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

Takaki Asano; Bertrand Boisson; Fanny Onodi; Daniela Matuozzo; Marcela Moncada-Velez; Majistor Raj Luxman Maglorius Renkilaraj; Peng Zhang; Laurent Meertens; Alexandre Bolze; Marie Materna; Sarantis Korniotis; Adrian Gervais; Estelle Talouarn; Benedetta Bigio; Yoann Seeleuthner; Kaya Bilguvar; Yu Zhang; Anna-Lena Neehus; Masato Ogishi; Simon J Pelham; Tom Le Voyer; Jérémie Rosain; Quentin Philippot; Pere Soler-Palacín; Roger Colobran; Andrea Martin-Nalda; Jacques G Rivière; Yacine Tandjaoui-Lambiotte; Khalil Chaïbi; Mohammad Shahrooei; Ilad Alavi Darazam; Nasrin Alipour Olyaei; Davood Mansouri; Nevin Hatipoğlu; Figen Palabiyik; Tayfun Ozcelik; Giuseppe Novelli; Antonio Novelli; Giorgio Casari; Alessandro Aiuti; Paola Carrera; Simone Bondesan; Federica Barzaghi; Patrizia Rovere-Querini; Cristina Tresoldi; Jose Luis Franco; Julian Rojas; Luis Felipe Reyes; Ingrid G Bustos; András N Spaan

doi:10.1126/sciimmunol.abl4348

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

Takaki Asano, Bertrand Boisson, Fanny Onodi, Daniela Matuozzo, Marcela Moncada-Velez, Majistor Raj Luxman Maglorius Renkilaraj, Peng Zhang, Laurent Meertens, Alexandre Bolze, Marie Materna, Sarantis Korniotis, Adrian Gervais, Estelle Talouarn, Benedetta Bigio, Yoann Seeleuthner, Kaya Bilguvar, Yu Zhang, Anna-Lena Neehus, Masato Ogishi, Simon J PelhamTom Le Voyer, Jérémie Rosain, Quentin Philippot, Pere Soler-Palacín, Roger Colobran, Andrea Martin-Nalda, Jacques G Rivière, Yacine Tandjaoui-Lambiotte, Khalil Chaïbi, Mohammad Shahrooei, Ilad Alavi Darazam, Nasrin Alipour Olyaei, Davood Mansouri, Nevin Hatipoğlu, Figen Palabiyik, Tayfun Ozcelik, Giuseppe Novelli, Antonio Novelli, Giorgio Casari, Alessandro Aiuti, Paola Carrera, Simone Bondesan, Federica Barzaghi, Patrizia Rovere-Querini, Cristina Tresoldi, Jose Luis Franco, Julian Rojas, Luis Felipe Reyes, Ingrid G Bustos, András N Spaan,

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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 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 × 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 × 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.

Original language	English
Article number	eabl4348
Journal	Science Immunology
Volume	6
Issue number	62
DOIs	https://doi.org/10.1126/sciimmunol.abl4348
Publication status	Published - 19 Aug 2021

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Alleles
COVID-19/complications
Child
Child, Preschool
Genetic Diseases, X-Linked/complications
Humans
Immune System Diseases/complications
Infant
Male
Middle Aged
Pedigree
Penetrance
Toll-Like Receptor 7/deficiency
Young Adult

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Asano, T., Boisson, B., Onodi, F., Matuozzo, D., Moncada-Velez, M., Maglorius Renkilaraj, M. R. L., Zhang, P., Meertens, L., Bolze, A., Materna, M., Korniotis, S., Gervais, A., Talouarn, E., Bigio, B., Seeleuthner, Y., Bilguvar, K., Zhang, Y., Neehus, A.-L., Ogishi, M. (2021). X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19. Science Immunology, 6(62), Article eabl4348. https://doi.org/10.1126/sciimmunol.abl4348

@article{56048817160f499788a8df0bd14d3526,

title = "X-linked recessive TLR7 deficiency in \textasciitilde{}1\% of men under 60 years old with life-threatening COVID-19",

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 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 × 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 × 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{\textquoteright} 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.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Alleles, COVID-19/complications, Child, Child, Preschool, Genetic Diseases, X-Linked/complications, Humans, Immune System Diseases/complications, Infant, Male, Middle Aged, Pedigree, Penetrance, Toll-Like Receptor 7/deficiency, Young Adult",

