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 IFNγ in anti-viral immunity, particularly in the context of SARS-CoV-2. We have previously observed that lung infection with attenuated bacteria Mycobacterium 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 IFNγ response and low levels of IFNβ. Here we examined the role of ongoing IFNγ responses due to pre-established bacterial infection on SCV2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads and that this outcome is dependent on IFNγ receptor expression by non-hematopoietic cells. Further analysis revealed that BCG infection promotes the upregulation of interferon-stimulated genes (ISGs) with reported anti-viral activity by pneumocytes and bronchial epithelial cells in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirmed the importance of IFNγ 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 IFNγ response within the lung is protective against SCV2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SCV2 and supporting possible prophylactic uses of IFNγ in COVID-19 management. ### Competing Interest Statement The authors have declared no competing interest.