Two alphaherpesvirus latency-associated gene products influence calcitonin gene-related peptide levels in rat trigeminal neurons

Abstract

Herpes simplex virus type-1 (HSV-1) initially infects mucoepithelial tissues of the eye and the orofacial region. Subsequently, the virus is retrogradely transported through the axons of the trigeminal sensory neurons. HSV-1 establishes a life-long latent infection in these neurons, during which the transcription of the viral genome is silent, except for the sequences encoding the latency associated transcript (LAT). To determine if HSV-1 latency might affect calcitonin gene-related peptide (CGRP) expression in trigeminal sensory neurons, we transfected primary neuronal cultures of trigeminal ganglia from rat embryos with plasmids expressing LAT. In the presence of Bone Morphogenetic Protein-7 (BMP7), CGRP was expressed in 49% of sensory neurons. However, this percentage was reduced to 19% in neurons transfected with LAT expressing plasmids. We also found that transfection of the IE63 gene of varicella-zoster virus (VZV) reduced the percentage of trigeminal neurons containing CGRP. However, the observed effect of IE63 in contrast to that of LAT, was completely reversed by treatment of cultures with MgCl 2 , which indicates that the effect of IE63 was due to increased release of CGRP from trigeminal neurons. We provide here the first evidence that HSV-1 LAT decreases the level of CGRP in trigeminal neurons. These effects may be important for reducing the neuroinflammatory response, thus protecting host neuronal cells during HSV-1 latency in trigeminal neurons. In contrast, increased release of CGRP in the presence of IE63 protein may contribute to the neuralgias associated with VZV infection.

Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

“…We suspect that transcription of VZV genes within virus-infected neurons may themselves lead to the chronic pain state either through induction of inflammatory mechanisms or through expression of proteins, such as transcriptional regulators, that may alter host cell expression patterns. 11,43,44 Studies are ongoing to determine whether viral transactivators, IE62 and IE63, are required for the induction of the chronic pain state.…”

Selective Changes in Human Corneal Sensation Associated with Herpes Simplex Virus Keratitis

“…[25][26][27] During the latency period, genes in sensory neurons encoding proteins involved in neurotransmission, voltage-gated ion channels, neuropeptides, and axonal elongation and remodeling, change their expression pattern. 28,29 After reactivation, herpes viruses spread within sensory neurons and transfer across junctions formed between nerve terminals and corneal epithelium cells. 2,30 It has been suggested that small quantities of viral antigens from the HSV-infected epithelial cells spill into the stroma and promote HSK.…”

Transforming Growth Factor-β in Normal Nociceptive Processing and Pathological Pain Models

“…Studies in vitro have shown that skin-cell-derived factors induce de novo CGRP expression in embryonic DRG neurons that are isolated before peripheral target contact, and this effect is antagonized by anti-activin A antibody or the activin and BMP inhibitory protein, follistatin [45,[54][55][56]. Furthermore, the addition of recombinant activin A, BMP2, BMP4, BMP6 or BMP7 to cultured embryonic neurons that were dissociated from DRG induces a strong increase in the expression of CGRP by the specific subset of unmyelinated C-fiber peptidergic neurons.…”