heart, Princess Margaret Hospital, Hong Kong (Particular Administrative Area), China. 124Aix Marseille College, IRD, MEPHI, IHU Méditerranée An infection, Marseille, France. 125Division of Paediatrics and Adolescent Medication, The College of Hong Kong, Hong Kong, China. 126Nationwide Centre for Infectious Ailments, Singapore. 127Hospital Universitario Reina Sofía, Cordoba, Spain. 128Imperial Faculty, London, UK. 129Endocrinology and Diabetes for Kids, AP-HP, Bicêtre Paris-Saclay Hospital, Le Kremlin-Bicêtre, France. 130Division of Medical Genetics, College Hospital Antwerp, Antwerp, Belgium. 131Neurology Unit, APHP Pitié-Salpêtrière Hospital, Paris College, Paris, France. 132Intensive Care Unit, APHP Pitié-Salpêtrière Hospital, Paris College, Paris, France. 133Nationwide Centre for Infectious Ailments; Tan Tock Seng Hospital; Yong Bathroom Lin College of Medication; Lee Kong Chian College of Medication, Singapore. 134Division of Scientific Immunology and Infectious Ailments, Nationwide Analysis Institute of Tuberculosis and Lung Ailments, Shahid Beheshti College of Medical Sciences, Tehran, Iran. 135Scientific Tuberculosis and Epidemiology Analysis Heart, Nationwide Analysis Institute of Tuberculosis and Lung Ailments (NRITLD), Shahid Beheshti College of Medical Sciences, Tehran, Iran. 136Hospital Sant Joan de Déu and College of Barcelona, Barcelona, Spain. 137Pediatric Infectious Ailments and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Analysis Institute, Vall d’Hebron Barcelona Hospital Campus. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 138Hospital Universitari Mutua de Terrassa, Universitat de Barcelona, Barcelona, Spain. 139IrsiCaixa AIDS Analysis Institute, ICREA, UVic-UCC, Analysis Institute “Germans Trias i Pujol,” Badalona, Spain. 140Division of Laboratory, Cruces College Hospital, Barakaldo, Bizkaia, Spain. 141College of New South Wales, New South Wales, Australia. 142APHP Pitié-Salpêtrière Hospital, Paris, France. 143Aix-Marseille College, APHM, Marseille, France. 144Robert Debré Hospital, Paris, France. 145APHP Cohin Hospital, Paris, France. 146Necmettin Erbakan College Meram College of Medication Division of Pediatric Infectious Ailments, Konya, Turkey. 147College Hospitals Leuven, Leuven, Belgium. 148Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France. 149Hôpital Erasme, Brussels, Belgium. 150CH Gonesse, Gonesse, France. 151Vascular Medication, Georges Pompidou Hospital, APHP, Paris, France. 152Division of Pulmonary and Important Care, College of Miami, Miami, FL, USA. 153Guanarteme Well being Care Heart, Canarian Well being System, Las Palmas de Gran Canaria, Spain. 154Regional College Hospital of Malaga, Malaga, Spain. 155Aix-Marseille Université, Marseille, France. 156Division of Basic Paediatrics, Hôpital Bicêtre, AP-HP, College of Paris Saclay, Le Kremlin-Bicêtre, France. 157Division of Inside Medication, Ghent College Hospital, Ghent, Belgium. 158CHU de La Timone, Marseille, France. 159Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal. 160Infectious Ailments Horizontal Technlogy Centre, A*STAR; Singapore Immunology Community, A*STAR, Singapore. 161Division of Pediatrics, Complejo Hospitalario Universitario Insular-Materno Infantil, Canarian Well being System, Las Palmas de Gran Canaria, Spain. 162Regional Universitary Hospital of Málaga, Málaga, Spain. 163Hospital Universitario Marqués de Valdecilla, Santander, Spain. 164College of Medication, Ataturk College, Erzurum, Turkey. 165Division of Molecular Biology and Genetics, Bilkent College, Ankara, Turkey. 166Division of Biosciences and Diet, Karolinska Institutet, SE14183, Stockholm, Sweden. 167L’Hôpital Foch, Suresnes, France. 168Division of Immunology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre imas12, Madrid, Spain. 169APHP Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France. 170Neurometabolic Ailments Laboratory, IDIBELL-Hospital Duran i Reynals, Barcelona; CIBERER U759, ISCiii, Madrid, Spain. 171Hospices Civils de Lyon, Lyon, France. 172Université de Lille, Inserm U1285, CHU Lille, Paris, France. 173Departement of Basic Pediatrics, College Hospital Robert Debré, APHP, Paris, France. 174Necmettin Erbakan College, Konya, Turkey. 175Germans Trias i Pujol Hospital, Badalona, Spain. 176Medical Intensive Care Unit, Hopital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France. 177Pediatric Infectious Ailments and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Analysis Institute, Vall d’Hebron Barcelona Hospital Campus., Barcelona, Spain. 178Division of Immunology, Hospital Universitario de Gran Canaria Dr. Negrín, Canarian Well being System, Las Palmas de Gran Canaria, Spain. College Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain. 179Neurometabolic Ailments Laboratory, IDIBELL-Hospital Duran i Reynals, Barcelona, Spain. 180Consorcio Hospital Basic Universitario, Valencia, Spain. 181APHP Hôpitaux Universitaires Paris-Sud, Paris, France. 182Virology Unit, Université de Paris, Cohin Hospital, APHP, Paris, France. 183Hospital San Pedro, Logroño, Spain. 184Respiratory Medication, Georges Pompidou Hospital, APHP, Paris, France. 185Division of Immunology, Hospital Clínico San Carlos, Madrid, Spain. 186Service de Médecine Intensive Réanimation, Institut de Cardiologie, Hopital Pitié-Salpêtrière, Paris, France. 187CHRU de Nancy, Hôpital d’Enfants, Vandoeuvre, France. 188Chair of Nephrology, College of Brescia, Brescia, Italy. 189Division of Immunology, 2nd College of Medication, Charles College and Motol College Hospital, Prague, Czech Republic. 190Clínica Universidad de Navarra, Madrid, Spain. 191HUS Helsinki College Hospital, Kids and Adolescents, Uncommon Illness Heart, and Irritation Heart, Grownup Immunodeficiency Unit, Majakka, Helsinki, Finland. 192Fundació Docència i Recerca Mútua Terrassa, Terrassa, Spain. 193Division of Pulmonology, ZNA Middelheim, Antwerp, Belgium. 194INSERM UMR-S 1140, Biosurgical Analysis Lab (Carpentier Basis), Paris College and Hopital Européen Georges Pompidou, Paris, France. 195Division of Pediatrics, College of Medication, Mansoura College, Mansoura, Egypt. 196Important Care Unit, Hospital Universitario de Gran Canaria Dr. Negrín, Canarian Well being System, Las Palmas de Gran Canaria, Spain. 197CHU de Saint Etienne, Saint-Priest-en-Jarez, France. 198Shupyk Nationwide Medical Academy for Postgraduate Training, Kiev, Ukraine. 199Gustave Roussy Most cancers Campus, Villejuif, France. 200Intensive Care Unit, Avicenne Hospital, APHP, Bobigny, France. 201Laboratory of Immunology and Histocompatibility, Saint-Louis Hospital, Paris College, Paris, France. 202Division of Inside Ailments and Pediatrics, Main Immune Deficiency Analysis Lab, Centre for Main Immunodeficiency Ghent, Jeffrey Modell Prognosis and Analysis Centre, Ghent College Hospital, Ghent, Belgium. 203Division of Inside Medication, Université de Paris, INSERM, U970, PARCC, F-75015, Paris, France. 204First Division of Anesthesiology and Important Care Medication, College of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy. 205Intensive Care Division, Hospital Universitari Mutua Terrassa, Universitat Barcelona, Terrassa, Spain. 206Hospices Civils de Lyon, Lyon Sud Hospital, Lyon, France. 207Infanta Leonor College Hospital, Madrid, Spain. 208Hematology Division, ASST Spedali Civili di Brescia, Brescia, Italy. 209Pneumologie, Hôpital Avicenne, APHP, INSERM U1272, Université Sorbonne Paris Nord, Bobigny, France. 210Dermatology Unit, Laboratoire GAD, INSERM UMR1231 LNC, Université de Bourgogne, Dijon, France. 211College Hospital of Burgos, Burgos, Spain. 212Intensive Care Unit, M. Middelares Ghent, Ghent, Belgium. 213Division of Nephrology and Infectiology, AZ Sint-Jan Brugge-Oostende AV, Bruges, Belgium. 214Heart of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 215Division of Chest Ailments, Necmettin Erbakan College, Meram Medical College, Konya, Turkey. 216CHU de Caen, Caen, France. 217Sorbonne Université, Service de Médecine Intensive Réanimation, Hôpital Tenon, Help Publique-Hôpitaux de Paris, Paris, France. 218Basic Intensive Care Unit, Konya Coaching and Analysis Hospital, Konya, Turkey. 219CHU de Nancy, Nancy, France. 220College of Lyon, CIRI, INSERM U1111, Nationwide Referee Centre RAISE, Pediatric Rheumatology, HFME, Hospices Civils de Lyon, Lyon, France.

