Nasally delivered interferon-λ protects mice against infection by SARS-CoV-2 variants including Omicron

• Published in: Cell reports (Cambridge) Vol. 39; no. 6; p. 110799
• Main Authors: Chong, Zhenlu, Karl, Courtney E., Halfmann, Peter J., Kawaoka, Yoshihiro, Winkler, Emma S., Keeler, Shamus P., Holtzman, Michael J., Yu, Jinsheng, Diamond, Michael S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.05.2022; The Authors
• Subjects: Animals; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; COVID-19 - prevention & control; COVID-19 Drug Treatment; Humans; immunity; interferon; Interferons; Mice; Mice, Transgenic; omicron; pathogenesis; RNA sequencing; SARS-CoV-2; therapy; RNA sequencing; CP: Immunology; pathogenesis; SARS-CoV-2; omicron; therapy; CP: Microbiology; immunity; interferon
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110799

Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, variants with constellations of mutations in the spike gene jeopardize their efficacy. Accordingly, antiviral interventions that are resistant to further virus evolution are needed. The host-derived cytokine interferon lambda (IFN-λ) has been proposed as a possible treatment based on studies in human coronavirus 2019 (COVID-19) patients. Here, we show that IFN-λ protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1.529 (Omicron) variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally delivered IFN-λ2 limits infection of historical or variant SARS-CoV-2 strains in the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-λ is produced preferentially in epithelial cells and acts on radio-resistant cells to protect against SARS-CoV-2 infection. Thus, inhaled IFN-λ may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures. [Display omitted] •IFN-λ protects mice against SARS-CoV-2 B.1.351- and B.1.1.529-variant infections•IFN-λ selectively induces antiviral genes without causing excess inflammation•IFN-λ is produced by lung epithelial cells via Mavs and Myd88 signaling pathways•Stromal cells mediate the antiviral effect of IFN-λ during SARS-CoV-2 infection Chong et al. show that intranasally delivered murine IFN-λ2 protects mice against historical, B.1.351 (Beta), and B.1.1.529 (Omicron) SARS-CoV-2 infection in the upper and lower respiratory tracts without excessive inflammation. In the lung, IFN-λ is produced mainly by epithelial cells and acts on stromal cells to protect against of SARS-CoV-2 infection.