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

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, 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.

Reovirus uses macropinocytosis-mediated entry and fast axonal transport to infect neurons

“…Some neurotropic viruses such as alphaherpesvirus can stimulate synthesis of dynein-regulatory factors to promote their transport following neuronal entry [9]. However, we found that reovirus, similar to rabies virus [97], does not require synthesis of new proteins for axonal transport (S3 Fig). During transport in axons, reovirus-containing vesicles remain predominantly non-acidified (Fig 7A and 7B).…”

Potential antiviral options against SARS-CoV-2 infection

“…It is also used to induce vomiting. In addition, it possessed antiviral effects against ZIKV, EBOV, RABV, CMV, HCoV-OC43, HSV-2, EV1, HMPV, RVF, FLUAV, HIV-1 and SARS-CoV-2 (Andersen et al, 2019;Chaves Valadao et al, 2015;Choy et al, 2020;MacGibeny et al, 2018;Mukhopadhyay et al, 2016;Shen et al, 2019;Yang et al, 2018) (https://doi.org/10.1101/2020.03.25.008482). Emetine was proposed to inhibit viral polymerases, though it could have some other targets (Khandelwal et al, 2017).…”

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

“…However, its potential cardiotoxicity has restricted its clinical use in the recent years. It was found to process antiviral activity against a broad range of RNA and DNA viruses, including Zika virus, Ebolavirus, Cytomegalovirus, rabies virus, HIV-1, echovirus 1, buffalo poxvirus, bovine herpesvirus 1, peste des petits ruminants virus, Newcastle disease virus, herpes simplex virus-2, metapneumovirus, Rift Valley fever virus, and influenza (Andersen et al, 2019;Chaves Valadao et al, 2015;Khandelwal et al, 2017;MacGibeny et al, 2018;Mukhopadhyay et al, 2016;Yang et al, 2018). Emetine was also identified to inhibit hCoV-OC43, hCoV-NL43, SARS-CoV, MERS-CoV, and MHV-A59 in vitro with EC 50 reported at low micromolar range (Dyall et al, 2014;Shen et al, 2019).…”