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.
Highlights
Clinical evidence is mounting that Zika virus can contribute to Guillain-Barré syndrome which causes temporary paralysis, yet the mechanism is unknown
Mice were infected with the PRVABC59 strain of Zika virus (ZIKV), 16% of infected mice became paralyzed as measured by the viral paresis scale of 5 or 621, 29% had observable behavioral motor deficits, while 71% had no observable deficits (Fig. 1A–D)
We showed that ZIKV can cause a temporary acute flaccid paralysis in mice that recover within a week, and that paralysis was associated with infection of the spinal cord without the destruction of motor neuron (MN)
Summary
Clinical evidence is mounting that Zika virus can contribute to Guillain-Barré syndrome which causes temporary paralysis, yet the mechanism is unknown. 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. Reversible synaptic retraction may be a previously unrecognized cofactor along with peripheral neuropathy for the development of Guillain-Barré syndrome during Zika virus outbreaks. Modeling of epidemiological data from 11 locations which report cases of both ZIKV and Guillain-Barré syndrome indicate that the incidence of Guillain-Barré syndrome during a ZIKV outbreak can be many times higher than normal[8]. Guillain-Barré syndrome-like models in mice have furthered our understanding of Guillain-Barré syndrome[13,14], but questions still remain regarding many other unknown aspects of human Guillain-Barré syndrome
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