Zika virus-induced acute myelitis and motor deficits in adult interferon αβ/γ receptor knockout mice

Abstract

Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/β receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity.Electronic supplementary materialThe online version of this article (10.1007/s13365-017-0595-z) contains supplementary material, which is available to authorized users.

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

“…The inflammation might be a common factor that cause seizures. Apart from immunocompetent neonatal mice, ZIKV induced seizures were also reported in immunocompromised adult mice ( Zukor et al, 2018 ). In our study, the immunocompromised adult mice (6-7 wk old) show seizure in 40-50% of infected untreated mice while handling them, and hence we considered it as provoked seizures.…”

“…The seizure-related activity was seen in a ZIKV infected immunocompetent neonatal mouse ( Manangeeswaran et al, 2016 ). In adult AG129 mice, the seizures were independent of hind limb motor deficit levels ( Zukor et al, 2018 ). The seizure-related activity has been reported in piglets with in-utero exposure to ZIKV ( Darbellay et al, 2017 ).…”

“…It is well known that brain inflammation can cause seizures. ZIKV infection can cause myelitis and encephalitis in AG129 adult mice ( Zukor et al, 2018 ). Astrocytes play an important role in brain inflammation.…”

“…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 ).…”

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

“…Mice were analyzed using the viral paresis scale 9 for signs of tail and hindlimb paresis/paralysis using a sensitive, open-field assay modified from the Basso Mouse Scale used to assess paralysis in spinal cord-injured mice 10 and a test used to track paralysis in amyotrophic lateral sclerosis mouse models. 11 Each mouse was placed on a tabletop and allowed to roam freely for 4 minutes.…”