X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Asano, Takaki; Boisson, Bertrand; Onodi, Fanny; Matuozzo, Daniela; Moncada-Velez, Marcela; Maglorius Renkilaraj, Majistor Raj Luxman; Zhang, Peng; Meertens, Laurent; Bolze, Alexandre; Materna, Marie; Korniotis, Sarantis; Gervais, Adrian; Talouarn, Estelle; Bigio, Benedetta; Seeleuthner, Yoann; Bilguvar, Kaya; Zhang, Yu; Neehus, Anna-Lena; Ogishi, Masato; Pelham, Simon J; Le Voyer, Tom; Rosain, Jérémie; Philippot, Quentin; Soler-Palacín, Pere; Colobran, Roger; Martin-Nalda, Andrea; Rivière, Jacques G; Tandjaoui-Lambiotte, Yacine; Chaïbi, Khalil; Shahrooei, Mohammad; Darazam, Ilad Alavi; Olyaei, Nasrin Alipour; Mansouri, Davood; Hatipoglu, Nevin; Palabiyik, Figen; Ozcelik, Tayfun; Novelli, Giuseppe; Novelli, Antonio; Casari, Giorgio; Aiuti, Alessandro; Carrera, Paola; Bondesan, Simone; Barzaghi, Federica; Rovere-Querini, Patrizia; Tresoldi, Cristina; Franco, Jose Luis; Rojas, Julian; Reyes, Luis Felipe; Bustos, Ingrid G; Arias, Andres Augusto

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 1,202 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, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) 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 < 6.5x10-4 We also 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.