Viral infections of neuraxial systems can induce distal sensory polyneuropathies leading to debilitating painful bilateral dysesthesias (burning, pins, and needles; numbness) and allodynia. A number of such neuropathies including those arising from infection by DNA (alpha, beta, and gamma herpesviruses)/RNA (West Nile, Hepatitis C, SARS-CoV-2) viruses can evolve into chronic disorders, with severe impact upon quality of life.

Advances in virology and our appreciation of neural mechanisms underlying nociceptive processing has led to an appreciation of the multiplicity of mechanisms that underlie this algogenic activity. This collection of articles will emphasize the direction of research that will illuminate this underlying complexity.

First, viruses can initiate acute primary infections with effects upon sensory function. Some consequences are direct as a result of viral replication within sensory neurons. Others are indirect, secondary to the activation of innate and adaptive immune signaling. Infection leads to the infiltration of polymorphonuclear and mononuclear cells, vascular congestion, edema, and the release of pro-analgesic factors. Through the permeability of the dorsal root ganglia (DRG), which lies outside the blood-nerve and blood-brain barrier, these factors can result in facilitatory cascades/axon potentials in the sensory axon. In addition to enhanced neural activation and excitability, inflammation, necrosis, and local myelitis in the sensory axon may be observed following infection.

While the threat posed by the virus is considered neutralized when these symptoms resolve, certain viral infections can persist for the lifetime of the host. As examples herpesviruses, hepatitis, HIV, and coronaviruses establish a latent infection, a state of dormancy where viral genomic material remains in select cells, but the virus is no longer actively replicated. Over the lifetime of a patient, these viruses can periodically reactivate, and robust viral gene expression and progeny virus production resume. Latency/persistence and reactivation take place in cells within or adjacent to the sensory ganglia that mediate nociception (peripheral nervous system, PNS) and sensitization (central nervous system, CNS), including sensory neurons and infiltrating immune cells. These persevering viruses are therefore unsurprisingly a significant contributor of persistent pain. However, whether these viruses induce neuropathy in their latent or reactivated form, and whether they alter neuronal excitability/activation through direct infection of neurons versus secondary immune responses is unclear, and possibly virus specific.

This topical series will focus on research related the intersection of both acute and chronic viral infections and pain pathologies. It seeks to encompass the clinical characterization, modeling, and biology of viral-induced hyperexcitability or neuropathology.

Specific topics of interest in this series will include:

• Role of cell types in viral infection leading to the neuropathic state e.g. macrophages, satellite cells, Schwann cells, and sensory neurons.

• Route of access of viral particle into the sensory components (peripheral nerve and DRG).

• Changes in cellular transcriptome regarding nociceptive machinery and electrophysiology in the acute, latent, and reactivation phase of viral infection.

• Differences in pain state generated in the acute and reactivation phase of the virus based on epidemiological factors like sex and age.

• Detailed characterization of the pain phenotypes (localization, modalities, dynamics) observed in the acute and viral reactivation phase of the different viral families.

• Assessments of the compatibility or discontinuity of therapies targeting viral replication versus neuropathic pain.

Original scientific research articles, review articles, and case series are welcome. Works discussing the repurposing of persistent viral vectors for pain-targeted therapies will be considered.

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Frontiers in Pain Research

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