*Chief of COVID Clinicians.

Think about COVID Group

Christine Bole-Feysot, Stanislas Lyonnet*, Cécile Masson, Patrick Nitschke, Aurore Pouliet, Yoann Schmitt, Frederic Tores, Mohammed Zarhrate

Think about Institute, Université de Paris, INSERM UMR 1163, Paris, France.

*Chief of the Think about COVID Group.

French COVID Cohort Research Group

Laurent Abel1, Claire Andrejak2, François Angoulvant3, Delphine Bachelet4, Romain Basmaci5, Sylvie Behillil6, Marine Beluze7, Dehbia Benkerrou8, Krishna Bhavsar4, François Bompart9, Lila Bouadma4, Maude Bouscambert10, Mireille Caralp11, Minerva Cervantes-Gonzalez12, Anissa Chair4, Alexandra Coelho13, Camille Couffignal4, Sandrine Couffin-Cadiergues14, Eric D’Ortenzio12, Charlene Da Silveira4, Marie-Pierre Debray4, Dominique Deplanque15, Diane Descamps16, Mathilde Desvallées17, Alpha Diallo18, Alphonsine Diouf13, Céline Dorival8, François Dubos19, Xavier Duval4, Philippine Eloy4, Vincent VE Enouf20, Hélène Esperou21, Marina Esposito-Farese4, Manuel Etienne22, Nadia Ettalhaoui4, Nathalie Gault4, Alexandre Gaymard10, Jade Ghosn4, Tristan Gigante23, Isabelle Gorenne4, Jérémie Guedj24, Alexandre Hoctin13, Isabelle Hoffmann4, Salma Jaafoura21, Ouifiya Kafif4, Florentia Kaguelidou25, Sabina Kali4, Antoine Khalil4, Coralie Khan17, Cédric Laouénan4, Samira Laribi4, Minh Le4, Quentin Le Hingrat4, Soizic Le Mestre18, Hervé Le Nagard24, François-Xavier Lescure4, Yves Lévy26, Claire Levy-Marchal27, Bruno Lina10, Guillaume Lingas24, Jean Christophe Lucet4, Denis Malvy28, Marina Mambert13, France Mentré4, Noémie Mercier18, Amina Meziane8, Hugo Mouquet20, Jimmy Mullaert4, Nadège Neant24, Marion Noret29, Justine Pages30, Aurélie Papadopoulos21, Christelle Paul18, Nathan Peiffer-Smadja4, Ventzislava Petrov-Sanchez18, Gilles Peytavin4, Olivier Picone31, Oriane Puéchal12, Manuel Rosa-Calatrava10, Bénédicte Rossignol23, Patrick Rossignol32, Carine Roy4, Marion Schneider4, Caroline Semaille12, Nassima Si Mohammed4, Lysa Tagherset4, Coralie Tardivon4, Marie-Capucine Tellier4, François Téoulé8, Olivier Terrier10, Jean-François Timsit4, Théo Trioux4, Christelle Tual33, Sarah Tubiana4, Sylvie van der Werf34, Noémie Vanel35, Aurélie Veislinger33, Benoit Visseaux16, Aurélie Wiedemann26, Yazdan Yazdanpanah36

