ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects

Shiers, Stephanie; Ray, Pradipta; Wangzhou, Andi; Sankaranarayanan, Ishwarya; Tatsui, Claúdio E.; Rhines, Laurence D.; Li, Yan; Uhelski, Megan L.; Dougherty, Patrick M.; Price, Theodore J.

doi:10.1097/j.pain.0000000000002051

Cited by 98 publications

(93 citation statements)

References 35 publications

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“…As already stated, DRG neurons are able to sequester antigen-specific antibodies [ 12 ]. Human DRG neurons express SARS-CoV-2 angiotensin converting enzyme receptor2, speculatively explaining post-COVID-19 chronic pain and fatigue [ 17 ]. These aggregated pieces of evidence suggest that, in given instances, environmental stress, retained immune complexes, viruses, or vaccine-derived antigens may induce DRG inflammation and chronic pain.…”

Section: Hypothetical Mechanisms Whereby Dorsal Root Ganglia May Indumentioning

confidence: 99%

Dorsal root ganglia: fibromyalgia pain factory?

Martı́nez-Lavı́n

2021

Clin Rheumatol

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This perspective article focuses on dorsal root ganglia (DRG) as potential fibromyalgia main pain source. Humans possess 31 pairs of DRG lying along the spine. These ganglia have unique anatomical and physiological features. During development, DRG are extruded from the central nervous system and from the blood-brain barrier but remain surrounded by meningeal layers and by cerebrospinal fluid. DRG house the pain-transmitting small nerve fiber nuclei; each individual nucleus is tightly enveloped by metabolically active glial cells. DRG possess multiple inflammatory/pro-nociceptive molecules including ion channels, neuropeptides, lymphocytes, and macrophages. DRG neurons have pseudo-unipolar structure making them able to generate pain signals; additionally, they can sequester antigen-specific antibodies thus inducing immune-mediated hyperalgesia. In rodents, diverse physical and/or environmental stressors induce DRG phenotypic changes and hyperalgesia. Unfolding clinical evidence links DRG pathology to fibromyalgia and similar syndromes. Severe fibromyalgia is associated to particular DRG ion channel genotype. Myalgic encephalomyelitis patients with comorbid fibromyalgia have exercise-induced DRG pro-nociceptive molecules gene overexpression. Skin biopsy demonstrates small nerve fiber pathology in approximately half of fibromyalgia patients. A confocal microscopy study of fibromyalgia patients disclosed strong correlation between corneal denervation and small fiber neuropathy symptom burden. DRG may be fibromyalgia neural hub where different stressors can be transformed in neuropathic pain. Novel neuroimaging technology and postmortem inquest may better define DRG involvement in fibromyalgia and similar maladies. DRG pro-nociceptive molecules are attractive fibromyalgia therapeutic targets.

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Section: Hypothetical Mechanisms Whereby Dorsal Root Ganglia May Indumentioning

confidence: 99%

Dorsal root ganglia: fibromyalgia pain factory?

Martı́nez-Lavı́n

2021

Clin Rheumatol

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“… 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. Two recent reports demonstrate that the expression of ACE2, furin, and NRP1 or NRP2 augments SARS-CoV-2 cellular infection and that this is a likely mechanism through which SARS-CoV-2 infects the olfactory epithelium.…”

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

confidence: 99%

“… 13 , 19 Because ACE2 is a secreted protein that shows diffuse staining in hDRG (Fig. 3 C) and furin and NRP1 are likely expressed by many nociceptors, 64 , 76 this increases the probability that the virus may infect these cells. Our view is that it will be very important to understand the consequences of spike protein and SARS-CoV-2 interactions with human nociceptors as this will inform our understanding of the long-term effects of the virus on these neurons.…”

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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101

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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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“…This deficit is dependent on the increased amyloid-beta (Aβ) peptide load and tau pathology and hyperactivity of the classical axis of the renin-angiotensin system [ 34 , 35 ]. Apart from AD, the presence of ACE2 has not been demonstrated in many neurons [ 36 ], despite increasing reports of neurological symptoms being common in COVID-19 patients [ 2 ]. However, apolipoprotein E (ApoE) is a potential link between AD and COVID-19.…”

Section: Functions Of Receptors In Brain Invasion Of Sars-cov-2mentioning

confidence: 99%

Current opinion in neurological manifestations of SARS-CoV-2 infection

Engin

2021

Current Opinion in Toxicology

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Neurological symptoms occur in approximately one third of hospitalized patients with coronavirus disease 2019 (COVID-19). Among these symptoms, hypoxic encephalopathy develops in one-fifth of severe cases, while ischemic strokes due to thrombotic complications are common in one-third of COVID-19 intensive care patients. Brain involvement of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is eventuated by several routes, including hematogenous spread, trans-synaptic entry through infected neurons, olfactory nerve, ocular epithelium, vascular endothelium and impaired blood–brain barrier. Besides the high angiotensin converting enzyme-2 (ACE2) binding affinity, and FURIN preactivation, SARS-CoV-2 maintains efficient neuronal entry while evading immune surveillance by utilizing basigin, and neuropilin-1 receptors. However, the neurological manifestations and their pathogenic mechanisms are still debated in COVID-19 patients.

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ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects

Cited by 98 publications

References 35 publications

Dorsal root ganglia: fibromyalgia pain factory?

Dorsal root ganglia: fibromyalgia pain factory?

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

Current opinion in neurological manifestations of SARS-CoV-2 infection

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