@article {1016, title = {Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 04 05}, abstract = {

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10\% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

}, keywords = {Adolescent, Adult, Aged, Antibodies, Neutralizing, Autoantibodies, Autoimmune Diseases, COVID-19, Female, Genetic Diseases, Inborn, HEK293 Cells, Humans, Interferon-alpha, Male, Middle Aged, Receptor, Interferon alpha-beta, SARS-CoV-2, Vaccines, Attenuated, Yellow Fever Vaccine, Yellow fever virus}, issn = {1540-9538}, doi = {10.1084/jem.20202486}, author = {Bastard, Paul and Michailidis, Eleftherios and Hoffmann, Hans-Heinrich and Chbihi, Marwa and Le Voyer, Tom and Rosain, J{\'e}r{\'e}mie and Philippot, Quentin and Seeleuthner, Yoann and Gervais, Adrian and Materna, Marie and de Oliveira, Patricia Mouta Nunes and Maia, Maria de Lourdes S and Dinis Ano Bom, Ana Paula and Azamor, Tamiris and Ara{\'u}jo da Concei{\c c}{\~a}o, Deborah and Goudouris, Ekaterini and Homma, Akira and Slesak, G{\"u}nther and Sch{\"a}fer, Johannes and Pulendran, Bali and Miller, Joseph D and Huits, Ralph and Yang, Rui and Rosen, Lindsey B and Bizien, Lucy and Lorenzo, Lazaro and Chrabieh, Maya and Erazo, Lucia V and Rozenberg, Flore and Jeljeli, Mohamed Maxime and B{\'e}ziat, Vivien and Holland, Steven M and Cobat, Aurelie and Notarangelo, Luigi D and Su, Helen C and Ahmed, Rafi and Puel, Anne and Zhang, Shen-Ying and Abel, Laurent and Seligman, Stephen J and Zhang, Qian and MacDonald, Margaret R and Jouanguy, Emmanuelle and Rice, Charles M and Casanova, Jean-Laurent} } @article {894, title = {Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.}, journal = {Genome Med}, volume = {13}, year = {2021}, month = {2021 04 21}, pages = {66}, abstract = {

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

}, keywords = {Adult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, Asthma, Bronchi, Cardiovascular Diseases, COVID-19, Gene Expression, Genetic Variation, Humans, Middle Aged, Obesity, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Respiratory Mucosa, Risk Factors, SARS-CoV-2, Smoking}, issn = {1756-994X}, doi = {10.1186/s13073-021-00866-2}, author = {Kasela, Silva and Ortega, Victor E and Martorella, Molly and Garudadri, Suresh and Nguyen, Jenna and Ampleford, Elizabeth and Pasanen, Anu and Nerella, Srilaxmi and Buschur, Kristina L and Barjaktarevic, Igor Z and Barr, R Graham and Bleecker, Eugene R and Bowler, Russell P and Comellas, Alejandro P and Cooper, Christopher B and Couper, David J and Criner, Gerard J and Curtis, Jeffrey L and Han, MeiLan K and Hansel, Nadia N and Hoffman, Eric A and Kaner, Robert J and Krishnan, Jerry A and Martinez, Fernando J and McDonald, Merry-Lynn N and Meyers, Deborah A and Paine, Robert and Peters, Stephen P and Castro, Mario and Denlinger, Loren C and Erzurum, Serpil C and Fahy, John V and Israel, Elliot and Jarjour, Nizar N and Levy, Bruce D and Li, Xingnan and Moore, Wendy C and Wenzel, Sally E and Zein, Joe and Langelier, Charles and Woodruff, Prescott G and Lappalainen, Tuuli and Christenson, Stephanie A} } @article {831, title = {Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells.}, journal = {Cell}, volume = {184}, year = {2021}, month = {2021 01 07}, pages = {92-105.e16}, abstract = {

To better understand host-virus genetic dependencies and find potential therapeutic targets for COVID-19, we performed a genome-scale CRISPR loss-of-function screen to identify host factors required for SARS-CoV-2 viral infection of human alveolar epithelial cells. Top-ranked genes cluster into distinct pathways, including the vacuolar ATPase proton pump, Retromer, and Commander complexes. We validate these gene targets using several orthogonal methods such as CRISPR knockout, RNA interference knockdown, and small-molecule inhibitors. Using single-cell RNA-sequencing, we identify shared transcriptional changes in cholesterol biosynthesis upon loss of top-ranked genes. In addition, given the key role of the ACE2 receptor in the early stages of viral entry, we show that loss of RAB7A reduces viral entry by sequestering the ACE2 receptor inside cells. Overall, this work provides a genome-scale, quantitative resource of the impact of the loss of each host gene on fitness/response to viral infection.

