Browsing by Author "Su, H. C."

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Open Access
Autoantibodies against type I IFNs in patients with life-threatening COVID-19
(2020) Bastard, P.; Rosen, L. B.; Zhang, Q.; Michailidis, E.; Hoffmann, H.-H.; Zhang, Y.; Dorgham, K.; Philippot, Q.; Rosain, J.; Béziat, V.; Manry, J.; Shaw, E.; Haljasmägi, L.; Peterson, P.; Lorenzo, L.; Bizien, L.; Trouillet-Assant, S.; Dobbs, K.; Almeida de Jesus, A.; Belot, A.; Kallaste, A.; Catherinot, E.; Tandjaoui-Lambiotte, Y.; Le Pen, J.; Kerner, G.; Bigio, B.; Seeleuthner, Y.; Yang, R.; Bolze, A.; Spaan, A. N.; Delmonte, O. M.; Abers, M. S.; Aiuti, A.; Casari, G.; Lampasona, V.; Piemonti, L.; Ciceri, F.; Bilguvar, K.; Lifton, R. P.; Vasse, M.; Smadja, D. M.; Migaud, M.; Hadjadj, J.; Terrier, B.; Duffy, D.; Quintana-Murci, L.; van de Beek, D.; Roussel, L.; Vinh, D. C.; Tangye, S. G.; Haerynck, F.; Dalmau, D.; Martinez-Picado, J.; Brodin, P.; Nussenzweig, M. C.; Boisson-Dupuis, S.; Rodríguez-Gallego, C.; Vogt, G.; Mogensen, T. H.; Oler, A. J.; Gu, J.; Burbelo, P. D.; Cohen, J. I.; Biondi, A.; Bettini, L. R.; D'Angio, M.; Bonfanti, P.; Rossignol, P.; Mayaux, J.; Rieux-Laucat, F.; Husebye, E. S.; Fusco, F.; Ursini, M. V.; Imberti, L.; Sottini, A.; Paghera, S.; Quiros-Roldan, E.; Rossi, C.; Castagnoli, R.; Montagna, D.; Özçelik, Tayfun; Licari, A.; Marseglia, G. L.; Duval, X.; Ghosn, J.; Tsang, J. S.; Goldbach-Mansky, R.; Kisand, K.; Lionakis, M. S.; Puel, A.; Zhang, S.- Y.; Holland, S. M.; Gorochov, G.; Jouanguy, E.; Rice, C. M.; Cobat, A.; Notarangelo, L. D.; Abel, L.; Su, H. C.; Casanova, J. L.; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort
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.
Open Access
Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths
(American Association for the Advancement of Science (AAAS), 2021-08-20) Bastard, P.; Gervais, A.; Le Voyer, T.; Rosain, J.; Philippot, Q.; Manry, J.; Michailidis, E.; Hoffmann, H. H.; Eto, S.; Garcia-Prat, M.; Bizien, L.; Parra-Martinez, A.; Yang, R.; Haljasmagi, L.; Migaud, M.; Sarekannu, K.; Maslovskaja, J.; de Prost, N.; Tandjaoui-Lambiotte, Y.; Luyt, C. E.; Amador-Borrero, B.; Gaudet, A.; Poissy, J.; Morel, P.; Richard, P.; Cognasse, F.; Troya, J.; Trouillet-Assant, S.; Belot, A.; Saker, K.; Garcon, P.; Riviere, J. G.; Lagier, J. C.; Gentile, S.; Rosen, L. B.; Shaw, E.; Morio, T.; Tanaka, J.; Dalmau, D.; Tharaux, PL.; Sene, D.; Stepanian, A.; Megarbane, B.; Triantafyllia, V.; Fekkar, A.; Heath, J. R.; Franco, JL.; Anaya, J. M.; Sole-Violan, J.; Imberti, L.; Biondi, A.; Bonfanti, P.; Castagnoli, R.; Delmonte, O. M.; Zhang, Y.; Snow, A. L.; Holland, S. M.; Biggs, C. M.; Moncada-Velez, M.; Arias, A. A.; Lorenzo, L.; Boucherit, S.; Coulibaly, B.; Anglicheau, D.; Planas, A. M.; Haerynck, F.; Duvlis, S.; Nussbaum, R. L.; Özçelik, Tayfun; Keles, S.; Bousfiha, A. A.; El