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 IFN{gamma} 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 IFN{gamma} response and low levels of IFN{beta}. Here we examined the role of ongoing IFN{gamma} responses due to pre-established bacterial infection on SCV2 disease outcomes in two murine models. We report that IFN{gamma} is required for iv BCG induced reduction in pulmonary viral loads and that this outcome is dependent on IFN{gamma} 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 IFN{gamma}-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirmed the importance of IFN{gamma} 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{gamma} response within the lung is protective against SCV2 infection, suggesting that concurrent or recent infections that drive IFN{gamma} may limit the pathogenesis of SCV2 and supporting possible prophylactic uses of IFN{gamma} in COVID-19 management.
Subject(s)
COVID-19 , Severe Acute Respiratory Syndrome , Lung Diseases , Bacterial InfectionsABSTRACT
Despite signs of infection, the involvement of the oral cavity in COVID-19 is poorly understood. To address this, single-cell RNA sequencing datasets were integrated from human minor salivary glands and gingiva to identify 11 epithelial, 7 mesenchymal, and 15 immune cell clusters. Analysis of SARS-CoV-2 viral entry factor expression showed enrichment in epithelia including the ducts and acini of the salivary glands and the suprabasal cells of the mucosae. COVID-19 autopsy tissues confirmed in vivo SARS CoV-2 infection in the salivary glands and mucosa. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 expression and SARS-CoV-2 RNA. Matched nasopharyngeal and saliva samples found distinct viral shedding dynamics and viral burden in saliva correlated with COVID-19 symptoms including taste loss. Upon recovery, this cohort exhibited salivary antibodies against SARS-CoV-2 proteins. Collectively, the oral cavity represents a robust site for COVID-19 infection andimplicates saliva in viral transmission.