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

Kerry L. Hilligan (), Sivaranjani Namasivayam, Chad S. Clancy, Paul J. Baker, Samuel I. Old, Victoria Peluf, Eduardo P. Amaral, Sandra D. Oland, Danielle O’Mard, Julie Laux, Melanie Cohen, Nicole L. Garza, Bernard A. P. Lafont, Reed F. Johnson, Carl G. Feng, Dragana Jankovic, Olivier Lamiable, Katrin D. Mayer-Barber and Alan Sher ()
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Kerry L. Hilligan: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Sivaranjani Namasivayam: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Chad S. Clancy: Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Paul J. Baker: Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Samuel I. Old: Malaghan Institute of Medical Research
Victoria Peluf: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Eduardo P. Amaral: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Sandra D. Oland: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Danielle O’Mard: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Julie Laux: Flow Cytometry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Melanie Cohen: Flow Cytometry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Nicole L. Garza: SARS-CoV2- Virology Core, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Bernard A. P. Lafont: SARS-CoV2- Virology Core, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Reed F. Johnson: SARS-CoV2- Virology Core, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Carl G. Feng: The University of Sydney
Dragana Jankovic: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Olivier Lamiable: Malaghan Institute of Medical Research
Katrin D. Mayer-Barber: Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Alan Sher: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-43447-0

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