1Inserm UMR 1163, Paris, France. 2CHU Amiens, France. 3Hôpital Necker, Paris, France. 4Hôpital Bichat, Paris, France. 5Hôpital Louis Mourrier, Colombes, France. 6Institut Pasteur, Paris, France. 7F-CRIN Companions Platform, AP-HP, Université de Paris, Paris, France. 8Inserm UMR 1136, Paris, France. 9Medication for Uncared for Ailments Initiative, Geneva, Switzerland. 10Inserm UMR 1111, Lyon, France. 11Inserm Transfert, Paris, France. 12REACTing, Paris, France. 13Inserm UMR 1018, Paris, France. 14Inserm, Pôle Recherche Clinique, Paris, France. 15CIC 1403 Inserm-CHU Lille, Paris, France. 16Université de Paris, IAME, INSERM UMR 1137, AP-HP, College Hospital Bichat Claude Bernard, Virology, Paris, France. 17Inserm UMR 1219, Bordeaux, France. 18ANRS, Paris, France. 19CHU Lille, Lille, France. 20Pasteur Institute, Paris, France. 21Inserm sponsor, Paris, France. 22CHU Rouen–SMIT, Rouen, France. 23FCRIN INI-CRCT, Nancy, France. 24Inserm UMR 1137, Paris, France. 25Centre d’Investigation Clinique, Inserm CIC1426, Hôpital Robert Debré, Paris, France. 26Inserm UMR 955, Créteil, France; Vaccine Analysis Instiute (VRI), Paris, France. 27F-CRIN INI-CRCT, Paris, France. 28CHU de Bordeaux–SMIT, Bordeaux, France. 29RENARCI, Annecy, France. 30Hôpital Robert Debré, Paris, France. 31Hôpital Louis Mourier–Gynécologie, Colombes, France. 32College of Lorraine, Plurithematic Scientific Investigation Centre Inserm CIC-P; 1433, Inserm U1116, CHRU Nancy Hopitaux de Brabois, F-CRIN INI-CRCT (Cardiovascular and Renal Scientific Trialists), Nancy, France. 33Inserm CIC-1414, Rennes, France. 34Institut Pasteur, UMR 3569 CNRS, Université de Paris, Paris, France. 35Hôpital la Timone, Marseille, France. 36Bichat–SMIT, Paris, France.

CoV-Contact Cohort

Loubna Alavoine1, Karine Ok. A. Amat2, Sylvie Behillil3, Julia Bielicki4, Patricia Bruijning5, Charles Burdet6, Eric Caumes7, Charlotte Charpentier8, Bruno Coignard9, Yolande Costa1, Sandrine Couffin-Cadiergues10, Florence Damond8, Aline Dechanet11, Christelle Delmas10, Diane Descamps8, Xavier Duval1, Jean-Luc Ecobichon1, Vincent Enouf3, Hélène Espérou10, Wahiba Frezouls1, Nadhira Houhou11, Emila Ilic-Habensus1, Ouifiya Kafif11, John Kikoine11, Quentin Le Hingrat8, David Lebeaux12, Anne Leclercq1, Jonathan Lehacaut1, Sophie Letrou1, Bruno Lina13, Jean-Christophe Lucet14, Denis Malvy15, Pauline Manchon11, Milica Mandic1, Mohamed Meghadecha16, Justina Motiejunaite17, Mariama Nouroudine1, Valentine Piquard11, Andreea Postolache11, Caroline Quintin1, Jade Rexach1, Layidé Roufai10, Zaven Terzian11, Michael Thy18, Sarah Tubiana1, Sylvie van der Werf3, Valérie Vignali1, Benoit Visseaux8, Yazdan Yazdanpanah14

1Centre d’Investigation Clinique, Inserm CIC 1425, Hôpital Bichat Claude Bernard, APHP, Paris, France. 2IMEA Fondation Léon M’Ba, Paris, France. 3Institut Pasteur, UMR 3569 CNRS, Université de Paris, Paris, France. 4College of Basel Kids’s Hospital. 5Julius Heart for Well being Sciences and Main Care, Utrecht, Netherlands. 6Université de Paris, IAME, Inserm UMR 1137, F-75018, Paris, France, Hôpital Bichat Claude Bernard, APHP, Paris, France. 7Hôpital Pitiè Salpétriere, APHP, Paris. 8Université de Paris, IAME, INSERM UMR 1137, AP-HP, College Hospital Bichat Claude Bernard, Virology, Paris, France. 9Santé Publique France, Saint Maurice, France. 10Pole Recherche Clinique, Inserm, Paris, France. 11Hôpital Bichat Claude Bernard, APHP, Paris, France. 12APHP, Paris, France. 13Virpath Laboratory, Worldwide Heart of Analysis in Infectiology, Lyon College, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France. 14IAME Inserm UMR 1138, Hôpital Bichat Claude Bernard, APHP, Paris, France. 15Service des Maladies Infectieuses et Tropicales; Groupe Pellegrin-Place Amélie-Raba-Léon, Bordeaux, France. 16Hôpital Resort Dieu, APHP, Paris, France. 17Service des Explorations Fonctionnelles, Hôpital Bichat–Claude Bernard, APHP, Paris, France. 18Heart for Scientific Investigation, Help Publique-Hôpitaux de Paris, Bichat-Claude Bernard College Hospital, Paris, France.

