TLR2/NF-κB signaling in macrophage/microglia mediated COVID-pain induced by SARS-CoV-2 envelope protein

Area of Science:

• Neuroscience
• Immunology
• Virology

Background:

• Long COVID-19 frequently presents with debilitating pain, lacking effective treatments.
• SARS-CoV-2 viral proteins, including envelope (S2E), spike (S2S), and membrane (S2M), possess independent pro-inflammatory properties.

Purpose of the Study:

• To elucidate the neuroinflammatory mechanisms underlying COVID-19-associated pain induced by SARS-CoV-2 membranal proteins.

Main Methods:

• Detection of SARS-CoV-2 membranal proteins in sensory ganglions and spinal dorsal horn of COVID-19 patients.
• Induction of pain behaviors in mice via intradermal and intrathecal injection of S2E, S2S, and S2M.
• Assessment of nuclear factor kappa B (NF-κB) phosphorylation and modulation by minocycline.
• Identification of Toll-like receptor 2 (TLR2) as the S2E target using TLR assays.

Main Results:

• The S2E protein was detected in sensory ganglions and spinal dorsal horn tissues of COVID-19 donors.
• Intradermal and intrathecal S2E administration induced pain behaviors in mice.
• S2E injection led to upregulated NF-κB phosphorylation, which minocycline treatment attenuated.
• Toll-like receptor 2 (TLR2) was identified as the specific target of S2E responsible for initiating inflammatory responses and pain.

Conclusions:

• SARS-CoV-2 envelope protein S2E directly induces pain by interacting with macrophage/microglia TLR2, triggering an NF-κB-mediated inflammatory cascade.
• Targeting S2E or inhibiting macrophage/microglia TLR2 presents promising therapeutic strategies for managing COVID-19-associated pain.