SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia
Laurent F. Martin,
Harrison J. Stratton,
Kerry Beth Gonzalez,
Mohab M. Ibrahim,
Posted 18 Jul 2020
bioRxiv DOI: 10.1101/2020.07.17.209288 (published DOI: 10.1097/j.pain.0000000000002097)
Posted 18 Jul 2020
Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2’s Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A) – a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A–triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A ‘silencing’ of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals. ### Competing Interest Statement R. Khanna is the co-founder of Regulonix LLC, a company developing non-opioids drugs for chronic pain. In addition, R. Khanna has patents US10287334 and US10441586 issued to Regulonix LLC. The other authors declare no competing financial interests. * ACE2 : Angiotensin converting enzyme 2 AUC : area under the curve CaV2.2 : N-type voltage-gated calcium channel COVID-19 : coronavirus disease 2019 DRG : dorsal root ganglia MEA : multi-well microelectrode array NaV1.7 : voltage-gated sodium channel isoform 7 NRP-1 : Neuropilin-1 PWTs : paw withdrawal thresholds SARS-CoV-2 : Severe acute respiratory syndrome coronavirus 2 sEPSCs : spontaneous excitatory postsynaptic currents SNI : spared nerve injury VEGF-A : vascular endothelial growth factor-A
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