Human TLR7 and plasmacytoid dendritic cells are essential for type I IFN pulmonary immunity to SARS-CoV-2

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 14 unrelated male individuals aged 13 to 71 years (mean: 36.7 years) from a cohort of 1,005 male individuals aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 326 asymptomatically infected male individuals aged 1.3 to 102 years (mean: 41.1 years) tested carried such TLR7 variants (p = 6x10-6). The cumulative allele frequency for deleterious TLR7 variants in the male general population was < 6.5x10-4. We also found that blood lymphoid cell lines and myeloid cell subsets from the patients failed to respond to TLR7 stimulation, a phenotype rescued with wild-type TLR7. Finally, the patients' blood plasmacytoid dendritic cells (pDCs) produced low levels of type I IFNs in response to SARS-CoV-2. X-linked recessive TLR7 deficiency is a genetic etiology of life-threatening COVID-19 pneumonia in about 1.6% of male patients below the age of 70 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the lungs.