}, keywords = {A549 Cells, Alveolar Epithelial Cells, Angiotensin-Converting Enzyme 2, Biosynthetic Pathways, Cholesterol, Clustered Regularly Interspaced Short Palindromic Repeats, COVID-19, Endosomes, Gene Expression Profiling, Gene Knockdown Techniques, Gene Knockout Techniques, Genome-Wide Association Study, Host-Pathogen Interactions, Humans, rab GTP-Binding Proteins, RNA Interference, SARS-CoV-2, Single-Cell Analysis, Viral Load}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.10.030}, author = {Daniloski, Zharko and Jordan, Tristan X and Wessels, Hans-Hermann and Hoagland, Daisy A and Kasela, Silva and Legut, Mateusz and Maniatis, Silas and Mimitou, Eleni P and Lu, Lu and Geller, Evan and Danziger, Oded and Rosenberg, Brad R and Phatnani, Hemali and Smibert, Peter and Lappalainen, Tuuli and tenOever, Benjamin R and Sanjana, Neville E} } @article {980, title = {IFN-α2a Therapy in Two Patients with Inborn Errors of TLR3 and IRF3 Infected with SARS-CoV-2.}, journal = {J Clin Immunol}, volume = {41}, year = {2021}, month = {2021 01}, pages = {26-27}, keywords = {Adult, COVID-19, Female, Humans, Interferon Regulatory Factor-3, Interferon Type I, Interferon-alpha, Polyethylene Glycols, Primary Immunodeficiency Diseases, Recombinant Proteins, SARS-CoV-2, Toll-Like Receptor 3, Treatment Outcome}, issn = {1573-2592}, doi = {10.1007/s10875-020-00933-0}, author = {L{\'e}vy, Romain and Bastard, Paul and Lanternier, Fanny and Lecuit, Marc and Zhang, Shen-Ying and Casanova, Jean-Laurent} } @article {1003, title = {Inhibition of HECT E3 ligases as potential therapy for COVID-19.}, journal = {Cell Death Dis}, volume = {12}, year = {2021}, month = {2021 03 24}, pages = {310}, abstract = {

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

}, keywords = {Adult, Aged, Animals, Antiviral Agents, Chlorocebus aethiops, COVID-19, Endosomal Sorting Complexes Required for Transport, Female, Humans, Indoles, Male, Mice, Mice, Inbred BALB C, Middle Aged, Nedd4 Ubiquitin Protein Ligases, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Ubiquitin-Protein Ligases, Ubiquitination, Vero Cells}, issn = {2041-4889}, doi = {10.1038/s41419-021-03513-1}, author = {Novelli, Giuseppe and Liu, Jing and Biancolella, Michela and Alonzi, Tonino and Novelli, Antonio and Patten, J J and Cocciadiferro, Dario and Agolini, Emanuele and Colona, Vito Luigi and Rizzacasa, Barbara and Giannini, Rosalinda and Bigio, Benedetta and Goletti, Delia and Capobianchi, Maria Rosaria and Grelli, Sandro and Mann, Justin and McKee, Trevor D and Cheng, Ke and Amanat, Fatima and Krammer, Florian and Guarracino, Andrea and Pepe, Gerardo and Tomino, Carlo and Tandjaoui-Lambiotte, Yacine and Uzunhan, Yurdagul and Tubiana, Sarah and Ghosn, Jade and Notarangelo, Luigi D and Su, Helen C and Abel, Laurent and Cobat, Aurelie and Elhanan, Gai and Grzymski, Joseph J and Latini, Andrea and Sidhu, Sachdev S and Jain, Suresh and Davey, Robert A and Casanova, Jean-Laurent and Wei, Wenyi and Pandolfi, Pier Paolo} } @article {1002, title = {Plasma Exchange to Rescue Patients with Autoantibodies Against Type I Interferons and Life-Threatening COVID-19 Pneumonia.}, journal = {J Clin Immunol}, volume = {41}, year = {2021}, month = {2021 04}, pages = {536-544}, abstract = {

