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 < 6.5×10 −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. One Sentence Summary: TLR7 and plasmacytoid dendritic cells are essential for type I IFN-dependent immunity to SARS-CoV-2 in the lungs.
【초록키워드】 COVID-19, SARS-CoV-2, Severe COVID-19 pneumonia, Immunity, Pneumonia, Human, allele frequency, variant, TLR7, cytokine, pDCs, Cohort, Asymptomatic, Lungs, male, Patient, phenotype, age, respiratory tract, General population, Critical, moderate, Blood, Protective, mild infection, B-cell, Deleterious, index case, Type I IFN, autoantibody, deficiency, type I, pneumonia cases, individual, wild-type, cumulative, myeloid cell, genetic etiology, FIVE, X-linked, tested, include, the patient, biochemically, subset, respond, rescued, underlie, infected with SARS-CoV-2, pDC, plasmacytoid dendritic cell, 【제목키워드】 COVID-19, TLR7, deficiency, life-threatening, men, X-linked,