Viral Invasion of Peripheral Nervous System Axons: Comparison of a Rhabdovirus and an Alpha Herpesvirus

Abstract

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, I constructed a spread-deficient (∆G) recombinant RABV expressing a P-mCherry fusion protein, derived from the virulent CVS-N2c strain. I studied retrograde RABV transport in the presence or absence of interferons (IFN) or protein synthesis inhibitors, both of which were reported to restrict axonal transport of αHV particles. Using neurons from rodent superior cervical ganglia grown in tri-chambers, I showed that axonal exposure to type I or type II IFN did not alter retrograde axonal transport of RABV particles. 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 few 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. The 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. The comparative virology studies presented here reveal important differences in virus lifecycle as well as the local and global host cell responses to infection. Such differences may contribute to our understanding of the distinct clinical pathologies caused by these infections.