Abstract
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.
Highlights
Interindividual clinical variability in the course of SARS-CoV-2 infection is vast, ranging from silent infection to lethal disease [1]
The same analysis performed on very rare (MAF
As plasmacytoid dendritic cells (pDCs) are normally the main leukocytes producing type I IFN in such conditions, and type I IFN is essential for protective immunity to SARS-CoV-2 [8, 9], these findings suggest that Xlinked recessive (XR) TLR7 deficiency underlies critical or severe COVID-19 pneumonia by disrupting TLR7-and pDC-dependent type I IFN production
Summary
Interindividual clinical variability in the course of SARS-CoV-2 infection is vast, ranging from silent infection to lethal disease [1]. We previously tested the hypothesis that critical influenza and critical COVID-19 can be allelic [5,6,7], and showed that lifethreatening COVID-19 pneumonia can be caused by rare immunology.sciencemag.org (Page numbers not final at time of first release) 2 inborn errors of autosomal genes controlling TLR3- and IRF7-dependent type I interferon (IFN) immunity [8] These disorders were found in 23 men and women aged 17 to 77 years (mean: 48 years). These patients had no previous history of severe viral illness, including influenza pneumonia, implying that these genetic disorders unexpectedly show incomplete penetrance for critical influenza These findings revealed that TLR3- and IRF7-dependent type I IFN immunity is essential for host defense against SARS-CoV-2 infection in the respiratory tract
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