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

Abstract

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.

Keywords: COVID-19; Neuropathy; Nociceptor; SARS-CoV-2.

Figure 1.

Cellular response to SARS-CoV-2 infection in the lung and its relationship to nociceptors. The cleavage of viral S protein by surface proteins such as TMPRSS2 and furin facilitates SARS-CoV-2 entry into lung epithelial cells through the ACE2 receptor. Neuropilin 1 and 2 (NRP1/2) act as additional viral entry factors. Viral RNA activates interferon regulatory factors (IRF3 and IRF7) that promote type I interferon (IFNα/β) production. The binding of type I IFNs to IFN receptors on pulmonary nociceptors is postulated to stimulate MNK-mediated eIF4E phosphorylation, resulting in nociceptor sensitization. When the viral load is high, viral proteins (NSP13, NSP6, and ORF6) suppress IFN production, contributing to evasion of type I IFN production and increasing the severity of COVID-19. ACE2, angiotensin-converting enzyme 2.

Figure 2.

Potential mechanism(s) for nociceptor sensitization in severe COVID-19. SARS-CoV-2 enters lung epithelial cells and resident immune cells through ACE2. In severe COVID-19 cases, IFN production is abrogated allowing the virus to replicate unrestricted. Subsequent increase in viral load further enhances the production of inflammatory mediators and leads to the development of a hyperinflammatory state known as a “cytokine storm.” Cytokines produced in the lower respiratory tract may interact with receptors on sensory nerve endings promoting neurogenic inflammation and nociceptor hypersensitivity. An exaggerated immune response leads to systemic inflammation affecting multiple organs. As such, peripheral blood mononuclear cells (PBMCs) produce potent inflammatory mediators that have known receptors in the sensory neurons and resident immune cells of the DRG, driving nociceptor sensitization. ACE2, angiotensin-converting enzyme 2; DRG, dorsal root ganglia.

Figure 3.

ACE2 expression in the dorsal root ganglia. (A) The ability of SARS-CoV-2 to directly target sensory neurons in the DRG depends on the expression of ACE2. (B) We recently demonstrated that ACE2 mRNA is expressed by P2X3R, CALCA, and MRGPRD expressing neurons. White arrowheads indicate ACE2-positive neurons in the human DRG. Lipofuscin in human DRG neurons appears white in the merged images. Although ACE2 mRNA is present in 20% of human DRG neurons, the expression level is low. (C) Interestingly, ACE2 immunoreactivity in human DRG is diffuse, suggesting that the extracellular protein may contact many cell types. ACE2, angiotensin-converting enzyme 2; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglia.