: 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.

Asano, T., Boisson, B., Onodi, F., Matuozzo, D., Moncada-Velez, M., Maglorius Renkilaraj, M., et al. (2021). X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19. SCIENCE IMMUNOLOGY, 6(62) [10.1126/sciimmunol.abl4348].

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

Novelli, Giuseppe
Investigation
;
Aiuti, Alessandro;Barzaghi, Federica;Biondi, Andrea;
2021-08-01

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.
ago-2021
Pubblicato
Rilevanza internazionale
Articolo
Esperti non anonimi
Settore MED/03 - GENETICA MEDICA
English
Adolescent
Adult
Aged
Aged, 80 and over
Alleles
COVID-19
Child
Child, Preschool
Genetic Diseases, X-Linked
Humans
Immune System Diseases
Infant
Male
Middle Aged
Pedigree
Penetrance
Toll-Like Receptor 7
Young Adult
Asano, T., Boisson, B., Onodi, F., Matuozzo, D., Moncada-Velez, M., Maglorius Renkilaraj, M., et al. (2021). X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19. SCIENCE IMMUNOLOGY, 6(62) [10.1126/sciimmunol.abl4348].
Asano, T; Boisson, B; Onodi, F; Matuozzo, D; Moncada-Velez, M; Maglorius Renkilaraj, Mrl; Zhang, P; Meertens, L; Bolze, A; Materna, M; Korniotis, S; G...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/294684
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