Tumor Necrosis Factor and Interleukin-1β Upregulate NRP2 Expression and Promote SARS-CoV-2 Proliferation

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 and Neuropilin-1 (NRP1) for cell entry.
• The role of NRP1's isoform, Neuropilin-2 (NRP2), in COVID-19 pathogenesis is largely unexplored.
• The connection between elevated proinflammatory cytokines in severe COVID-19 and viral replication is unknown.

Purpose of the Study:

• To investigate the role of proinflammatory cytokines in regulating Neuropilin (NRP) expression.
• To determine the impact of cytokine-induced NRP expression on SARS-CoV-2 infection and proliferation.

Main Methods:

• Utilized next-generation sequencing (RNA-seq), immunohistochemistry, quantitative real-time PCR, and Western blotting.
• Examined NRP expression in fibroblast-like synoviocytes, MH7A, MRC5 cell lines, and synovial tissues under inflamed and non-inflamed conditions.
• Conducted SARS-CoV-2 infection experiments to assess viral proliferation and Spike protein binding.

Main Results:

• Neuropilin-2 (NRP2) expression was significantly upregulated in inflamed tissues.
• Co-stimulation with tumor necrosis factor α (TNFα) and interleukin-1 beta (IL-1β) increased NRP2 expression in human fibroblast cell lines.
• TNFα and IL-1β promoted SARS-CoV-2 proliferation and Spike protein binding, correlating with NRP2 expression levels.

Conclusions:

• Proinflammatory cytokines, specifically TNFα and IL-1β, drive NRP2 upregulation in host cells.
• NRP2 plays a crucial role in facilitating SARS-CoV-2 proliferation and infection.
• Targeting cytokine-induced NRP2 expression may offer a therapeutic strategy against COVID-19.