Bacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2

• Published in: Nature communications Vol. 14; no. 1; pp. 8229 - 16
• Main Authors: Hilligan, Kerry L., Namasivayam, Sivaranjani, Clancy, Chad S., Baker, Paul J., Old, Samuel I., Peluf, Victoria, Amaral, Eduardo P., Oland, Sandra D., O’Mard, Danielle, Laux, Julie, Cohen, Melanie, Garza, Nicole L., Lafont, Bernard A. P., Johnson, Reed F., Feng, Carl G., Jankovic, Dragana, Lamiable, Olivier, Mayer-Barber, Katrin D., Sher, Alan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.12.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/21; 13/31; 14/63; 38/32; 38/91; 631/250/127/1212; 631/326/596/2553; 631/326/596/4130; 64/60; Animal models; Animals; Antiviral agents; Bacteria; Bacterial diseases; Bacterial infections; Bronchopulmonary infection; COVID-19; COVID-19 - prevention & control; Epithelial cells; Epithelium; Hematopoietic stem cells; Humanities and Social Sciences; Immunity; Infections; Interferon; Interferon Type I - pharmacology; Interferon-gamma; Lung; Lungs; Mice; multidisciplinary; Pathogenesis; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Viral diseases; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43447-0

Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role of Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that lung infection with Mycobacterium bovis BCG achieved though intravenous ( iv ) administration provides strong protection against SARS-CoV-2 in mice yet drives low levels of type-1 IFNs but robust IFNγ. Here we examine the role of ongoing IFNγ responses to pre-established bacterial infection on SARS-CoV-2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads, an outcome dependent on IFNγ receptor expression by non-hematopoietic cells. Importantly, we show that BCG infection prompts pulmonary epithelial cells to upregulate IFN-stimulated genes with reported anti-viral activity in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirm the anti-viral properties of IFNγ by demonstrating that the recombinant cytokine itself provides strong protection against SARS-CoV-2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SARS-CoV-2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SARS-CoV-2 and supporting possible prophylactic uses of IFNγ in COVID-19 management. The role of interferon-γ (IFNγ) in anti-viral immunity has been unclear. Here the authors show that bacterial-induced or intranasally administered IFNγ effectively restricts SARS-CoV-2 infection in mice through effects on non-hematopoietic cells.