Human genetic and immunological determinants of critical COVID-19 pneumonia

Journal article : Review

SARS-CoV-2 infection is benign in most individuals but, in _˜10% of cases, it triggers hypoxemic COVID-19 pneumonia, which becomes critical in _˜3% of cases. The ensuing risk of death (_˜1%) doubles every five years from childhood onward and is _˜1.5 times greater in men than in women. What are the molecular and cellular determinants of critical COVID-19 pneumonia? Inborn errors of type I IFNs, including autosomal TLR3 and X-linked TLR7 deficiencies, are found in _˜1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing autoantibodies neutralizing IFN-α, -β, and/or -ω, which are more common in men than in women, are found in _˜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 apparently 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 defense 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.

Authors: Zhang, Q; Bastard, P; Cobat, A; Casanova, J-L; Constantinescu, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature
• Volume: 603
• Pages: 587–598
• Publication date: 2022-01-28
• Acceptance date: 2022-01-19
• DOI: 10.1038/s41586-022-04447-0
• EISSN: 1476-4687
• ISSN: 0028-0836
• Pmid: 35090163
• Language: English
• Keywords: COVID Human Genetic Effort; FFR
• Subtype: Review