Pre-existing interferon gamma conditions the lung to mediate early control of SARS-CoV-2

Interferons (IFNs) are critical for anti-viral host defence. Type-1 and type-3 IFNs are typically associated with early control of viral replication and promotion of inflammatory immune responses; however, less is known about the role of IFN? in anti-viral immunity, particularly in the context of SARS-CoV-2. We have previously observed that lung infection with attenuated bacteria M. bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 (SCV2) infection and disease in two mouse models. Assessment of the pulmonary cytokine milieu revealed that iv BCG induces a robust IFN? response and low levels of IFNß. Here we examined the role of ongoing IFN? responses due to concurrent bacterial infection on SCV2 disease outcomes in two murine models. We report that IFN? is required for iv BCG induced reduction in pulmonary viral loads and that this outcome is dependent on IFN? receptor expression by non-hematopoietic cells. Further analysis revealed that BCG infection promotes the upregulation of ISGs with reported anti-viral activity by pneumocytes and bronchial epithelial cells in an IFN? dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirmed the importance of IFN? in these anti-viral effects by demonstrating that the recombinant cytokine itself provides strong protection against SCV2 challenge when administered intranasally. Together, our data show that a pre-established IFN? response within the lung is protective against SCV2 infection, suggesting that concurrent or recent infections that drive IFN? may limit the pathogenesis of this virus and supporting possible prophylactic uses of this cytokine in COVID-19 management. Overall design: PBS iv, BCG iv inoculated mice as well as each group administred anti-IFN? were infected with SARS-CoV-2 via the intra-nasal route. Lungs were harvested from the mice 3 days post infection and single cell suspenions were generated for scRNAseq analysis