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

Severe 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 SARS-CoV-2. In contrast, compared to subjects with other infectious or non-infectious lung pathologies, IFNs are over-represented 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. Overall design: For targeted transcriptome sequencing, RNA (15ng) isolated from nasopharingeal swabs and bronchio alveolar lavage fluid (as desceibed below) was retro-transcribed to cDNA using SuperScript VILO cDNA Synthesis Kit (11754-05, Thermo Fisher). Barcoded libraries were prepared using the Ion AmpliSeq Transcriptome Human Gene Expression Kit (A26325, Thermo Fisher) as per the manufacturer's protocol and sequenced using an Ion S5 system (A27212, Thermo Fisher). Differential gene expression analysis was performed using the Transcriptome Analysis Console (TAC) software with the ampliSeqRNA plugin (ThermoFisher Scientific).