Bakkouri, J.; Ramirez-Santana, C.; Paul, S.; Pan-Hammarstrom, Q.; Hammarstrom, L.; Dupont, A.; Kurolap, A.; Metz, CN.; Aiuti, A.; Casari, G.; Lampasona, V.; Ciceri, F.; Barreiros, L. A.; Dominguez-Garrido, E.; Vidigal, M.; Zatz, M.; van de Beek, D.; Sahanic, S.; Tancevski, I.; Stepanovskyy, Y.; Boyarchuk, O.; Nukui, Y.; Tsumura, M.; Vidaur, L.; Tangye, S. G.; Burrel, S.; Duffy, D.; Quintana-Murci, L.; Klocperk, A.; Kann, N. Y.; Shcherbina, A.; Lau, Y. L.; Leung, D.; Coulongeat, M.; Marlet, J.; Koning, R.; Reyes, L. F.; Chauvineau-Grenier, A.; Venet, F.; Monneret, G.; Nussenzweig, MC.; Arrestier, R.; Boudhabhay, I.; Baris-Feldman, H.; Hagin, D.; Wauters, J.; Meyts, I.; Dyer, A. H.; Kennelly, SP.; Bourke, N. M.; Halwani, R.; Sharif-Askari, N. S.; Dorgham, K.; Sallette, J.; Sedkaoui, S. M.; AlKhater, S.; Rigo-Bonnin, R.; Morandeira, F.; Roussel, L.; Vinh, DC.; Ostrowski, SR.; Condino-Neto, A.; Prando, C.; Bondarenko, A.; Spaan, A. N.; Gilardin, L.; Fellay, J.; Lyonnet, S.; Bilguvar, K.; Lifton, R. P.; Mane, S.; Anderson, M. S.; Boisson, B.; Beziat, V.; Zhang, SY.; Andreakos, E.; Hermine, O.; Pujol, A.; Peterson, P.; Mogensen, T. H.; Rowen, L.; Mond, J.; Debette, S.; de Lamballerie, X.; Duval, X.; Mentre, F.; Zins, M.; Soler-Palacin, P.; Colobran, R.; Gorochov, G.; Solanich, X.; Susen, S.; Martinez-Picado, J.; Raoult, D.; Vasse, M.; Gregersen, P. K.; Piemonti, L.; Rodriguez-Gallego, C.; Notarangelo, LD.; Su, H. C.; Kisand, K.; Okada, S.; Puel, A.; Jouanguy, E.; Rice, C. M.; Tiberghien, P.; Zhang, Q.; Cobat, A.; Abel, L.; Casanova, J. L.
Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.
Open Access
A global effort to define the human genetics of protective immunity to SARS-CoV-2 infection
(Elsevier, 2020) Casanova, J.-L.; Su, H. C.; Abel, L.; Aiuti, A.; Almuhsen, S.; Arias, A. A.; Bastard, P.; Biggs, C.; Bogunovic, D.; Boisson, B.; Boisson-Dupuis, S.; Bolze, A.; Bondarenko, A.; Bousfiha, A.; Brodin, P.; Bustamante, J.; Butte, M.; Casari, G.; Ciancanelli, M.; Cobat, A.; Condino-Neto, A.; Cooper, M.; Dalgard, C.; Espinosa, S.; Feldman, H.; Fellay, J.; Franco, J. L.; Hagin, D.; Itan, Y.; Jouanguy, E.; Lucas, C.; Mansouri, D.; Meyts, I.; Milner, J.; Mogensen, T.; Morio, T.; Ng, L.; Notarangelo, L. D.; Okada, S.; Özçelik, Tayfun; Palacín, P. S.; Planas, A.; Prando, C.; Puel, A.; Pujol, A.; Redin, C.; Renia, L.; Gallego, J. C. R.; Quintana-Murci, L.; Sancho-Shimizu, V.; Sankaran, V.; Seppänen, M. R. J.; Shahrooei, M.; Snow, A.; Spaan, A.; Tangye, S.; Tur, J. P.; Turvey, S.; Vinh, D. C.; von Bernuth, H.; Wang, X.; Zawadzki, P.; Zhang, Q.; Zhang, S.
SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers—individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease—present a unique opportunity to reveal human genetic determinants of infection and disease.
