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

• DOI: 10.1371/journal.ppat.1012776
• Publication Date: 2024-12-09T18:40:35Z
• Authors: Moe Kobayashi; Nene Kobayashi; Kyoka Deguchi; Seira Omori; Minami Nagai; Ryutaro Fukui; Isaiah Song; Shinji Fukuda; Kensuke Miyake; Takeshi Ichinohe
• Keywords: CXCL1

Since most genetically modified mice are C57BL/6 background, a mouse-adapted SARS-CoV-2 that causes lethal infection in young is useful for studying innate immune protection against infection. Here, we established two SARS-CoV-2, ancestral and Delta variants, by serial passaging 80 times mice. Although were resistant to with the variant caused In contrast, MyD88 IFNAR1 KO exhibited resistance variant. Treatment recombinant IFN-α/β at time of protected from variant, but intranasal administration 2 days post exacerbated disease severity following Moreover, showed TNF-α amplified type I IFN signals stimulating CXCL1 production macrophages neutrophil recruitment into lung tissue. Finally, intravenous or hamsters TNF protease inhibitor alleviated influenza virus Our results uncover an unexpected mechanism which interferon-mediated signaling exacerbates will aid development novel therapeutic strategies treat respiratory associated diseases such as COVID-19.