SARS-CoV-2 Spike Peptides Trigger Nociceptive Responses Through Spinal TLR4 Pathways

Area of Science:

• Neuroscience
• Immunology
• Virology

Background:

• COVID-19 often causes neurological pain, but the mechanisms involving SARS-CoV-2 spike proteins are unclear.
• This study investigates if spike protein fragments activate spinal neuroimmune pathways contributing to pain signaling.

Purpose of the Study:

• To determine if SARS-CoV-2 spike-derived peptides directly activate spinal neuroimmune pathways.
• To elucidate the mechanisms underlying spike protein-induced nociception.

Main Methods:

• Intrathecal administration of synthetic SARS-CoV-2 spike peptides in mice.
• Assessment of mechanical nociception and investigation of spinal Toll-like receptor 4 (TLR4), microglia, and p38 MAPK/NF-κB signaling pathways.
• Utilized pharmacological antagonists, knockout mice, cellular assays, and molecular dynamics simulations.

Main Results:

• Spike-derived peptides induced mechanical nociception, with PSPD2003 showing the most significant effect.
• PSPD2003 increased spinal TLR4 expression and microglial activation, leading to neuroinflammation.
• These effects were dependent on TLR4, microglia, p38 MAPK, and NF-κB signaling, confirmed in TLR4 knockout mice.

Conclusions:

• SARS-CoV-2 spike-derived peptides activate spinal nociception via TLR4-dependent microglial activation and p38 MAPK/NF-κB signaling.
• The spinal TLR4-microglia axis is identified as a potential therapeutic target for COVID-19-associated and post-viral pain.