Amsterdam UMC Covid-19 Biobank

Michiel van Agtmael1, Anna Geke Algera2, Frank van Baarle2, Diane Bax3, Martijn Beudel4, Hurt Jan Bogaard5, Marije Bomers1, Lieuwe Bos2, Michela Botta2, Justin de Brabander6, Godelieve de Bree6, Matthijs C. Brouwer4, Sanne de Bruin2, Marianna Bugiani7, Esther Bulle2, Osoul Chouchane1, Alex Cloherty3, Paul Elbers2, Lucas Fleuren2, Suzanne Geerlings1, Bart Geerts8, Theo Geijtenbeek9, Armand Girbes2, Bram Goorhuis1, Martin P. Grobusch1, Florianne Hafkamp9, Laura Hagens2, Jorg Hamann10, Vanessa Harris1, Robert Hemke11, Sabine M. Hermans1, Leo Heunks2, Markus W. Hollmann8, Janneke Horn2, Joppe W. Hovius1, Menno D. de Jong12, Rutger Koning4, Niels van Mourik2, Jeaninne Nellen1, Frederique Paulus2, Edgar Peters1, Tom van der Ballot1, Benedikt Preckel8, Jan M. Prins1, Jorinde Raasveld2, Tom Reijnders1, Michiel Schinkel1, Marcus J. Schultz2, Alex Schuurman13, Kim Sigaloff1, Marry Smit2, Cornelis S. Stijnis1, Willemke Stilma2, Charlotte Teunissen14, Patrick Thoral2, Anissa Tsonas2, Marc van der Valk1, Denise Veelo8, Alexander P.J. Vlaar15, Heder de Vries2, Michèle van Vugt1, W. Joost Wiersinga1, Dorien Wouters16, A. H. (Koos) Zwinderman17, Diederik van de Beek4*

1Division of Infectious Ailments, Amsterdam UMC, Amsterdam, Netherlands. 2Division of Intensive Care, Amsterdam UMC, Amsterdam, Netherlands. 3Experimental Immunology, Amsterdam UMC, Amsterdam, Netherlands. 4Division of Neurology, Amsterdam UMC, Amsterdam Neuroscience, Amsterdam, Netherlands. 5Division of Pulmonology, Amsterdam UMC, Amsterdam, Netherlands. 6Division of Infectious Ailments, Amsterdam UMC, Amsterdam, Netherlands. 7Division of Pathology, Amsterdam UMC, Amsterdam, Netherlands. 8Division of Anesthesiology, Amsterdam UMC, Amsterdam, Netherlands. 9Division of Experimental Immunology, Amsterdam UMC, Amsterdam, Netherlands. 10Amsterdam UMC Biobank Core Facility, Amsterdam UMC, Amsterdam, Netherlands. 11Division of Radiology, Amsterdam UMC, Amsterdam, Netherlands. 12Division of Medical Microbiology, Amsterdam UMC, Amsterdam, Netherlands. 13Division of Inside Medication, Amsterdam UMC, Amsterdam, Netherlands. 14Neurochemical Laboratory, Amsterdam UMC, Amsterdam, Netherlands. 15Division of Intensive Care, Amsterdam UMC, Amsterdam, Netherlands. 16Division of Scientific Chemistry, Amsterdam UMC, Amsterdam, Netherlands. 17Division of Scientific Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Amsterdam, Netherlands. 18Division of Neurology, Amsterdam UMC, Amsterdam, Netherlands.

*Chief of the AMC Consortium.

COVID Human Genetic Effort

Laurent Abel1, Alessandro Aiuti2, Saleh Al Muhsen3, Fahd Al-Mulla4, Mark S. Anderson5, Andrés Augusto Arias6, Hagit Baris Feldman7, Dusan Bogunovic8, Alexandre Bolze9, Anastasiia Bondarenko10, Ahmed A. Bousfiha11, Petter Brodin12, Yenan Bryceson12, Carlos D. Bustamante13, Manish Butte14, Giorgio Casari15, Samya Chakravorty16, John Christodoulou17, Elizabeth Cirulli9, Antonio Condino-Neto18, Megan A. Cooper19, Clifton L. Dalgard20, Alessia David21, Joseph L. DeRisi22, Murkesh Desai23, Beth A. Drolet24, Sara Espinosa25, Jacques Fellay26, Carlos Flores27, Jose Luis Franco28, Peter Ok. Gregersen29, Filomeen Haerynck30, David Hagin31, Rabih Halwani​32, Jim Heath33, Sarah E. Henrickson34, Elena Hsieh35, Kohsuke Imai36, Yuval Itan8, Timokratis Karamitros37, Kai Kisand38, Cheng-Lung Ku39, Yu-Lung Lau40, Yun Ling41, Carrie L. Lucas42, Tom Maniatis43, Davoud Mansouri44, Laszlo Marodi45, Isabelle Meyts46, Joshua Milner47, Kristina Mironska48, Trine Mogensen49, Tomohiro Morio50, Lisa FP. Ng51, Luigi D. Notarangelo52, Antonio Novelli53, Giuseppe Novelli54, Cliona O’Farrelly55, Satoshi Okada56, Tayfun Ozcelik57, Rebeca Perez de Diego58, Anna M. Planas59, Carolina Prando60, Aurora Pujol61, Lluis Quintana-Murci62, Laurent Renia63, Alessandra Renieri64, Carlos Rodríguez-Gallego65, Vanessa Sancho-Shimizu66, Vijay Sankaran67, Kelly Schiabor Barrett9, Mohammed Shahrooei68, Andrew Snow69, Pere Soler-Palacín70, András N. Spaan71, Stuart Tangye72, Stuart Turvey73, Furkan Uddin74, Mohammed J. Uddin75, Diederik van de Beek76, Sara E. Vazquez77, Donald C. Vinh78, Horst von Bernuth79, Nicole Washington9, Pawel Zawadzki80, Helen C. Su52, Jean-Laurent Casanova81