Open Access
Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children
(American Association for the Advancement of Science (AAAS), 2022-12-20) Lee, D.; Pen, J. L.; Yatim, A.; Dong, B.; Aquino, Y.; Ogishi, M.; Pescarmona, R.; Talouarn, E.; Rinchai, D.; Zhang, P.; Perret, M.; Liu, Z.; Jordan, L.; Bozdemir, S. E.; Bayhan, G. I.; Beaufils, C.; Bizien, L.; Bisiaux, A.; Lei, W.; Hasan, M.; Chen, J.; Gaughan, C.; Asthana, A.; Libri, V.; Luna, Joseph M.; Jaffré, Fabrice; Hoffmann, H.; Michailidis, E.; Moreews, M.; Seeleuthner, Y.; Bilguvar, K.; Mane, S.; Flores, C.; Zhang, Y.; Arias, A. A.; Bailey, R.; Schlüter, A.; Milisavljevic, B.; Bigio, B.; Voyer, T. L.; Materna, M.; Gervais, A.; Moncada-Velez, M.; Pala, F.; Lazarov, T.; Levy, R.; Neehus, A.; Rosain, J.; Peel, J.; Chan, Y.; Morin, M.; Pino-Ramirez, R. M.; Belkaya, Serkan; Lorenzo, L.; Anton, J.; Delafontaine, S.; Toubiana, J.; Bajolle, F.; Fumadó, V.; DeDiego, M. L.; Fidouh, N.; Rozenberg, F.; Pérez-Tur, J.; Chen, S.; Evans, T.; Geissmann, F.; Lebon, P.; Weiss, S. R.; Bonnet, D.; Duval, X.; Cohort§, C.; Effort, C.; Pan-Hammarström, Q.; Planas, A. M.; Meyts, I.; Haerynck, F.; Pujol, A.; Sancho-Shimizu, V.; Dalgard, C.; Bustamante, J.; Puel, A.; Boisson-Dupuis, S.; Boisson, B.; Maniatis, T.; Zhang, Q.; Bastard, P.; Notarangelo, L.; Béziat, V.; Diego, R.; Rodriguez-Gallego, C.; Su, H. C.; Lifton, R. P.; Jouanguy, E.; Cobat, A.; Alsina, L.; Keles, S.; Haddad, E.; Abel, L.; Belot, A.; Quintana-Murci, L.; Rice, C. M.; Silverman, R. H.; Zhang, S.; Casanova, J.
Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.
Open Access
The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies
(National Academy of Sciences, 2022-05-16) Manry, J.; Bastard, P.; Gervais, A.; Le Voyer, T.; Rosain, J.; Philippot, Q.; Michailidis, E.; Hoffmann, H.; Eto, S.; Garcia-Prat, M.; Bizien, L.; Parra-Martínez, A.; Yang, R.; Haljasmägi, L.; Migaud, M.; Särekannu, K.; Maslovskaja, J.; de Prost, N.; Tandjaoui-Lambiotte, Y.; Luyt, C.; Amador-Borrero, B.; Gaudet, A.; Poissy, J.; Morel, P.; Richard, P.; Cognasse, F.; Troya, J.; Trouillet-Assant, S.; Belot, A.; Saker, K.; Garçpn, P.; Rivière, J. G.; Lagier, J.; Gentile, S.; Rosen, L. B.; Shaw, E.; Morio, T.; Tanaka, J.; Dalmau, D.; Tharaux, P.; Sene, D.; Stepanian, A.; Mégarbane, B.; Triantafyllia, V.; Fekkar, A.; Heath, J. R.; Franco, J. L.; Anaya, J.; Solé-Violán, J.; Imberti, L.; Biondi, A.; Bonfanti, P.; Castagnoli, R.; Delmonte, O. M.; Zhang, Y.; Snow, A. L.; Holland, S. M.; Biggs, C. M.; Moncada-Vélez, M.; Arias, A. A.; Lorenzo, L.; Boucherit, S.; Anglicheau, D.; Planas, A. M.; Haerynck, F.; Duvlis, S.; Ozcelik, Tayfun; Keles, S.; Bousfiha, A. A.; El Bakkouri, J.; Ramirez-Santana, C.; Paul, S.; Pan-Hammarström, Q.; Hammarström, L.; Dupont, A.; Kurolap, A.; Metz, C. N.; Aiuti, A.; Casari, G.; Lampasona, V.; Ciceri, F.; Barreiros, L. A.; Dominguez-Garrido, E.; Vidigal, M.; Zatz, M.; van de