The interferon landscape along the respiratory tract impacts the severity of COVID-19

• Published in: Cell Vol. 184; no. 19; pp. 4953 - 4968.e16
• Main Authors: Sposito, Benedetta, Broggi, Achille, Pandolfi, Laura, Crotta, Stefania, Clementi, Nicola, Ferrarese, Roberto, Sisti, Sofia, Criscuolo, Elena, Spreafico, Roberto, Long, Jaclyn M., Ambrosi, Alessandro, Liu, Enju, Frangipane, Vanessa, Saracino, Laura, Bozzini, Sara, Marongiu, Laura, Facchini, Fabio A., Bottazzi, Andrea, Fossali, Tommaso, Colombo, Riccardo, Clementi, Massimo, Tagliabue, Elena, Chou, Janet, Pontiroli, Antonio E., Meloni, Federica, Wack, Andreas, Mancini, Nicasio, Zanoni, Ivan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.09.2021; Elsevier; Cell Press
• Subjects: Age Factors; Aging - pathology; airways; apoptosis; COVID-19; COVID-19 - genetics; COVID-19 - immunology; COVID-19 - pathology; COVID-19 infection; dendritic cell; epithelial cell; Epithelial Cells - pathology; Epithelial Cells - virology; Gene Expression Regulation; genes; Humans; interferon; interferons; Interferons - genetics; Interferons - metabolism; landscapes; Leukocytes - pathology; Leukocytes - virology; Life Sciences; lung; Lung - pathology; Lung - virology; lungs; pattern recognition receptor; Respiratory Distress Syndrome - pathology; Respiratory Distress Syndrome - virology; Respiratory System - virology; risk; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Severity of Illness Index; Type I IFN; Type III IFN; Viral Load; COVID-19; lung; Type III IFN; SARS-CoV-2; airways; interferon; epithelial cell; Type I IFN; dendritic cell; pattern recognition receptor
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2021.08.016

Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites. [Display omitted] •IFN expression in COVID-19 varies based on location, viral load, age, and severity•IFN-λ1 and IFN-λ3 drive protective ISGs in the upper airways of mildly ill patients•Critical patients express IFN-αβ and IFN-λ2 and have low ISGs and high p53 expression•Epithelial cells efficiently produce protective IFN-λ1, while cDCs express IFN-λ2,3 An in-depth analysis of IFNs in COVID-19 reveals differences in their roles based on anatomical location, viral load, age, and disease severity. In the upper respiratory tract, high levels of IFN-III are protective and result in mild disease in spite of higher SARS-CoV-2 viral burden, while the lower airways of patients with severe COVID-19 demonstrate elevated IFN-I and IFN-III, cell death, and a reduction in IFN-stimulated genes.