Characterization of Neuronal Populations in the Human Trigeminal Ganglion and Their Association with Latent Herpes Simplex Virus-1 Infection

Abstract

Following primary infection Herpes simplex virus-1 (HSV-1) establishes lifelong latency in the neurons of human sensory ganglia. Upon reactivation HSV-1 can cause neurological diseases such as facial palsy, vestibular neuritis or encephalitis. Certain populations of sensory neurons have been shown to be more susceptible to latent infection in the animal model, but this has not been addressed in human tissue. In the present study, trigeminal ganglion (TG) neurons expressing six neuronal marker proteins were characterized, based on staining with antibodies against the GDNF family ligand receptor Ret, the high-affinity nerve growth factor receptor TrkA, neuronal nitric oxide synthase (nNOS), the antibody RT97 against 200kDa neurofilament, calcitonin gene-related peptide and peripherin. The frequencies of marker-positive neurons and their average neuronal sizes were assessed, with TrkA-positive (61.82%) neurons being the most abundant, and Ret-positive (26.93%) the least prevalent. Neurons positive with the antibody RT97 (1253 µm2) were the largest, and those stained against peripherin (884 µm2) were the smallest. Dual immunofluorescence revealed at least a 4.5% overlap for every tested marker combination, with overlap for the combinations TrkA/Ret, TrkA/RT97 and Ret/nNOS lower, and the overlap between Ret/CGRP being higher than would be expected by chance. With respect to latent HSV-1 infection, latency associated transcripts (LAT) were detected using in situ hybridization (ISH) in neurons expressing each of the marker proteins. In contrast to the mouse model, co-localization with neuronal markers Ret or CGRP mirrored the magnitude of these neuron populations, whereas for the other four neuronal markers fewer marker-positive cells were also LAT-ISH+. Ret and CGRP are both known to label neurons related to pain signaling.

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

“…In the adult spinal cord, mRNAs were found encoding for GFRα1 and RET, but, notably, the GFRα2 mRNA was only detected in embryos [27]. RET was also localized to the human trigeminal ganglion [28].…”

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…Combined, these studies suggest that the olfactory route of CNS entry is highly relevant in human cases of symptomatic and asymptomatic herpesvirus infections. The role of the trigeminal nerve as a portal of entry for herpesviruses in humans is less clear, although the sensory neurons of the trigem-inal ganglia are the principal site of herpes simplex virus type 1 latent infection in humans (360,361).…”

Herpes Simplex Virus and Neurotrophic Factors

“…In particular, NGF dependent neurons seem to support HSV-2 productive infection, but not latency, whereas the contrary is true for HSV-1 [27]. These results obtained in mice do not explain the fact that the presence of latent HSV-1 in postmortem human trigeminal ganglia does not seem to correlate with the expression of a particular cellular marker [29], clearly indicating the need to perform more research in this field. The use of neurons from different species, different antibodies to detect the receptors and the time post-infection when the neurons are examined may be responsible for some the differences observed.…”