1INSERM U1163, College of Paris, Think about Institute, Paris, France. 2San Raffaele Telethon Institute for Gene Remedy, IRCCS Ospedale San Raffaele, Milan, Italy. 3King Saud College, Riyadh, Saudi Arabia. 4Kuwait College, Kuwait Metropolis, Kuwait. 5College of California, San Francisco, San Francisco, CA, USA. 6Universidad de Antioquia, Group of Main Immunodeficiencies, Antioquia, Colombia. 7The Genetics Institute, Tel Aviv Sourasky Medical Heart and Sackler College of Medication, Tel Aviv College, Tel Aviv, Israel. 8Icahn College of Medication at Mount Sinai, New York, NY, USA. 9Helix, San Mateo, CA, USA. 10Shupyk Nationwide Medical Academy for Postgraduate Training, Kiev, Ukraine. 11Scientific Immunology Unit, Pediatric Infectious Illness Departement, College of Medication and Pharmacy, Averroes College Hospital; LICIA Laboratoire d’Immunologie Clinique, d’Irritation et d’Allergie, Hassann Ii College, Casablanca, Morocco. 12Karolinska Institute, Stockholm, Sweden. 13Stanford College, Stanford, CA, USA. 14College of California, Los Angeles, CA, USA. 15Medical Genetics, IRCCS Ospedale San Raffaele, Milan, Italy. 16Emory College Division of Pediatrics and Kids’s Healthcare of Atlanta, Atlanta, GA, USA. 17Murdoch Kids’s Analysis Institute, Victoria, Australia. 18College of São Paulo, São Paulo, Brazil. 19Washington College College of Medication, St. Louis, MO, USA. 20The American Genome Heart; Uniformed Companies College of the Well being Sciences, Bethesda, MD, USA. 21Centre for Bioinformatics and System Biology, Division of Life Sciences, Imperial Faculty London, South Kensington Campus, London, UK. 22College of California, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. 23Bai Jerbai Wadia Hospital for Kids, Mumbai, India. 24College of Medication and Public Well being, College of Wisconsin, Madison, WI, USA. 25Instituto Nacional de Pediatria (Nationwide Institute of Pediatrics), Mexico Metropolis, Mexico. 26Swiss Federal Institute of Know-how Lausanne, Lausanne, Switzerland. 27Analysis Unit, Hospital Universitario Nuestra Señora de Candelaria, Canarian Well being System, Santa Cruz de Tenerife, Spain. 28College of Antioquia, Medellín, Colombia. 29Feinstein Institute for Medical Analysis, Northwell Well being USA, Manhasset, NY, USA. 30Division of Paediatric Immunology and Pulmonology, Centre for Main Immunodeficiency Ghent (CPIG), PID Analysis Lab, Jeffrey Modell Prognosis and Analysis Centre, Ghent College Hospital, Edegem, Belgium. 31The Genetics Institute, Tel Aviv Sourasky Medical Heart, Tel Aviv, Israel. 32Sharjah Institute of Medical Analysis, Faculty of Medication, College of Sharjah, Sharjah, UAE. 33Institute for Methods Biology, Seattle, WA, USA. 34Kids’s Hospital of Philadelphia, Philadelphia, PA, USA. 35Anschutz Medical Campus, Aurora, CO, USA. 36Riken, Tokyo, Japan. 37Hellenic Pasteur Institute, Athens, Greece. 38College of Tartu, Tartu, Estonia. 39Chang Gung College, Taoyuan County, Taiwan. 40The College of Hong Kong, Hong Kong, China. 41Shanghai Public Well being Scientific Heart, Fudan College, Shanghai, China. 42Yale College of Medication, New Haven, CT, USA. 43New York Genome Heart, New York, NY, USA. 44Shahid Beheshti College of Medical Sciences, Tehran, Iran. 45Semmelweis College Budapest, Budapest, Hungary. 46KU Leuven, Division of Immunology, Microbiology and Transplantation, Leuven, Belgium. 47Columbia College Medical Heart, New York, NY, USA. 48College Clinic for Kids’s Ailments, Skopje, North Macedonia. 49Aarhus College, Aarhus, Denmark. 50Tokyo Medical & Dental College Hospital, Tokyo, Japan. 51Singapore Immunology Community, Singapore. 52Nationwide Institute of Allergy and Infectious Ailments, Nationwide Institutes of Well being, Bethesda, MD, USA. 53Bambino Gesù Kids’s Hospital, Rome, Italy. 54Division of Biomedicine and Prevention, College of Rome “Tor Vergata,” Rome, Italy. 55Trinity Faculty, Dublin, Eire. 56Hiroshima College, Hiroshima, Japan. 57Bilkent College, Ankara, Turkey. 58Laboratory of Immunogenetics of Human Ailments, Innate Immunity Group, IdiPAZ Institute for Well being Analysis, La Paz Hospital, Madrid, Spain. 59IIBB-CSIC, IDIBAPS, Barcelona, Spain. 60Faculdades Pequeno Príncipe e Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil. 61Neurometabolic Ailments Laboratory, IDIBELL–Hospital Duran I Reynals; Catalan Establishment for Analysis and Superior Research (ICREA); CIBERER U759, ISCiii Madrid Spain, Barcelona, Spain. 62Institut Pasteur (CNRS UMR2000) and Collège de France, Paris, France. 63Infectious Ailments Horizontal Know-how Heart and Singapore Immunology Community, Company for Science Know-how (A*STAR), Singapore. 64Medical Genetics, College of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy; GEN-COVID Multicenter Research. 65Hospital Universitario de Gran Canaria Dr. Negrín, Canarian Well being System, Canary Islands, Spain. 66Imperial Faculty London, London, UK. 67Boston Kids’s Hospital, Harvard Medical College, Boston, MA, USA. 68Saeed Pathobiology and Genetic Lab, Tehran, Iran. 69Uniformed Companies College of the Well being Sciences, Bethesda, MD, USA. 70Hospital Universitari Vall d’Hebron, Barcelona, Spain. 71College Medical Heart Utrecht, Amsterdam, The Netherlands. 72Garvan Institute of Medical Analysis, Sydney, Australia. 73The College of British Columbia, Vancouver, Canada. 74Holy Household Pink Crescent Medical Faculty; Centre for Precision Therapeutics, NeuroGen Kids’s Healthcare; Genetics and Genomic Medication Centre, NeuroGen Kids’s Healthcare, Dhaka, Bangladesh. 75Mohammed Bin Rashid College of Medication and Well being Sciences, Faculty of Medication, Dubai, UAE; The Centre for Utilized Genomics, Division of Genetics and Genome Biology, The Hospital for Sick Kids, Toronto, Ontario, Canada. 76Amsterdam UMC, College of Amsterdam, Division of Neurology, Amsterdam Neuroscience, Amsterdam, The Netherlands. 77College of California, San Francisco, CA, USA. 78McGill College Well being Centre, Montreal, Canada. 79Charité–Berlin College Hospital Heart, Berlin, Germany. 80Molecular Biophysics Division, College of Physics, A. Mickiewicz College, Uniwersytetu Poznanskiego 2, Poznań, Poland. 81Rockefeller College, Howard Hughes Medical Institute, Necker Hospital, New York, NY, USA.

