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 x 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 x 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.
