Botulinum neurotoxin light chains expressed by defective herpes simplex virus type-1 vectors cleave snare proteins and inhibit cgrp release in rat sensory neurons

Charles Joussain, Olivier Le Coz, Andrey Pichugin, Peggy Marconi, Filip Lim, Mariaconcetta Sicurella, Andrea Salonia, Francesco Montorsi, Francisco Wandosell, Keith Foster, François Giuliano, Alberto L. Epstein, Alejandro Aranda Muñoz

Research output: Contribution to journalArticlepeer-review

Abstract

A set of herpes simplex virus type 1 (HSV-1) amplicon vectors expressing the light chains (LC) of botulinum neurotoxins (BoNT) A, B, C, D, E and F was constructed. Their properties have been assessed in primary cultures of rat embryonic dorsal root ganglia (DRG) neurons, and in organotypic cultures of explanted DRG from adult rats. Following infection of primary cultures of rat embryonic DRG neurons, the different BoNT LC induced efficient cleavage of their corresponding target Soluble N-ethylmaleimide-sensitive-factor Attachment protein Receptor (SNARE) protein (VAMP, SNAP25, syntaxin). A similar effect was observed following infection by BoNT-A LC of organotypic cultures of adult rat DRG. To quantify and compare the functional activities of the different BoNT LC, the inhibition of calcitonin gene-related protein (CGRP) secretion was assessed in DRG neurons following infection by the different vectors. All BoNT-LC were able to inhibit CGRP secretion although to different levels. Vectors expressing BoNT-F LC displayed the highest inhibitory activity, while those expressing BoNT-D and-E LC induced a significantly lower CGRP release inhibition. Cleavage of SNARE proteins and inhibition of CGRP release could be detected in neuron cultures infected at less than one transducing unit (TU) per neuron, showing the extreme efficacy of these vectors. To our knowledge this is the first study investigating the impact of vector-expressed transgenic BoNT LC in sensory neurons.

Original languageEnglish
Article number123
JournalToxins
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 2019

Keywords

  • DRG
  • HSV-1 amplicon vectors
  • Light chains
  • Sensory neurons
  • SNARE proteins
  • Transgenic botulinum neurotoxins

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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