*Leaders of the COVID Human Genetic Effort.

NIAID-USUHS/TAGC COVID Immunity Group

Huie Jing1,2, Wesley Tung1,2, Christopher R. Luthers3, Bradly M. Bauman3, Samantha Shafer2,4, Lixin Zheng2,4, Zinan Zhang2,4, Satoshi Kubo2,4, Samuel D. Chauvin2,4, Kazuyuki Meguro1,2, Elana Shaw1,2, Michael Lenardo2,4, Justin Lack5, Eric Karlins6, Daniel M. Hupalo7, John Rosenberger7, Gauthaman Sukumar7, Matthew D. Wilkerson7, Xijun Zhang7

1Laboratory of Scientific Immunology and Microbiology, Division of Intramural Analysis, NIAID, NIH, Bethesda, MD, USA. 2NIAID Scientific Genomics Program, Nationwide Institutes of Well being, Bethesda, MD, USA. 3Division of Pharmacology & Molecular Therapeutics, Uniformed Companies College of the Well being Sciences, Bethesda, MD, USA. 4Laboratory of Immune System Biology, Division of Intramural Analysis, NIAID, NIH, Bethesda, MD, USA. 5NIAID Collaborative Bioinformatics Useful resource, Frederick Nationwide Laboratory for Most cancers Analysis, Leidos Biomedical Analysis, Inc., Frederick, MD, USA. 6Bioinformatics and Computational Biosciences Department, Workplace of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA. 7The American Genome Heart, Uniformed Companies College of the Well being Sciences, Bethesda, MD, USA.

References and Notes

  1. M. Bouaziz, J. Mullaert, B. Bigio, Y. Seeleuthner, J.-L. Casanova, A. Alcais, L. Abel, A. Cobat, Controlling for human inhabitants stratification in uncommon variant affiliation research. bioRxiv 969477 [Preprint]. 28 February 2020. .doi:10.1101/2020.02.28.969477

  2. Q. Zhang, P. Bastard, Z. Liu, J. Le Pen, M. Moncada-Velez, J. Chen, M. Ogishi, I. Ok. D. Sabli, S. Hodeib, C. Korol, J. Rosain, Ok. Bilguvar, J. Ye, A. Bolze, B. Bigio, R. Yang, A. Augusto Arias Sierra, Q. Zhou, Y. Zhang, F. Onodi, S. Korniotis, L. Karpf, Q. Philippot, M. Chbihi, L. Bonnet-Madin, Ok. Dorgham, N. Smith, W. M. Schneider, B. S. Razooky, H.-H. Hoffmann, E. Michailidis, L. Moens, J. E. Han, L. Lorenzo, L. Bizien, P. Meade, A.-L. Neehus, A. C. Ugurbil, A. Corneau, G. Kerner, P. Zhang, F. Rapaport, Y. Seeleuthner, J. Manry, C. Masson, Y. Schmitt, A. Schlüter, T. Le Voyer, T. Khan, J. Li, J. Fellay, L. Roussel, M. Shahrooei, M. F. Alosaimi, D. Mansouri, H. Al-Saud, F. Al-Mulla, F. Almourfi, S. Z. Al-Muhsen, F. Alsohime, S. Al Turki, R. Hasanato, D. van de Beek, A. Biondi, L. R. Bettini, M. D’Angio, P. Bonfanti, L. Imberti, A. Sottini, S. Paghera, E. Quiros-Roldan, C. Rossi, A. J. Oler, M. F. Tompkins, C. Alba, I. Vandernoot, J.-C. Goffard, G. Smits, I. Migeotte, F. Haerynck, P. Soler-Palacin, A. Martin-Nalda, R. Colobran, P.-E. Morange, S. Keles, F. Çölkesen, T. Ozcelik, Ok. Ok. Yasar, S. Senoglu, Ş. N. Karabela, C. Rodríguez-Gallego, G. Novelli, S. Hraiech, Y. Tandjaoui-Lambiotte, X. Duval, C. Laouenan, COVID-STORM Clinicians, COVID Clinicians, Think about COVID Group, French COVID Cohort Research Group, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank, COVID Human Genetic Effort, NIAID-USUHS/TAGC COVID Immunity Group, A. L. Snow, C. L. Dalgard, J. Milner, D. C. Vinh, T. H. Mogensen, N. Marr, A. N. Spaan, B. Boisson, S. Boisson-Dupuis, J. Bustamante, A. Puel, M. Ciancanelli, I. Meyts, T. Maniatis, V. Soumelis, A. Amara, M. Nussenzweig, A. García-Sastre, F. Krammer, A. Pujol, D. Duffy, R. Lifton, S.-Y. Zhang, G. Gorochov, V. Béziat, E. Jouanguy, V. Sancho-Shimizu, C. M. Rice, L. Abel, L. D. Notarangelo, A. Cobat, H. C. Su, J.-L. Casanova, Detailed genotype counts for all coding variants for: Inborn errors of kind I IFN immunity in sufferers with life-threatening COVID-19, Dryad (2020); . doi:10.5061/dryad.8pk0p2nkk

