TNF-α exacerbates SARS-CoV-2 infection by stimulating CXCL1 production from macrophages

Since most genetically modified mice are C57BL/6 background, a mouse-adapted SARS-CoV-2 that causes lethal infection in young C57BL/6 mice is useful for studying innate immune protection against SARS-CoV-2 infection. Here, we established two mouse-adapted SARS-CoV-2, ancestral and Delta variants, by serial passaging 80 times in C57BL/6 mice. Although young C57BL/6 mice were resistant to infection with the mouse-adapted ancestral SARS-CoV-2, the mouse-adapted SARS-CoV-2 Delta variant caused lethal infection in young C57BL/6 mice. In contrast, MyD88 and IFNAR1 KO mice exhibited resistance to lethal infection with the mouse-adapted SARS-CoV-2 Delta variant. Treatment with recombinant IFN-α/β at the time of infection protected mice from lethal infection with the mouse-adapted SARS-CoV-2 Delta variant, but intranasal administration of recombinant IFN-α/β at 2 days post infection exacerbated the disease severity following the mouse-adapted ancestral SARS-CoV-2 infection. Moreover, we showed that TNF-α amplified by type I IFN signals exacerbated the SARS-CoV-2 infection by stimulating CXCL1 production from macrophages and neutrophil recruitment into the lung tissue. Finally, we showed that intravenous administration to mice or hamsters with TNF protease inhibitor 2 alleviated the severity of SARS-CoV-2 and influenza virus infection. Our results uncover an unexpected mechanism by which type I interferon-mediated TNF-α signaling exacerbates the disease severity and will aid in the development of novel therapeutic strategies to treat respiratory virus infection and associated diseases such as influenza and COVID-19.Author summary: Coronavirus disease 2019 (COVID-19) cause severe morbidity and mortality worldwide. Although mounting evidence indicates that the virus-induced cytokine storm associates with severity of COVID-19, the pathological role of inflammatory cytokines in severe COVID-19 remains unknown. Here, we demonstrated that the virus-induced pulmonary TNF-α amplified by MyD88 and type I interferon receptor signals exacerbated the SARS-CoV-2 infection by stimulating CXCL1 production from macrophages. In addition, we found that TNF-α protease inhibitor 2 alleviated the severity of SARS-CoV-2 and influenza virus infection in mice and hamsters. Our results provide important insights into the role of type I interferon-mediated TNF-α signaling in neutrophil-induced lung pathology and will aid the development of novel therapeutic strategies to treat respiratory viral infections and associated diseases.