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

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.

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

SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis-loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.

A pharmacological interactome between COVID-19 patient samples and human sensory neurons reveals potential drivers of neurogenic pulmonary dysfunction.

The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We hypothesized that SARS-CoV-2 infection drives changes in immune cell-derived factors that then interact with receptors expressed by the sensory neuronal innervation of the lung to further promote important aspects of disease severity, including ARDS. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 pulmonary disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.