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SARS-CoV-2 Spike protein hijacks VEGF-A/Neuropilin-1 receptor signaling to induce analgesia

View ORCID ProfileAubin Moutal, View ORCID ProfileLaurent F. Martin, View ORCID ProfileLisa Boinon, View ORCID ProfileKimberly Gomez, View ORCID ProfileDongzhi Ran, Yuan Zhou, View ORCID ProfileHarrison J. Stratton, Song Cai, Shizhen Luo, Kerry Beth Gonzalez, View ORCID ProfileSamantha Perez-Miller, Amol Patwardhan, Mohab M. Ibrahim, View ORCID ProfileRajesh Khanna
doi: https://doi.org/10.1101/2020.07.17.209288
Aubin Moutal
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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  • ORCID record for Aubin Moutal
Laurent F. Martin
2Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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  • ORCID record for Laurent F. Martin
Lisa Boinon
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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  • ORCID record for Lisa Boinon
Kimberly Gomez
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Dongzhi Ran
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Yuan Zhou
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Harrison J. Stratton
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Song Cai
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Shizhen Luo
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Kerry Beth Gonzalez
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Samantha Perez-Miller
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
2Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Amol Patwardhan
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
2Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
4Comprehensive Pain and Addiction Center, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Mohab M. Ibrahim
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
2Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
4Comprehensive Pain and Addiction Center, The University of Arizona, Tucson, Arizona, 85724 United States of America
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Rajesh Khanna
1Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
2Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, Arizona, 85724 United States of America
3Center for Innovation in Brain Sciences, University of Arizona, Tucson, Arizona 85721, United States of America
4Comprehensive Pain and Addiction Center, The University of Arizona, Tucson, Arizona, 85724 United States of America
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  • For correspondence: rkhanna@arizona.edu
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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 pronociceptive 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.

One Sentence Summary SARS-CoV-2’s Spike protein promotes analgesia by interfering with VEGF-A/NRP1 pathway, which may affect disease transmission dynamics.

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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 18, 2020.
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SARS-CoV-2 Spike protein hijacks VEGF-A/Neuropilin-1 receptor signaling to induce analgesia
Aubin Moutal, Laurent F. Martin, Lisa Boinon, Kimberly Gomez, Dongzhi Ran, Yuan Zhou, Harrison J. Stratton, Song Cai, Shizhen Luo, Kerry Beth Gonzalez, Samantha Perez-Miller, Amol Patwardhan, Mohab M. Ibrahim, Rajesh Khanna
bioRxiv 2020.07.17.209288; doi: https://doi.org/10.1101/2020.07.17.209288
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SARS-CoV-2 Spike protein hijacks VEGF-A/Neuropilin-1 receptor signaling to induce analgesia
Aubin Moutal, Laurent F. Martin, Lisa Boinon, Kimberly Gomez, Dongzhi Ran, Yuan Zhou, Harrison J. Stratton, Song Cai, Shizhen Luo, Kerry Beth Gonzalez, Samantha Perez-Miller, Amol Patwardhan, Mohab M. Ibrahim, Rajesh Khanna
bioRxiv 2020.07.17.209288; doi: https://doi.org/10.1101/2020.07.17.209288

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