  3. M. Ogishi, R. Yang, C. Gruber, S. Pelham, A. N. Spaan, J. Rosain, M. Chbihi, J. E. Han, V. Ok. Rao, L. Kainulainen, J. Bustamante, B. Boisson, D. Bogunovic, S. Boisson-Dupuis, J.-L. Casanova, Multi-batch cytometry information integration for optimum immunophenotyping. bioRxiv 202432 [Preprint]. 15 July 2020. doi:10.1101/2020.07.14.202432

Acknowledgments: We thank the sufferers, their households, and wholesome donors for putting their belief in us; Y. Nemirowskaya, D. Papandrea, M. Woollet, D. Liu, C. Rivalain, and C. Patissier for administrative help; A. Adeleye, D. Bacikova, E. McGrath Martinez, A. R. Soltis, Ok. Dobbs, J. Danielson, H. Matthews, and S. Weber for technical and different help; M. M. A. Ata and F. Al Ali for his or her contribution to VirScan experiments; S. Elledge (Brigham and Ladies’s Hospital and Harvard Medical College, Boston, MA) for kindly offering the VirScan phage library used on this research; A. W. Ashbrook, the BSL3 supervisor of the Rice laboratory help; M. Lazzaro, Director of Immigration and Tutorial Appointments, for help; W. Chung, Ok. Kiryluk, S. O’Byrne, D. Pendrick, J. Williamson, C. Andrews, and M. Disco within the J.M. lab for help; M. Andreoni (Tor Vergata, Italy) for his scientific contribution; and A. Novelli (Bambino Gesù Hospital, Italy) for his collaboration. We thank the GEN-COVID Multicenter research (https://sites.google.com/dbm.unisi.it/gen-covid). This research used the high-performance computational assets of the Nationwide Institutes of Well being (NIH) HPC Biowulf cluster (http://hpc.nih.gov) and the Workplace of Cyber Infrastructure and Computational Biology (OCICB) Excessive Efficiency Computing (HPC) cluster on the Nationwide Institute of Allergy and Infectious Ailments (NIAID), Bethesda, MD. The opinions and assertions expressed herein are these of the authors and are to not be construed as reflecting the views of the Uniformed Companies College of the Well being Sciences (USUHS) or the U.S. Division of Protection (DoD). Funding: This work was supported by a beneficiant donation from the Fisher Heart for Alzheimer’s Analysis Basis. The Laboratory of Human Genetics of Infectious Ailments is supported by the Howard Hughes Medical Institute, the Rockefeller College, the St. Giles Basis, the NIH (R01AI088364), the Nationwide Heart for Advancing Translational Sciences (NCATS), the NIH Scientific and Translational Science Award (CTSA) program (UL1 TR001866), a Quick Grant from Emergent Ventures, Mercatus Heart at George Mason College, the Yale Heart for Mendelian Genomics and the GSP Coordinating Heart funded by the Nationwide Human Genome Analysis Institute (NHGRI) (UM1HG006504 and U24HG008956), the French Nationwide Analysis Company (ANR) beneath the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Rising Infectious Ailments Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Basis for Medical Analysis (FRM) (EQU201903007798), the FRM and ANR GENCOVID challenge, ANRS-COV05, the Sq. Basis, Grandir–Fonds de Solidarité pour l’Enfance, the SCOR Company Basis for Science, Institut Nationwide de la Santé et de la Recherche Médicale (INSERM), the College of Paris. The French COVID Cohort research group was sponsored by Inserm and supported by the REACTing consortium and by a grant from the French Ministry of Well being (PHRC 20-0424). Regione Lombardia, Italy (challenge “Risposta immune in pazienti con COVID-19 e co-morbidità”), and the Intramural Analysis Program of the NIAID, NIH. The laboratory of Genomes & Cell Biology of Illness is supported by “Integrative Biology of Rising Infectious Ailments” (grant no. ANR-10-LABX-62-IBEID), the “Fondation pour la Recherche Medicale” (grant FRM–EQU202003010193), the “Agence Nationale de la Recherche” (ANR FLASH COVID challenge IDISCOVR cofounded by the “Fondation pour la Recherche Médicale”), College of Paris (“Plan de Soutien Covid-19”: RACPL20FIR01-COVID-SOUL). I.M. is a senior scientific investigator with the FWO Vlaanderen; I.M. and L.M. are supported by FWO G0C8517N – GOB5120N. The VS staff was supported by “Agence Nationale de la Recherche” (ANR-17-CE15-0003, ANR-17-CE15-0003-01) and by Université de Paris “PLAN D’URGENCE COVID19”. L.Ok. was supported by a fellowship from the French Ministry of Analysis. V.S.-S. is supported by a UKRI Future Leaders Fellowship (MR/S032304/1). S.Z.A.-M. is supported by the Elite Journals Program at King Saud College by grant no. PEJP-16-107. The J.M. laboratory is supported by Columbia College COVID biobank and grant no. UL1TR001873. Work within the Laboratory of Virology and Infectious Illness was supported by NIH grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1; a George Mason College Quick Grant; and the G. Harold and Leila Y. Mathers Charitable Basis. J.L.P. is supported by a European Molecular Biology Group Lengthy-Time period Fellowship (ALTF 380-2018). Work on the Neurometabolic Ailments Laboratory obtained funding from the European Union’s Horizon 2020 analysis and innovation program beneath grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342) to A.P., and Roche and Illumina Covid Match Funds to M.G.. C.R.G. and colleagues are supported by Instituto de Salud Carlos III (COV20_01333 and COV20_01334), Spanish Ministry of Science and Innovation, with the funding of European Regional Growth Fund-European Social Fund -FEDER-FSE; (RTC-2017-6471-1; AEI/FEDER, UE), and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). D.C.V. is supported by the Fonds de la recherche en santé du Québec clinician-scientist scholar program. H.S. is adjunct college on the College of Pennsylvania. A.