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Human genetic and immunological determinants of critical COVID-19 pneumonia

Author

Listed:
  • Qian Zhang

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute)

  • Paul Bastard

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute
    Necker Hospital for Sick Children)

  • Aurélie Cobat

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute)

  • Jean-Laurent Casanova

    (The Rockefeller University
    Necker Hospital for Sick Children
    Imagine Institute
    Necker Hospital for Sick Children)

Abstract

SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1–5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15–20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation.

Suggested Citation

  • Qian Zhang & Paul Bastard & Aurélie Cobat & Jean-Laurent Casanova, 2022. "Human genetic and immunological determinants of critical COVID-19 pneumonia," Nature, Nature, vol. 603(7902), pages 587-598, March.
  • Handle: RePEc:nat:nature:v:603:y:2022:i:7902:d:10.1038_s41586-022-04447-0
    DOI: 10.1038/s41586-022-04447-0
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    References listed on IDEAS

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    1. Sen Pei & Teresa K. Yamana & Sasikiran Kandula & Marta Galanti & Jeffrey Shaman, 2021. "Burden and characteristics of COVID-19 in the United States during 2020," Nature, Nature, vol. 598(7880), pages 338-341, October.
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    1. Ilya Tsukalov & Ildefonso Sánchez-Cerrillo & Olga Rajas & Elena Avalos & Gorane Iturricastillo & Laura Esparcia & María José Buzón & Meritxell Genescà & Camila Scagnetti & Olga Popova & Noa Martin-Cóf, 2024. "NFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Matthew C. Woodruff & Kevin S. Bonham & Fabliha A. Anam & Tiffany A. Walker & Caterina E. Faliti & Yusho Ishii & Candice Y. Kaminski & Martin C. Ruunstrom & Kelly Rose Cooper & Alexander D. Truong & A, 2023. "Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Manon Venet & Margarida Sa Ribeiro & Elodie Décembre & Alicia Bellomo & Garima Joshi & Célia Nuovo & Marine Villard & David Cluet & Magali Perret & Rémi Pescamona & Helena Paidassi & Thierry Walzer & , 2023. "Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    4. Sunil K. Ahuja & Muthu Saravanan Manoharan & Grace C. Lee & Lyle R. McKinnon & Justin A. Meunier & Maristella Steri & Nathan Harper & Edoardo Fiorillo & Alisha M. Smith & Marcos I. Restrepo & Anne P. , 2023. "Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection," Nature Communications, Nature, vol. 14(1), pages 1-31, December.
    5. Hideki Ogura & Jin Gohda & Xiuyuan Lu & Mizuki Yamamoto & Yoshio Takesue & Aoi Son & Sadayuki Doi & Kazuyuki Matsushita & Fumitaka Isobe & Yoshihiro Fukuda & Tai-Ping Huang & Takamasa Ueno & Naomi Mam, 2022. "Dysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Nikaïa Smith & Céline Possémé & Vincent Bondet & Jamie Sugrue & Liam Townsend & Bruno Charbit & Vincent Rouilly & Violaine Saint-André & Tom Dott & Andre Rodriguez Pozo & Nader Yatim & Olivier Schwart, 2022. "Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Al Ozonoff & Naresh Doni Jayavelu & Shanshan Liu & Esther Melamed & Carly E. Milliren & Jingjing Qi & Linda N. Geng & Grace A. McComsey & Charles B. Cairns & Lindsey R. Baden & Joanna Schaenman & Albe, 2024. "Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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