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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

COVID-19*/immunology ; COVID-19*/virology ; SARS-CoV-2*/immunology ; Mice, Inbred C57BL* ; Macrophages*/immunology ; Macrophages*/metabolism ; Macrophages*/virology ; Tumor Necrosis Factor-alpha*/metabolism ; Tumor Necrosis Factor-alpha*/immunology ; Mice, Knockout* ; Chemokine CXCL1*/metabolism; Animals ; Mice ; Humans ; Receptor, Interferon alpha-beta/genetics ; Receptor, Interferon alpha-beta/metabolism ; Myeloid Differentiation Factor 88/metabolism ; Myeloid Differentiation Factor 88/genetics ; Female

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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Kobayashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

0 (Tumor Necrosis Factor-alpha)
0 (Chemokine CXCL1)
0 (Cxcl1 protein, mouse)
156986-95-7 (Receptor, Interferon alpha-beta)
0 (Myeloid Differentiation Factor 88)

SARS-CoV-2 variants

Date Created: 20241209 Date Completed: 20241219 Latest Revision: 20241219

20241220

10.1371/journal.ppat.1012776

39652608