PURPOSE: To report four cases of life-threatening COVID-19 pneumonia in patients with high blood concentrations of neutralizing autoantibodies against type I interferons (IFNs), who were treated with plasma exchange (PE) as a rescue therapy.

METHODS: Prospective case series, which included patients, diagnosed with RT-PCR-confirmed SARS-CoV-2 infection and positive autoantibodies against type I IFNs in two French intensive care units (ICUs) between October 8 and November 14, 2020. Six critically ill COVID-19 patients with no anti-IFN antibodies were used as controls. Anti-IFN autoantibodies and IFN concentrations, together with the levels of anti-SARS-CoV-2 antibodies, were measured sequentially in serum. Viral load was determined in the upper and lower respiratory tract. Patients were followed during hospital stay.

RESULTS: Three men and one woman were included. Three of the patients had four PE sessions each, while another had three PE sessions. PE decreased the concentrations of autoantibodies against type I IFN in all four patients, whereas anti-SARS-CoV-2 antibody levels remained stable. Autoantibodies against type I IFN levels were high in tracheal aspirates of one patient and decreased after three PE sessions. By contrast, anti-IFN autoantibodies were not detected in tracheal aspirates from five control patients without detectable anti-IFN autoantibodies in serum. During PE, serum IFN-α levels slightly increased in three out of four patients, and upper respiratory tract viral load decreased in all patients. All patients were alive at day 28 of ICU admission. Two patients eventually died in the ICU, while the two survivors were discharged from the ICU at days 50 and 66.

CONCLUSIONS: PE efficiently removes autoantibodies against type I IFNs, including those detected in tracheal aspirates, without affecting anti-SARS-CoV-2 antibody levels, in patients with life-threatening COVID-19 pneumonia. The clinical benefit of PE in patients with autoantibodies against type I IFNs should be tested in a larger study.

}, keywords = {Adult, Aged, Autoantibodies, COVID-19, Female, Humans, Interferon Type I, Male, Plasma Exchange, Prospective Studies, SARS-CoV-2}, issn = {1573-2592}, doi = {10.1007/s10875-021-00994-9}, author = {de Prost, Nicolas and Bastard, Paul and Arrestier, Romain and Fourati, Slim and Mah{\'e}vas, Mathieu and Burrel, Sonia and Dorgham, Karim and Gorochov, Guy and Tandjaoui-Lambiotte, Yacine and Azzaoui, Iname and Fernandes, Ignacio and Combes, Alain and Casanova, Jean-Laurent and Mekontso-Dessap, Armand and Luyt, Charles-Edouard} } @article {1017, title = {Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 07 05}, abstract = {

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10\% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86\%) were hospitalized for COVID-19 pneumonia, including 15 (68\%) admitted to an intensive care unit, 11 (50\%) who required mechanical ventilation, and four (18\%) who died. Ambulatory disease in three patients (14\%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

