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

Abstract

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.

BCG mediated protection of the lung against experimental SARS-CoV-2 infection

“…At 42 days following BCG administration, the virus challenged mice showed a striking protection from SCV2 induced weight loss and mortality along with pronounced reductions in pulmonary viral loads at 5 days post infection. This protection was still evident 112 days following BCG inoculation but at lower levels (33). To confirm that the COVID-19 resistance induced by IV BCG is not peculiar to hACE2 transgenic mice, the experiments were repeated using a second model in which wild type C57BL/6 mice were challenged with the more virulent B.1.1.7 SCV2 variant.…”

“…The hypothesis that prior BCG vaccination might offer protection against COVID-19 prompted a series of studies in different animal models to examine the effects of prior BCG administration on resistance to SCV2 challenge (Table 2). This work has generated a consensus that when inoculated by the conventional ID (or subcutaneous) route to mice (33,(35)(36)(37) or hamsters (35,38) or by aerosol to monkeys (39), BCG fails to trigger significant protection against intranasal or intra-bronchial infection with the virus. Nevertheless, a number of independent studies have shown that when administered by the IV route to mice or hamsters, BCG can confer high levels of resistance to both SCV2 infection and disease (Table 2) (33,34,38,40,41).…”

“…This work has generated a consensus that when inoculated by the conventional ID (or subcutaneous) route to mice (33,(35)(36)(37) or hamsters (35,38) or by aerosol to monkeys (39), BCG fails to trigger significant protection against intranasal or intra-bronchial infection with the virus. Nevertheless, a number of independent studies have shown that when administered by the IV route to mice or hamsters, BCG can confer high levels of resistance to both SCV2 infection and disease (Table 2) (33,34,38,40,41). In the initial description of this effect, K18 transgenic mice which express the human ACE2 receptor (K18-hACE2) for the virus were IV inoculated with BCG (Pasteur strain) before intranasal SCV2 infection with a lethal dose of the WA/2020 strain (33).…”

“…Nevertheless, a number of independent studies have shown that when administered by the IV route to mice or hamsters, BCG can confer high levels of resistance to both SCV2 infection and disease (Table 2) (33,34,38,40,41). In the initial description of this effect, K18 transgenic mice which express the human ACE2 receptor (K18-hACE2) for the virus were IV inoculated with BCG (Pasteur strain) before intranasal SCV2 infection with a lethal dose of the WA/2020 strain (33). At 42 days following BCG administration, the virus challenged mice showed a striking protection from SCV2 induced weight loss and mortality along with pronounced reductions in pulmonary viral loads at 5 days post infection.…”

Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors

“…Transcriptomic studies in monocytes from individuals inoculated with BCG have revealed long-lasting (more than 3 months) changes in the expression of cytokine (IL1B, IL6, TNF) and chemokine (CXCL9, CCL2, CCL3, CCL4) genes, among many others [63,64], that are inferred to allow the body to react more swiftly to new infections. In normal human volunteers given BCG before an attenuated yellow fever virus vaccine strain, the key correlate of the rise in antiviral titers was IL-1␤ [52], whereas heightened IFN-␥ production was implicated in BCG-induced protection against SARS-CoV-2 [65].…”