Journal Article

Retrograde axonal transport of rabies virus is unaffected by interferon treatment but blocked by emetine locally in axons

Wirblich, Christoph, Schnell, Matthias J., MacGibeny, Margaret A., Koyuncu, Orkide O., Enquist, Lynn W.

2018

Overview

Neuroinvasive viruses, such as alpha herpesviruses (αHV) and rabies virus (RABV), initially infect peripheral tissues, followed by invasion of the innervating axon termini. Virus particles must undergo long distance retrograde axonal transport to reach the neuron cell bodies in the peripheral or central nervous system (PNS/CNS). How virus particles hijack the axonal transport machinery and how PNS axons respond to and regulate infection are questions of significant interest. To track individual virus particles, we constructed a recombinant RABV expressing a P-mCherry fusion protein, derived from the virulent CVS-N2c strain. We studied retrograde RABV transport in the presence or absence of interferons (IFN) or protein synthesis inhibitors, both of which were reported previously to restrict axonal transport of αHV particles. Using neurons from rodent superior cervical ganglia grown in tri-chambers, we showed that axonal exposure to type I or type II IFN did not alter retrograde axonal transport of RABV. However, exposure of axons to emetine, a translation elongation inhibitor, blocked axonal RABV transport by a mechanism that was not dependent on protein synthesis inhibition. The minority of RABV particles that still moved retrograde in axons in the presence of emetine, moved with slower velocities and traveled shorter distances. Emetine's effect was specific to RABV, as transport of cellular vesicles was unchanged. These findings extend our understanding of how neuroinvasion is regulated in axons and point toward a role for emetine as an inhibitory modulator of RABV axonal transport.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Axonal transport / Axonal Transport - drug effects / Axons / Axons - virology / Biology and Life Sciences / Central nervous system / Chemical vapor synthesis / Cytokines / Development and progression / Drug resistance / Elongation / Emetine / Emetine - pharmacology / Exposure / Funding / Fusion protein / Ganglia / Genetic aspects / Health aspects / Herpes viruses / Immunology / Infections / Interferon / Interferons - pharmacology / Invasiveness / Kinases / Lyssavirus / Microscopy / Molecular biology / Nervous system / Neurons / Neurosciences / Physiological aspects / Protein biosynthesis / Protein synthesis / Protein Synthesis Inhibitors - pharmacology / Proteins / Rabies / Rabies - virology / Rabies virus - metabolism / Rabies virus - pathogenicity / Rats / Rats, Sprague-Dawley / Research and Analysis Methods / Translation elongation / Transport / Virulence (Microbiology) / Viruses