}, keywords = {Adolescent, Adult, Autoantibodies, Child, COVID-19, Female, Humans, Interferon Type I, Male, Middle Aged, Pneumonia, Polyendocrinopathies, Autoimmune, SARS-CoV-2, Young Adult}, issn = {1540-9538}, doi = {10.1084/jem.20210554}, author = {Bastard, Paul and Orlova, Elizaveta and Sozaeva, Leila and L{\'e}vy, Romain and James, Alyssa and Schmitt, Monica M and Ochoa, Sebastian and Kareva, Maria and Rodina, Yulia and Gervais, Adrian and Le Voyer, Tom and Rosain, J{\'e}r{\'e}mie and Philippot, Quentin and Neehus, Anna-Lena and Shaw, Elana and Migaud, M{\'e}lanie and Bizien, Lucy and Ekwall, Olov and Berg, Stefan and Beccuti, Guglielmo and Ghizzoni, Lucia and Thiriez, G{\'e}rard and Pavot, Arthur and Goujard, C{\'e}cile and Fr{\'e}mond, Marie-Louise and Carter, Edwin and Rothenbuhler, Anya and Linglart, Agn{\`e}s and Mignot, Brigite and Comte, Aur{\'e}lie and Cheikh, Nathalie and Hermine, Olivier and Breivik, Lars and Husebye, Eystein S and Humbert, S{\'e}bastien and Rohrlich, Pierre and Coaquette, Alain and Vuoto, Fanny and Faure, Karine and Mahlaoui, Nizar and Kotnik, Primo{\v z} and Battelino, Tadej and Trebu{\v s}ak Podkraj{\v s}ek, Katarina and Kisand, Kai and Ferr{\'e}, Elise M N and DiMaggio, Thomas and Rosen, Lindsey B and Burbelo, Peter D and McIntyre, Martin and Kann, Nelli Y and Shcherbina, Anna and Pavlova, Maria and Kolodkina, Anna and Holland, Steven M and Zhang, Shen-Ying and Crow, Yanick J and Notarangelo, Luigi D and Su, Helen C and Abel, Laurent and Anderson, Mark S and Jouanguy, Emmanuelle and Neven, B{\'e}n{\'e}dicte and Puel, Anne and Casanova, Jean-Laurent and Lionakis, Michail S} } @article {1024, title = {SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 04 05}, abstract = {

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.

}, keywords = {Biomarkers, Cell Plasticity, COVID-19, Cytokines, Dendritic Cells, Host-Pathogen Interactions, Humans, Hydroxychloroquine, Immunomodulation, Immunophenotyping, Inflammation Mediators, Interferon Type I, Interferons, Interleukin-1 Receptor-Associated Kinases, Membrane Transport Proteins, SARS-CoV-2}, issn = {1540-9538}, doi = {10.1084/jem.20201387}, author = {Onodi, Fanny and Bonnet-Madin, Lucie and Meertens, Laurent and Karpf, L{\'e}a and Poirot, Justine and Zhang, Shen-Ying and Picard, Capucine and Puel, Anne and Jouanguy, Emmanuelle and Zhang, Qian and Le Goff, J{\'e}r{\^o}me and Molina, Jean-Michel and Delaugerre, Constance and Casanova, Jean-Laurent and Amara, Ali and Soumelis, Vassili} } @article {992, title = {SARS-CoV-2-related MIS-C: A key to the viral and genetic causes of Kawasaki disease?}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 06 07}, abstract = {

Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

}, keywords = {Biomarkers, Child, COVID-19, Cytokines, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammation, Inflammation Mediators, Lymphohistiocytosis, Hemophagocytic, Models, Biological, Mucocutaneous Lymph Node Syndrome, Pandemics, SARS-CoV-2, Systemic Inflammatory Response Syndrome}, issn = {1540-9538}, doi = {10.1084/jem.20210446}, author = {Sancho-Shimizu, Vanessa and Brodin, Petter and Cobat, Aurelie and Biggs, Catherine M and Toubiana, Julie and Lucas, Carrie L and Henrickson, Sarah E and Belot, Alexandre and Tangye, Stuart G and Milner, Joshua D and Levin, Michael and Abel, Laurent and Bogunovic, Dusan and Casanova, Jean-Laurent and Zhang, Shen-Ying} } @article {904, title = {Autoantibodies against type I IFNs in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, abstract = {

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6\% of women and 12.5\% of men.

