SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia
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Abstract
Global spread of severe acute respiratory syndrome coronavirus 2 continues unabated. Binding of severe acute respiratory syndrome coronavirus 2's spike protein to host angiotensin-converting enzyme 2 triggers viral entry, but other proteins may participate, including the neuropilin-1 receptor (NRP-1). Because both spike protein and vascular endothelial growth factor-A (VEGF-A)—a pronociceptive and angiogenic factor, bind NRP-1, we tested whether spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuron firing was blocked by spike protein and NRP-1 inhibitor EG00229. Pronociceptive behaviors of VEGF-A were similarly blocked through 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 through subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.
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SciScore for 10.1101/2020.07.17.209288: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The Institutional Animal Care and Use Committee of the College of Medicine at the University of Arizona approved all experiments. Randomization Animals were randomly assigned to treatment or control groups for the behavioral experiments. Blinding All behavioral experiments were performed by experimenters who were blinded to the experimental groups and treatments. 2.2. Power Analysis not detected. Sex as a biological variable Animals: Pathogen-free adult male and female Sprague-Dawley rats (225-250g; Envigo, Indianapolis, IN) were housed in temperature-controlled (23±3 °C) and light-controlled (12-h light/12-h dark cycle; lights on 07:00-19:00) rooms with standard … SciScore for 10.1101/2020.07.17.209288: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The Institutional Animal Care and Use Committee of the College of Medicine at the University of Arizona approved all experiments. Randomization Animals were randomly assigned to treatment or control groups for the behavioral experiments. Blinding All behavioral experiments were performed by experimenters who were blinded to the experimental groups and treatments. 2.2. Power Analysis not detected. Sex as a biological variable Animals: Pathogen-free adult male and female Sprague-Dawley rats (225-250g; Envigo, Indianapolis, IN) were housed in temperature-controlled (23±3 °C) and light-controlled (12-h light/12-h dark cycle; lights on 07:00-19:00) rooms with standard rodent chow and water available ad libitum. Table 2: Resources
Antibodies Sentences Resources After transfer, the membranes were blocked at room temperature for 1 hour with TBST (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.1 % Tween 20), 5% (mass/vol) non-fat dry milk, then incubated separately in the primary antibodies VEGFR2 (Cat#PA5-16487, ThermoFisher), pY1175 VEGFR2 (Cat#PA5-105167, ThermoFisher), Flotilin (Cat#F1180, Sigma) or Neuropilin-1 (Cat#sc-5307, Santa Cruz biotechnology) in TBST, 5% (mass/vol) BSA, overnight at 4°C. VEGFR2suggested: NoneNeuropilin-1suggested: (Santa Cruz Biotechnology Cat# sc-5307, RRID:AB_2282634)Experimental Models: Organisms/Strains Sentences Resources Rat DRG neurons were isolated from 100g female Sprague-Dawley rats using previously developed procedures [36]. 2.4. Sprague-Dawleysuggested: RRID:RGD_70508)Software and Algorithms Sentences Resources Data were analyzed by non-linear regression analysis using GraphPad Prism 8 (GraphPad, San Diego, CA, USA). 2.3. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Films were scanned, digitized, and quantified using Un-Scan-It gel version 7.1 scanning software by Silk Scientific Inc. 2.14. Un-Scan-Itsuggested: NoneMolecular figures generated with PyMol 1.8 (Schrödinger, LLC.) 2.15. PyMolsuggested: (PyMOL, RRID:SCR_000305)Statistical Analysis: All data was first tested for a Gaussian distribution using a D’Agostino-Pearson test (Prism 8 Software, Graphpad, San Diego, CA). Graphpadsuggested: (GraphPad, RRID:SCR_000306)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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