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.
Highlights
Zika virus (ZIKV) is an emerging flavivirus that has received widespread attention because of its effect on the developing fetus
viral paresis scale (VPS) scores did not appear to correlate with virus levels in the motor cortex (Fig. 8g, h) or with sciatic nerve infection levels. These results suggest that hindlimb motor deficits in these AG129 mice during the acute phase of ZIKV infection are likely caused primarily by spinal cord myelitis, though upper motor neuron disease and peripheral neuropathy may contribute
The finding that myelitis is likely the primary cause of ZIKV-induced paralysis is in alignment with what has been seen with other flavivirus-induced motor deficits (Sejvar et al 2003; Solomon et al 1998)
Summary
Zika virus (ZIKV) is an emerging flavivirus that has received widespread attention because of its effect on the developing fetus. Recent outbreaks have been associated with higher incidences of peripheral neuropathies such as Guillian-Barrë syndrome (GBS) (Brasil et al 2016; Cao-Lormeau et al 2016; Cardoso et al 2015; Samarasekera and Triunfol 2016) and other neurological diseases such as myelitis (Anaya et al 2017; Dirlikov et al 2016; Mecharles et al 2016), encephalitis (Carteaux et al 2016; Nicastri et al 2016; Soares et al 2016), seizures (Asadi-Pooya 2016), and various ophthalmological conditions (Pastula et al 2016; Smith et al 2016) This is not surprising considering that related flaviviruses such as West Nile virus (WNV) and Japanese encephalitis virus (Solomon et al 1998) can cause myelitis and motor deficits (Sejvar et al 2003). We focus on adult models because ZIKV-related motor deficits have been primarily associated with adult infection, as opposed to in utero infection (Anaya et al 2017; Dirlikov et al 2016; Mecharles et al 2016)
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