}, keywords = {Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing, Asymptomatic Infections, Autoantibodies, Betacoronavirus, Case-Control Studies, Coronavirus Infections, COVID-19, Critical Illness, Female, Humans, Immunoglobulin G, Interferon alpha-2, Interferon Type I, Male, Middle Aged, Pandemics, Pneumonia, Viral, SARS-CoV-2}, issn = {1095-9203}, doi = {10.1126/science.abd4585}, author = {Bastard, Paul and Rosen, Lindsey B and Zhang, Qian and Michailidis, Eleftherios and Hoffmann, Hans-Heinrich and Zhang, Yu and Dorgham, Karim and Philippot, Quentin and Rosain, J{\'e}r{\'e}mie and B{\'e}ziat, Vivien and Manry, Jeremy and Shaw, Elana and Haljasm{\"a}gi, Liis and Peterson, P{\"a}rt and Lorenzo, Lazaro and Bizien, Lucy and Trouillet-Assant, Sophie and Dobbs, Kerry and de Jesus, Adriana Almeida and Belot, Alexandre and Kallaste, Anne and Catherinot, Emilie and Tandjaoui-Lambiotte, Yacine and Le Pen, J{\'e}r{\'e}mie and Kerner, Gaspard and Bigio, Benedetta and Seeleuthner, Yoann and Yang, Rui and Bolze, Alexandre and Spaan, Andr{\'a}s N and Delmonte, Ottavia M and Abers, Michael S and Aiuti, Alessandro and Casari, Giorgio and Lampasona, Vito and Piemonti, Lorenzo and Ciceri, Fabio and Bilguvar, Kaya and Lifton, Richard P and Vasse, Marc and Smadja, David M and Migaud, M{\'e}lanie and Hadjadj, J{\'e}rome and Terrier, Benjamin and Duffy, Darragh and Quintana-Murci, Lluis and van de Beek, Diederik and Roussel, Lucie and Vinh, Donald C and Tangye, Stuart G and Haerynck, Filomeen and Dalmau, David and Martinez-Picado, Javier and Brodin, Petter and Nussenzweig, Michel C and Boisson-Dupuis, St{\'e}phanie and Rodr{\'\i}guez-Gallego, Carlos and Vogt, Guillaume and Mogensen, Trine H and Oler, Andrew J and Gu, Jingwen and Burbelo, Peter D and Cohen, Jeffrey I and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio, Mariella and Bonfanti, Paolo and Rossignol, Patrick and Mayaux, Julien and Rieux-Laucat, Fr{\'e}d{\'e}ric and Husebye, Eystein S and Fusco, Francesca and Ursini, Matilde Valeria and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Castagnoli, Riccardo and Montagna, Daniela and Licari, Amelia and Marseglia, Gian Luigi and Duval, Xavier and Ghosn, Jade and Tsang, John S and Goldbach-Mansky, Raphaela and Kisand, Kai and Lionakis, Michail S and Puel, Anne and Zhang, Shen-Ying and Holland, Steven M and Gorochov, Guy and Jouanguy, Emmanuelle and Rice, Charles M and Cobat, Aurelie and Notarangelo, Luigi D and Abel, Laurent and Su, Helen C and Casanova, Jean-Laurent} } @article {903, title = {Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, 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.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Asymptomatic Infections, Betacoronavirus, Child, Child, Preschool, Coronavirus Infections, COVID-19, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Infant, Interferon Regulatory Factor-7, Interferon Type I, Loss of Function Mutation, Male, Middle Aged, Pandemics, Pneumonia, Viral, Receptor, Interferon alpha-beta, SARS-CoV-2, Toll-Like Receptor 3, Young Adult}, issn = {1095-9203}, doi = {10.1126/science.abd4570}, author = {Zhang, Qian and Bastard, Paul and Liu, Zhiyong and Le Pen, J{\'e}r{\'e}mie and Moncada-Velez, Marcela and Chen, Jie and Ogishi, Masato and Sabli, Ira K D and Hodeib, Stephanie and Korol, Cecilia and Rosain, J{\'e}r{\'e}mie and Bilguvar, Kaya and Ye, Junqiang and Bolze, Alexandre and Bigio, Benedetta and Yang, Rui and Arias, Andr{\'e}s Augusto and Zhou, Qinhua and Zhang, Yu and