Zika Virus Replication in Dorsal Root Ganglia Explants from Interferon Receptor1 Knockout Mice Causes Myelin Degeneration

Vera Giulia Volpi,Elisa Vicenzi,Matteo Iannacone,Isabel Pagani,Silvia Ghezzi,Maurizio D’Antonio

doi:10.1038/s41598-018-28257-5

Vera Giulia Volpi, Elisa Vicenzi + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-28257-5

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Abstract

Zika virus (ZIKV) is a neurotropic agent that targets the developing fetal brain in women infected during pregnancy. In addition to the developing central nervous system, ZIKV has been recently shown to infect cells of the peripheral nervous system (PNS), highlighting its potential to cause acute peripheral neuropathies in adults, such as Guillain-Barré Syndrome (GBS). Here we show that myelinating dorsal root ganglia (DRG) explants obtained from interferon-alpha/beta receptor knock-out mice are productively infected by ZIKV. Virus replication is cytopathic in both peripheral neurons and myelinating Schwann cells leading to myelin disruption. These results confirm and extend previous observations suggesting that the PNS is indeed a potential site of ZIKV infection, replication and cytopathicity.

Highlights

Zika virus (ZIKV) tropism for the central nervous system (CNS) has been extensively studied in several model systems[13,14,15,16], its capacity to infect the peripheral nervous system (PNS) has been poorly explored
In order to investigate whether ZIKV could induce pathology in the PNS, we took advantage of myelinating dorsal root ganglia (DRG) explants obtained from Ifnar1-KO mice, previously shown to be highly permissive to ZIKV infection and replication, in contrast to immunocompetent mice that are relatively resistant[19]
A faint signal was detected upon infection with the contemporary PRVABC59 strain (Fig. 7b), whereas in the MR766-infected co-cultures, several PNS cells, many of which P0-positive myelinating Schwann cells (SC), displayed signal of C/Ebp-Homologous Protein (CHOP) induction (Fig. 7c–e). This evidence suggests that ZIKV infection can induce endoplasmic reticulum (ER) stress in our multicellular culture system by activating the P-eIF2-alpha/CHOP pathway, which may contribute to axon demyelination. We show that both the historical MR766 and the 2015 Puerto Rican PRVABC59 isolates establish a productive infection in DRG explants obtained from mice deficient in IFNAR1

Summary

Introduction

ZIKV tropism for the central nervous system (CNS) has been extensively studied in several model systems[13,14,15,16], its capacity to infect the PNS has been poorly explored. A recent study performed in interferon-alpha/beta receptor subunit 1 knock-out (Ifnar1-KO) mice, permissive to ZIKV replication, suggested that peripheral neurons and Schwann cells (SC) derived from dorsal root ganglia (DRG) explants are less susceptible to ZIKV infection as compared to CNS cells[17]. Another study showed that ZIKV can directly infect SC and peripheral neurons derived from re-programming of human pluripotent stem cells[18]. The same study showed that ZIKV infected the somatosensory neurons of A129 mice, defective of IFNAR1 expression, causing neuronal cell death[18]. Whether ZIKV can directly infect mature SC, which have already formed myelin, and cause demyelination is unknown For this reason, we tested whether ZIKV productively infected myelinating SC and, eventually, altered myelin stability in myelinating DRG explants from Ifnar1-KO mice.

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