Abstract
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.
Footnotes
1. We clarified which Spike protein fragment we used throughout our experiments. We have removed references to the receptor binding domain (RBD) of Spike for clarity. 2. We added a new panel to Figure 1 (A) which replicates the binding between Spike and NRP-1. An interaction between Spike (S1 domain aa 16-685, containing the CendR motif 682RRAR685) and the extracellular portion of NRP-1 was confirmed by enzyme-linked immunosorbent assay (ELISA) (Fig. 1A). We calculated an equilibrium constant of dissociation (Kd) for this interaction to be ~166.2 nM (Fig. 1A). 3. We added new data panels (Fig. 6E, F) showing that Spike reverses mechanical allodynia in female rats with SNI.
ABBREVIATIONS USED
- 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