-L.N. was supported by the Basis Bettencourt Schueller. The Amsterdam UMC Covid-19 Biobank was funded by the Netherlands Group for Well being Analysis and Growth (ZonMw, NWO-vici 91819627), The Corona Analysis Fund (Amsterdam UMC), Dr. J. C. Vaillantfonds, and Amsterdam UMC. Work on COVID-19 on the A.G.-S. laboratory is partly supported by NIH dietary supplements to grants U19AI135972, U19AI142733, and R35 HL135834, and to contract HHSN272201800048C, by a DoD complement to grant W81XWH-20-1-0270, by DARPA challenge HR0011-19-2-0020, by CRIP (Heart for Analysis on Influenza Pathogenesis), a NIAID funded Heart of Excellence for Influenza Analysis and Surveillance (CEIRS, contract HHSN272201400008C), by an NIAID funded Collaborative Influenza Vaccine Innovation Heart (SEM-CIVIC, contract 75N93019C00051) and by the beneficiant assist of the JPB Basis, the Open Philanthropy Mission (analysis grant 2020-215611(5384)) and nameless donors. The Virscan evaluation introduced in fig. S11 was carried out with monetary assist from Sidra Medication. J.R.H. is supported by Biomedical Superior Analysis and Growth Authority beneath Contract (HHSO10201600031C). Writer contributions: A.G., A.A., A.A.A., A.L.S., A.-L.N., A.C., A.C., A.P., B.B., B.S.R., C.A., C.M., C.Ok., C.L., C.M.R., C.L.D., D.D., E.M., E.J., F.A., F.A-M., F.O., F.A., F.Ok., G.N., G.S., G.G., H.-H.H., H.Ok.A.S., H.S., I.Ok.D.S., I.M., J.L.P., J.R., J.E.H., J.C., J.M., J.Y., Ok.D., Ok.B., L.A., L.L.-D., L.Ok., L.M., L.B-M., L.B., L.D.N., M.M-V., M.C., M.O., M.C., M.N., M.F.T., M.S., M.F.A., N.M., N.S., P.B., P.M., Q.Z., Q.Z., Q.P., R.L., R.Y., S.A.T., S.Z.A-M., S.H., S.Ok., S.H., S.B.-D., T.Ok., T.M., T.H.M., V.S.-S., V.S., V.B., W.S., X.D., Y.S., and Z.L. both carried out or supervised experiments, generated and analyzed information, and contributed to the manuscript. A.S., A.C.U., A.B., A.O., A.P., B.B., D.V.D.B., F.R., G.Ok., J.M., P.Z., S-Y.Z., T.L.-V., Y.S., and Y.Z. carried out computational evaluation. A.S., A.N.S., A.M.-N., A.B., C.R., D.M., D.C.V., E.Q.-R., F.H., I.M., I.V., J.B., J.-C.G., L.R.B., L.R., L.I., M.D., P.B., P.S.-P., P.-E.M., R.H., R.C., S.Ok., S.P., T.O., Y.T.-L., Ok.Ok., S.S., J.F., and S.N.Ok. evaluated and recruited sufferers to COVID and/or management cohorts. Q.Z. and J.-L.C. wrote the manuscript. All authors edited the manuscript. J.-L.C. supervised the challenge. Competing pursuits: The authors declare no competing monetary pursuits. J.-L.C. is listed as an inventor on patent utility US63/055,155 filed by The Rockefeller College that encompasses features of this publication. R.L. is a non-executive director of Roche and its subsidiary Genentech. Knowledge and supplies availability: Plasma, cells, and genomic DNA can be found from J.-L.C. or D.V. beneath a fabric switch settlement with Rockfeller College/Analysis Institute-McGill College Well being Centre. pSCRPSY_TMPRSS2-2A-NeoR_ACE2 and Huh-7.5 cells can be found upon request from C.R. beneath a fabric switch settlement with The Rockefeller College, or The Rockefeller College and Apath, LLC, respectively. Scientific information, DNA, and different affected person samples can be found from the Amsterdam UMC Covid-19 Biobank (D.v.d.B.) beneath a fabric switch settlement with Amsterdam UMC. Materials and reagents used are nearly completely commercially obtainable and nonproprietary. Requests for materals derived from human samples could also be made obtainable, topic to any underlying restrictions on such samples. J.-L.C. could make materials switch agreements obtainable by The Rockefeller College. Detailed genotype counts for all coding variants within the genes investigated on this manuscript can be found at Dryad (41). The entire-genome sequencing datasets used for the analyses, together with vital sufferers and asymptomatic controls described on this manuscript, had been deposited in dbGaP beneath accession quantity phs002245.v1.p1. All different information can be found within the manuscript or the supplementary materials. This work is licensed beneath a Artistic Commons Attribution 4.0 Worldwide (CC BY 4.0) license, which allows unrestricted use, distribution, and replica in any medium, supplied the unique work is correctly cited. To view a duplicate of this license, go to https://creativecommons.org/licenses/by/4.0/. This license doesn’t apply to figures/pictures/art work or different content material included within the article that’s credited to a 3rd get together; receive authorization from the rights holder earlier than utilizing such materials.



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