Zika Virus Infection Disrupts Astrocytic Proteins Involved in Synapse Control and Axon Guidance

Abstract

The first human Zika virus (ZIKV) outbreak was reported in Micronesia in 2007, followed by one in Brazil in 2015. Recent studies have reported cases in Europe, Oceania and Latin America. In 2016, ZIKV transmission was also reported in the US and the World Health Organization declared it a Public Health Emergency of International Concern. Because various neurological conditions are associated with ZIKV, such as microcephaly, Guillain-Barré syndrome, and other disorders of both the central and peripheral nervous systems, including encephalopathy, (meningo)encephalitis and myelitis, and because of the lack of reliable patient diagnosis, numerous ongoing studies seek to understand molecular mechanisms underlying ZIKV pathogenesis. Astrocytes are one of the most abundant cells in the CNS. They control axonal guidance, synaptic signaling, neurotransmitter trafficking and maintenance of neurons, and are targeted by ZIKV. In this study, we used a newly developed multiplexed aptamer-based technique (SOMAScan) to examine > 1300 human astrocyte cell proteins. We identified almost 300 astrocyte proteins significantly dysregulated by ZIKV infection that span diverse functions and signaling pathways, including protein translation, synaptic control, cell migration and differentiation.

Zika virus infection leads to mitochondrial failure, oxidative stress and DNA damage in human iPSC-derived astrocytes

“…These may explain malformations observed in infected neonates, such as dysplastic cortex and over migration to subarachnoid spaces in brains 14 , probably due to the damage of radial glia and limitant glia, respectively. In fact, proteomic analysis of ZIKV-infected human astrocytoma cell line (U-251) at 48 hpi showed disruption in pathways involved in cell migration and proliferation, and in the ones related to synaptic plasticity 59 . Considering that astrocytes play crucial roles during brain development as well as in post-natal and adult stages, such as blood-brain barrier (BBB) maintenance, metabolic neuronal support, guidance for neural progenitor migration, and synaptic regulation, their dysregulation could have severe implications not only for congenital diseases, such as microcephaly, but also for the onset of neurologic disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD) [60][61][62] .…”

Neurocognitive impacts of arbovirus infections

“…Data indicate that the combinatorial effect of synapse loss and reduced neurogenesis can negatively impact hippocampal spatial learning and memory long beyond the initial episode of infection via a shift in sources of cytokines cells [178]. ZIKV-infection on human astrocytes led to disruption of pathways and cellular protein levels involved in synaptogenesis axonal guidance signaling [179]. This could also participate to ZIKV-induced impairment of neuronal circuits and network development [179].…”

Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome

“…Non-treated and pharmacologically-treated U-251 samples were harvested at each of various time points (12,24, and 48 h post-treatment-hpt) and washed 3× with > 50-volumes of ice-cold PBS to remove media and FBS. Washed cells were lysed with MPER ® (Pierce, Rockford, IL, USA) supplemented with 1× HALT ® Protease inhibitor (Pierce, Rockford, IL, USA).…”

“…Protein concentrations of BCA-determined cell lysates were adjusted to 200 ng/µL, and 70 µL of each sample submitted for SOMAscan ® analysis in-house on a SomaLogics ® -licensed platform in the Manitoba Centre for Proteomics and Systems Biology as described [17,23,24]. Briefly, the SOMAscan assay is a novel proteomic tool that uses single-stranded DNA-based Slow Off-rate Modified Aptamer reagents (SOMAmers).…”