Alpha-herpesvirus glycoprotein D interaction with sensory neurons triggers formation of varicosities that serve as virus exit sites.
Alpha-herpesviruses constitute closely related neurotropic viruses, including herpes simplex virus in man and pseudorabies virus (PRV) in pigs. Peripheral sensory neurons, such as trigeminal ganglion (TG) neurons, are predominant target cells for virus spread and lifelong latent infections. We report that in vitro infection of swine TG neurons with the homologous swine alpha-herpesvirus PRV results in the appearance of numerous synaptophysin-positive synaptic boutons (varicosities) along the axons. Nonneuronal cells that were juxtaposed to these varicosities became preferentially infected with PRV, suggesting that varicosities serve as axonal exit sites for the virus. Viral envelope glycoprotein D (gD) was found to be necessary and sufficient for the induction of varicosities. Inhibition of Cdc42 Rho GTPase and p38 mitogen-activated protein kinase signaling pathways strongly suppressed gD-induced varicosity formation. These data represent a novel aspect of the cell biology of alpha-herpesvirus infections of sensory neurons, demonstrating that virus attachment/entry is associated with signaling events and neuronal changes that may prepare efficient egress of progeny virus.
De Regge
Nick
N
Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
Nauwynck
Hans J
HJ
Geenen
Kristin
K
Krummenacher
Claude
C
Cohen
Gary H
GH
Eisenberg
Roselyn J
RJ
Mettenleiter
Thomas C
TC
Favoreel
Herman W
HW
D000818:Animals; D000906:Antibodies / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D011558:Herpesvirus 1, Suid / Q000502:physiology*; D006801:Humans; D000075983:Nectins; D009475:Neurons, Afferent / Q000166:cytology / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000821:virology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D012668:Trigeminal Ganglion / Q000166:cytology; D014759:Viral Envelope Proteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000906:Antibodies; D015815:Cell Adhesion Molecules; D000075983:Nectins; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; C107752:glycoprotein D, pseudorabies virus; D048051:p38 Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein