Zika virus infection causes temporary paralysis in adult mice with motor neuron synaptic retraction and evidence for proximal peripheral neuropathy

Abstract

Clinical evidence is mounting that Zika virus can contribute to Guillain-Barré syndrome which causes temporary paralysis, yet the mechanism is unknown. We investigated the mechanism of temporary acute flaccid paralysis caused by Zika virus infection in aged interferon αβ-receptor knockout mice used for their susceptibility to infection. Twenty-five to thirty-five percent of mice infected subcutaneously with Zika virus developed motor deficits including acute flaccid paralysis that peaked 8-10 days after viral challenge. These mice recovered within a week. Despite Zika virus infection in the spinal cord, motor neurons were not destroyed. We examined ultrastructures of motor neurons and synapses by transmission electron microscopy. The percent coverage of motor neurons by boutons was reduced by 20%; more specifically, flattened-vesicle boutons were reduced by 46%, and were normalized in recovering mice. Using electromyographic procedures employed in people to help diagnose Guillain-Barré syndrome, we determined that nerve conduction velocities between the sciatic notch and the gastrocnemius muscle were unchanged in paralyzed mice. However, F-wave latencies were increased in paralyzed mice, which suggests that neuropathy may exist between the sciatic notch to the nerve rootlets. Reversible synaptic retraction may be a previously unrecognized cofactor along with peripheral neuropathy for the development of Guillain-Barré syndrome during Zika virus outbreaks.

Memantine treatment reduces the incidence of flaccid paralysis in a zika virus mouse model of temporary paralysis with similarities to Guillain-Barré syndrome

“…This statistical test of the percentage of paralyzed mice also revealed statistical significance ( p = 0.0381) in experiment #1, but not experiment #2. As previously observed, 5 most animals survive ( Figure 1(c) and (f) ) and recover from paralysis ( Figure 1(a) and (d) ).…”

“…A distinguishing pathological event in this mouse model is that pre-synaptic terminals becomes detached or retracted from alpha-motor neurons in paralyzed mice. 5 The synapses are then re-associated upon recovery of paralysis. A hypothesis for future studies, therefore, is that glutamate excitotoxicity mediated by N-methyl-D-aspartate receptors signals synaptic retraction and paralysis, and that resolution of glutamate excitotoxicity might reverse the paralysis of ZIKV-induced Guillain-Barré syndrome.…”

“…Unlike more pathogenic flaviviruses, like West Nile virus or Japanese encephalitis virus, that infect and destroy motor neurons in the spinal cord, 5 Zika virus infection in aged IFNAR -/mice does not destroy motor neurons. Zika virus immunoreactivity cannot be readily detected with colocalization of motor neuron-immunoreactive markers in the lumbosacral spinal cords of paralyzed mice, yet there is some Zika virus immunoreactivity outside of motor neurons.…”

“…A recent mouse model of Zika virus-induced temporary paralysis has provided an opportunity to evaluate cellular mechanisms. 5 Since Zika virus does not cause robust disease in adult laboratory mice, interferon αβ-receptor (IFNAR −/− ) knockout mice were used. Infection is lethal in young IFNAR −/− mice, but infection in aged mice greater than 4-months-old is sublethal.…”

Castanospermine reduces Zika virus infection-associated seizure by inhibiting both the viral load and inflammation in mouse models

“…With ZIKV infection, there was an increase in the expression of glial fibrillary acidic protein (GFAP) a marker of astrocytes ( Souza et al, 2018 ). ZIKV infection is associated with inflammation and synaptic retractions in motor neurons ( Morrey et al, 2019 ; Zukor et al, 2018 ). The motor abnormalities can be assessed by rotarod and wire suspension tests ( Barker-Haliski et al, 2016 ; Rabl et al, 2016 ).…”