Onodi, Fanny and Korniotis, Sarantis and Karpf, L{\'e}a and Philippot, Quentin and Chbihi, Marwa and Bonnet-Madin, Lucie and Dorgham, Karim and Smith, Nika{\"\i}a and Schneider, William M and Razooky, Brandon S and Hoffmann, Hans-Heinrich and Michailidis, Eleftherios and Moens, Leen and Han, Ji Eun and Lorenzo, Lazaro and Bizien, Lucy and Meade, Philip and Neehus, Anna-Lena and Ugurbil, Aileen Camille and Corneau, Aur{\'e}lien and Kerner, Gaspard and Zhang, Peng and Rapaport, Franck and Seeleuthner, Yoann and Manry, Jeremy and Masson, Cecile and Schmitt, Yohann and Schluter, Agatha and Le Voyer, Tom and Khan, Taushif and Li, Juan and Fellay, Jacques and Roussel, Lucie and Shahrooei, Mohammad and Alosaimi, Mohammed F and Mansouri, Davood and Al-Saud, Haya and Al-Mulla, Fahd and Almourfi, Feras and Al-Muhsen, Saleh Zaid and Alsohime, FAHd and Al Turki, Saeed and Hasanato, Rana and van de Beek, Diederik and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio{\textquoteright}, Mariella and Bonfanti, Paolo and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Oler, Andrew J and Tompkins, Miranda F and Alba, Camille and Vandernoot, Isabelle and Goffard, Jean-Christophe and Smits, Guillaume and Migeotte, Isabelle and Haerynck, Filomeen and Soler-Palacin, Pere and Martin-Nalda, Andrea and Colobran, Roger and Morange, Pierre-Emmanuel and Keles, Sevgi and {\c C}{\"o}lkesen, Fatma and Ozcelik, Tayfun and Yasar, Kadriye Kart and Senoglu, Sevtap and Karabela, {\c S}emsi Nur and Rodr{\'\i}guez-Gallego, Carlos and Novelli, Giuseppe and Hraiech, Sami and Tandjaoui-Lambiotte, Yacine and Duval, Xavier and Laou{\'e}nan, C{\'e}dric and Snow, Andrew L and Dalgard, Clifton L and Milner, Joshua D and Vinh, Donald C and Mogensen, Trine H and Marr, Nico and Spaan, Andr{\'a}s N and Boisson, Bertrand and Boisson-Dupuis, St{\'e}phanie and Bustamante, Jacinta and Puel, Anne and Ciancanelli, Michael J and Meyts, Isabelle and Maniatis, Tom and Soumelis, Vassili and Amara, Ali and Nussenzweig, Michel and Garc{\'\i}a-Sastre, Adolfo and Krammer, Florian and Pujol, Aurora and Duffy, Darragh and Lifton, Richard P and Zhang, Shen-Ying and Gorochov, Guy and B{\'e}ziat, Vivien and Jouanguy, Emmanuelle and Sancho-Shimizu, Vanessa and Rice, Charles M and Abel, Laurent and Notarangelo, Luigi D and Cobat, Aurelie and Su, Helen C and Casanova, Jean-Laurent} } @article {844, title = {Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 10 12}, pages = {5139}, abstract = {

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

}, keywords = {Angiotensin-Converting Enzyme 2, Betacoronavirus, Child, Coronavirus Infections, COVID-19, Epithelial Cells, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Host-Pathogen Interactions, Humans, Inflammation, Interferons, Interleukin-13, Middle Aged, Nasal Mucosa, Pandemics, Peptidyl-Dipeptidase A, Pneumonia, Viral, SARS-CoV-2, Serine Endopeptidases, Virus Internalization}, issn = {2041-1723}, doi = {10.1038/s41467-020-18781-2}, author = {Sajuthi, Satria P and DeFord, Peter and Li, Yingchun and Jackson, Nathan D and Montgomery, Michael T and Everman, Jamie L and Rios, Cydney L and Pruesse, Elmar and Nolin, James D and Plender, Elizabeth G and Wechsler, Michael E and Mak, Angel C Y and Eng, Celeste and Salazar, Sandra and Medina, Vivian and Wohlford, Eric M and Huntsman, Scott and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Rice, Kenneth M and Kumar, Rajesh and Oh, Sam and Rodriguez-Santana, Jose and Burchard, Esteban G and Seibold, Max A} }