SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia

Moutal, Aubin; Martin, Laurent; Boinon, Lisa; Gómez, Kimberly; Ran, Dongzhi; Zhou, Yuan; Stratton, Harrison J.; Cai, Sanjun; Luo, Shizhen; Gonzalez, Kerry Beth; Perez‐Miller, Samantha; Patwardhan, Amol; Ibrahim, Mohab; Khanna, Rajesh

doi:10.1097/j.pain.0000000000002097

Cited by 126 publications

(159 citation statements)

References 68 publications

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“…IFITM3 serves as the first line of defense against viral infection 49 and its upregulation is a marker of SARS-CoV-2 infection across publicly available datasets 50 . We also observed in the cortex parenchyma a consistent upregulation of the newly described viral entry receptor NRP1 41,51,52 (Fig. 3b, Extended Data Fig.…”

Section: Sars-cov-2 Accumulation In Barrier Cells Stimulates Inflammasupporting

confidence: 69%

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Yang

Kern

et al. 2020

Preprint

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Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons--evolutionarily expanded in humans--show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.

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Section: Sars-cov-2 Accumulation In Barrier Cells Stimulates Inflammasupporting

confidence: 69%

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Yang

Kern

et al. 2020

Preprint

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“…As ACE2 receptors in rodents have shown a much lower affinity to the SARS Spike protein as compared with human ACE2 receptor [21,25,26], the uptake of Spp lentivirus is less likely solely through the endogenous ACE2 in the lungs of mice. We speculate that other receptors or co-factors may facilitate the S protein-mediated viral entry of host cells via an ACE2-dependent or independent pathway for example NRP1-mediated entry pathway [8][9][10]. These data provide insight into the possibility of multiple factors/pathways involving SARS-CoV-2 entry of various target cells.…”

Section: Discussionmentioning

confidence: 99%

“…ACE2 and TMPRSS2 have been found to co-express in lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells [7], which are thought to be host determinants for viral infection in the initial stage. Recently, Neuropillin (NRP) 1 has been identified as the second host factor to facilitate SARS-CoV-2 entry of target cells which appears to be ACE2-independent since a different binding motif is used [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Spike Protein of SARS-CoV-2 Activates Macrophages and Contributes to Induction of Acute Lung Inflammations in Mice

Cao

Tian

Nguyen

et al. 2020

Preprint

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Background: Coronavirus disease 2019 (COVID-19) patients exhibit multiple organ malfunctions with a primary manifestation of acute and diffuse lung injuries. The Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to mediate viral entry into host cells; however, whether it can be cellularly pathogenic and contribute to pulmonary hyper-inflammations in COVID-19 is not well known. Methods and Findings: In this study, we developed a Spike protein-pseudotyped (Spp) lentivirus with the proper tropism of SARS-CoV-2 Spike protein on the surface and tracked down the fate of Spp in wild type C57BL/6J mice receiving intravenous injection of the virus. A lentivirus with vesicular stomatitis virus glycoprotein (VSV-G) was used as the control. Two hours post-infection (hpi), Spp showed more than 27-75 times more viral burden in the lungs than other organs; it also exhibited about 3-5 times more viral burden than VSV-G lentivirus in the lungs, liver, kidney and spleen. Acute pneumonia was evident in animals 24 hpi. Spp lentivirus was mainly found in LDLR+ macrophages and pneumocytes in the lungs, but not in MARC1+ macrophages. IL6, IL10, CD80 and PPAR-γ were quickly upregulated in response to infection of Spp lentivirus in the lungs in vivo as well as in macrophage-like RAW264.7 cells in vitro. We further confirmed that forced expression of the Spike protein in RAW264.7 cells could significantly increase the mRNA levels of the same panel of inflammatory factors. Conclusions: Our results demonstrate that the Spike protein of SARS-CoV-2 alone can induce cellular pathology, e.g. activating macrophages and contributing to induction of acute inflammatory responses.

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“…Khanna et al recently reported that the SARS-CoV-2 spike protein interacts with NRP1 to induce signaling in nociceptors that then causes antinociceptive effects. 64 Neuropilin 1 is strongly expressed in hDRG 71 , 90 and is found in rodent nociceptors. 64 Importantly, NRP1 was recently reported as a host entry receptor for SARS-CoV-2.…”

Section: Sars-cov-2 Neurotropism and Its Implications For Pain Andmentioning

confidence: 99%

“… 64 Neuropilin 1 is strongly expressed in hDRG 71 , 90 and is found in rodent nociceptors. 64 Importantly, NRP1 was recently reported as a host entry receptor for SARS-CoV-2. 13 , 19 This happens because when the spike protein is cleaved by the protease furin, which is also expressed in hDRG, 76 the processed protein has a high affinity for NRP1 and NRP2.…”

Section: Sars-cov-2 Neurotropism and Its Implications For Pain Andmentioning

confidence: 99%

Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain

McFarland

Yousuf

Shiers

et al. 2021

PR9

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SARS-CoV-2 is a novel coronavirus that infects cells through the angiotensin-converting enzyme 2 receptor, aided by proteases that prime the spike protein of the virus to enhance cellular entry. Neuropilin 1 and 2 (NRP1 and NRP2) act as additional viral entry factors. SARS-CoV-2 infection causes COVID-19 disease. There is now strong evidence for neurological impacts of COVID-19, with pain as an important symptom, both in the acute phase of the disease and at later stages that are colloquially referred to as "long COVID." In this narrative review, we discuss how COVID-19 may interact with the peripheral nervous system to cause pain in the early and late stages of the disease. We begin with a review of the state of the science on how viruses cause pain through direct and indirect interactions with nociceptors. We then cover what we currently know about how the unique cytokine profiles of moderate and severe COVID-19 may drive plasticity in nociceptors to promote pain and worsen existing pain states. Finally, we review evidence for direct infection of nociceptors by SARS-CoV-2 and the implications of this potential neurotropism. The state of the science points to multiple potential mechanisms through which COVID-19 could induce changes in nociceptor excitability that would be expected to promote pain, induce neuropathies, and worsen existing pain states.

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SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia

Abstract: Supplemental Digital Content is Available in the Text. Severe acute respiratory syndrome coronavirus 2's spike protein promotes analgesia by interfering with vascular endothelial growth factor-A/NRP1 pathway, which may affect disease transmission dynamics.

Cited by 126 publications

References 68 publications

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Spike Protein of SARS-CoV-2 Activates Macrophages and Contributes to Induction of Acute Lung Inflammations in Mice

Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain

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