author = "Takaki Asano and Bertrand Boisson and Fanny Onodi and Daniela Matuozzo and Marcela Moncada-Velez and \{Maglorius Renkilaraj\}, \{Majistor Raj Luxman\} and Peng Zhang and Laurent Meertens and Alexandre Bolze and Marie Materna and Sarantis Korniotis and Adrian Gervais and Estelle Talouarn and Benedetta Bigio and Yoann Seeleuthner and Kaya Bilguvar and Yu Zhang and Anna-Lena Neehus and Masato Ogishi and Pelham, \{Simon J\} and \{Le Voyer\}, Tom and J{\'e}r{\'e}mie Rosain and Quentin Philippot and Pere Soler-Palac{\'i}n and Roger Colobran and Andrea Martin-Nalda and Rivi{\`e}re, \{Jacques G\} and Yacine Tandjaoui-Lambiotte and Khalil Cha{\"i}bi and Mohammad Shahrooei and Darazam, \{Ilad Alavi\} and Olyaei, \{Nasrin Alipour\} and Davood Mansouri and Nevin Hatipoğlu and Figen Palabiyik and Tayfun Ozcelik and Giuseppe Novelli and Antonio Novelli and Giorgio Casari and Alessandro Aiuti and Paola Carrera and Simone Bondesan and Federica Barzaghi and Patrizia Rovere-Querini and Cristina Tresoldi and Franco, \{Jose Luis\} and Julian Rojas and Reyes, \{Luis Felipe\} and Bustos, \{Ingrid G\} and Spaan, \{Andr{\'a}s N\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021",

year = "2021",

month = aug,

day = "19",

doi = "10.1126/sciimmunol.abl4348",

language = "English",

volume = "6",

number = "62",

}

Asano, T, Boisson, B, Onodi, F, Matuozzo, D, Moncada-Velez, M, Maglorius Renkilaraj, MRL, Zhang, P, Meertens, L, Bolze, A, Materna, M, Korniotis, S, Gervais, A, Talouarn, E, Bigio, B, Seeleuthner, Y, Bilguvar, K, Zhang, Y, Neehus, A-L, Ogishi, M, Pelham, SJ, Le Voyer, T, Rosain, J, Philippot, Q, Soler-Palacín, P, Colobran, R, Martin-Nalda, A, Rivière, JG, Tandjaoui-Lambiotte, Y, Chaïbi, K, Shahrooei, M, Darazam, IA, Olyaei, NA, Mansouri, D, Hatipoğlu, N, Palabiyik, F, Ozcelik, T, Novelli, G, Novelli, A, Casari, G, Aiuti, A, Carrera, P, Bondesan, S, Barzaghi, F, Rovere-Querini, P, Tresoldi, C, Franco, JL, Rojas, J, Reyes, LF, Bustos, IG, Spaan, AN 2021, 'X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19', Science Immunology, vol. 6, no. 62, eabl4348. https://doi.org/10.1126/sciimmunol.abl4348

TY - JOUR

T1 - X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

AU - Asano, Takaki

AU - Boisson, Bertrand

AU - Onodi, Fanny

AU - Matuozzo, Daniela

AU - Moncada-Velez, Marcela

AU - Maglorius Renkilaraj, Majistor Raj Luxman

AU - Zhang, Peng

AU - Meertens, Laurent

AU - Bolze, Alexandre

AU - Materna, Marie

AU - Korniotis, Sarantis

AU - Gervais, Adrian

AU - Talouarn, Estelle

AU - Bigio, Benedetta

AU - Seeleuthner, Yoann

AU - Bilguvar, Kaya

AU - Zhang, Yu

AU - Neehus, Anna-Lena

AU - Ogishi, Masato

AU - Pelham, Simon J

AU - Le Voyer, Tom

AU - Rosain, Jérémie

AU - Philippot, Quentin

AU - Soler-Palacín, Pere

AU - Colobran, Roger

AU - Martin-Nalda, Andrea

AU - Rivière, Jacques G

AU - Tandjaoui-Lambiotte, Yacine

AU - Chaïbi, Khalil

AU - Shahrooei, Mohammad

AU - Darazam, Ilad Alavi

AU - Olyaei, Nasrin Alipour

AU - Mansouri, Davood

AU - Hatipoğlu, Nevin

AU - Palabiyik, Figen

AU - Ozcelik, Tayfun

AU - Novelli, Giuseppe

AU - Novelli, Antonio

AU - Casari, Giorgio

AU - Aiuti, Alessandro

AU - Carrera, Paola

AU - Bondesan, Simone

AU - Barzaghi, Federica

AU - Rovere-Querini, Patrizia

AU - Tresoldi, Cristina

AU - Franco, Jose Luis

AU - Rojas, Julian

AU - Reyes, Luis Felipe

AU - Bustos, Ingrid G

AU - Spaan, András N

PY - 2021/8/19

Y1 - 2021/8/19

N2 - 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 × 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 × 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.

AB - 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 × 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 × 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - COVID-19/complications

KW - Child

KW - Child, Preschool

KW - Genetic Diseases, X-Linked/complications

KW - Humans

KW - Immune System Diseases/complications

KW - Infant

KW - Male

KW - Middle Aged

KW - Pedigree

KW - Penetrance

KW - Toll-Like Receptor 7/deficiency

KW - Young Adult

UR - https://www.scopus.com/pages/publications/85113561257

U2 - 10.1126/sciimmunol.abl4348

DO - 10.1126/sciimmunol.abl4348

M3 - Article

C2 - 34413140

VL - 6

JO - Science Immunology

JF - Science Immunology

IS - 62

M1 - eabl4348

ER -

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

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