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

Area of Science:

• Virology
• Immunology
• Infectious Diseases

Background:

• Most genetically modified mice utilize the C57BL/6 background, necessitating a mouse-adapted SARS-CoV-2 for studying innate immune responses.
• Understanding SARS-CoV-2 pathogenesis in immunocompetent models is crucial for developing effective treatments.

Purpose of the Study:

• To establish mouse-adapted SARS-CoV-2 variants for studying innate immunity.
• To investigate the role of type I interferon and TNF-α signaling in SARS-CoV-2 pathogenesis.
• To explore therapeutic strategies targeting exacerbated disease mechanisms.

Main Methods:

• Serial passaging of SARS-CoV-2 (ancestral and Delta variants) in C57BL/6 mice.
• Infection studies using wild-type, MyD88 knockout (KO), and IFNAR1 KO mice.
• Administration of recombinant interferon-α/β and TNF protease inhibitor 2.
• Analysis of lung tissue for immune cell infiltration and cytokine production (CXCL1).

Main Results:

• A mouse-adapted SARS-CoV-2 Delta variant caused lethal infections in young C57BL/6 mice, unlike the ancestral variant.
• MyD88 and IFNAR1 KO mice showed resistance to the Delta variant, indicating their importance in pathogenesis.
• Early interferon treatment protected mice, while late treatment exacerbated disease; TNF-α signaling amplified by type I IFNs worsened infection.
• TNF protease inhibitor 2 alleviated disease severity in both SARS-CoV-2 and influenza virus infections.

Conclusions:

• Type I interferon-mediated TNF-α signaling unexpectedly exacerbates SARS-CoV-2 disease severity.
• Targeting TNF-α signaling offers a potential therapeutic strategy for respiratory viral infections, including COVID-19 and influenza.
• Mouse models are critical for dissecting complex immune responses and evaluating novel therapeutic interventions.