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

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 (IFN gamma) 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 IFN gamma. Here we examine the role of ongoing IFN gamma responses to pre-established bacterial infection on SARS-CoV-2 disease outcomes in two murine models. We report that IFN gamma is required for iv BCG induced reduction in pulmonary viral loads, an outcome dependent on IFN gamma 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 IFN gamma-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirm the anti-viral properties of IFN gamma 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 IFN gamma response within the lung is protective against SARS-CoV-2 infection, suggesting that concurrent or recent infections that drive IFN gamma may limit the pathogenesis of SARS-CoV-2 and supporting possible prophylactic uses of IFN gamma in COVID-19 management. The role of interferon-gamma (IFN gamma) in anti-viral immunity has been unclear. Here the authors show that bacterial-induced or intranasally administered IFN gamma effectively restricts SARS-CoV-2 infection in mice through effects on non-hematopoietic cells.