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.