Beek, D.; Sahanic, S.; Tancevski, I.; Stepanovskyy, Y.; Boyarchuk, O.; Nukui, Y.; Tsumura, M.; Vidaur, L.; Tangye, S. G.; Burrel, S.; Duffy, D.; Quintana-Murci, L.; Klocperk, A.; Kann, N. Y.; Shcherbina, A.; Lau, Y.; Leung, D.; Coulongeat, M.; Marlet, J.; Koning, R.; Reyes, L. F.; Chauvineau-Grenier, A.; Venet, F.; Monneret, G.; Nussenzweig, M. C.; Arrestier, R.; Boudhabhay, I.; Baris-Feldman, H.; Hagin, D.; Wauters, J.; Meyts, I.; Dyer, A. H.; Kennelly, S. P.; Bourke, N. M.; Halwani, R.; Sharif-Askari, F. S.; Dorgham, K.; Sallette, J.; Sedkaoui, S. M.; AlKhater, S.; Rigo-Bonnin, R.; Morandeira, F.; Roussel, L.; Vinh, D. C.; Erikstrup, C.; Condino-Neto, A.; Prando, C.; Bondarenko, A.; Spaan, A. N.; Gilardin, L.; Fellay, J.; Lyonnet, S.; Bilguvar, K.; Lifton, R. P.; Mane, S.; Anderson, M. S.; Boisson, B.; Béziat, V.; Zhang, S.; Andreakos, E.; Hermine, O.; Pujol, A.; Peterson, P.; Mogensen, T. H.; Rowen, L.; Mond, J.; Debette, S.; de Lamballerie, X.; Burdet, C.; Bouadma, L.; Zins, M.; Soler-Palacin, P.; Colobran, R.; Gorochov, G.; Solanich, X.; Susen, S.; Martinez-Picado, J.; Raoult, D.; Vasse, M.; Gregersen, P. K.; Piemonti, L.; Rodríguez-Gallego, C.; Notarangelo, L. D.; Su, H. C.; Kisand, K.; Okada, S.; Puel, A.; Jouanguy, E.; Rice, C. M.; Tiberghien, P.; Zhang, Q.; Casanova, J.; Abel, L.; Cobat, A.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged [removed]4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
Open Access
X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
(American Association for the Advancement of Science (AAAS), 2021-08-20) Asano, T.; Boisson, B.; Onodi, F.; Matuozzo, D.; Moncada-Velez, M.; Renkilaraj, M. R. L. M.; Zhang, P.; Meertens, L.; Bolze, A.; Materna, M.; Korniotis, S.; Gervais, A.; Talouarn, E.; Bigio, B.; Seeleuthner, Y.; Bilguvar, K.; Zhang, Y.; Neehus, AL.; Ogishi, M.; Pelham, SJ.; Le Voyer, T.; Rosain, J.; Philippot, Q.; Soler-Palacin, P.; Colobran, R.; Martin-Nalda, A.; Riviere, J. G.; Tandjaoui-Lambiotte, Y.; Chaibi, K.; Shahrooei, M.; Darazam, I. A.; Olyaei, NA.; Mansouri, D.; Palabiyik, F.; Özçelik, Tayfun; Novelli, G.; Novelli, A.; Casari, G.; Aiuti, A.; Carrera, P.; Bondesan, S.; Barzaghi, F.; Rovere-Querini, P.; Tresoldi, C.; Franco, J. L.; Rojas, J.; Reyes, LF.; Bustos, IG.; Arias, AA.; Morelle, G.; Kyheng, C.; Troya, J.; Planas-Serra, L.; Schluter, A.; Gut, M.; Pujol, A.; Allende, L. M.; Rodriguez-Gallego, C.; Flores, C.; Cabrera-Marante, O.; Pleguezuelo, DE.; de Diego, R. P.; Keles, S.; Aytekin, G.; Akcan, O. M.; Bryceson, Y. T.; Bergman, P.; Brodin, P.; Smole, D.; Smith, C. I. E.; Norlin, A. C.; Campbell, T. M.; Covill, LE.; Hammarstrom, L.; Pan-Hammarstrom, Q.; Abolhassani, H.; Mane, S.; Marr, N.; Ata, M.; Al Ali, F.; Khan, T.; Spaan, A. N.; Dalgard, C. L.; Bonfanti, P.; Biondi, A.; Tubiana, S.; Burdet, C.; Nussbaum, R.; Kahn-Kirby, A.; Snow, AL.; Bustamante, J.; Puel, A.; Boisson-Dupuis, S.; Zhang, S. Y.; Beziat, V.; Lifton, R. P.; Bastard, P.; Notarangelo, L. D.; Abel, L.; Su, H. C.; Jouanguy, E.; Amara, A.; Soumelis, V.; Cobat, A.; Zhang, Q.; Casanova, J. L.
Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean, 36.7 years) from a cohort of 1202 male patients aged 0.5 to 99 years (mean, 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean, 38.7 years) tested carry such TLR7 variants (P = 3.5 × 10−5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n = 2) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients from a cohort of 262 male patients with severe COVID-19 pneumonia (mean, 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is <6.5 × 10−4. We show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7. The patients’ blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.