Abstract
Zika virus (ZIKV) is a mosquito-borne, single-stranded RNA virus belonging to the genus Flavivirus. Although ZIKV infection is usually known to exhibit mild clinical symptoms, intrauterine ZIKV infections have been associated with severe neurological manifestations, including microcephaly and Guillain Barre syndrome (GBS). Therefore, it is imperative to understand the mechanisms of ZIKV entry into the central nervous system (CNS) and its effect on brain cells. Several routes of neuro-invasion have been identified, among which blood–brain barrier (BBB) disruption is the commonest mode of access. The molecular receptors involved in viral entry remain unknown; with various proposed molecular ZIKV-host interactions including potential non-receptor mediated cellular entry. As ZIKV invade neuronal cells, they trigger neurotoxic mechanisms via cell-autonomous and non-cell autonomous pathways, resulting in neurogenesis dysfunction, viral replication, and cell death, all of which eventually lead to microcephaly. Together, our understanding of the biological mechanisms of ZIKV exposure would aid in the development of anti-ZIKV therapies targeting host cellular and/or viral components to combat ZIKV infection and its neurological manifestations. In this present work, we review the current understanding of ZIKV entry mechanisms into the CNS and its implications on the brain. We also highlight the status of the drug repurposing approach for the development of potential antiviral drugs against ZIKV.
Highlights
Zika virus (ZIKV) is a mosquito-vectored flavivirus, consisting of three structural proteins [capsid (C), pre-membrane/membrane, and envelope (E)], seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) and a single-stranded RNA genome of positive polarity (Yun and Lee, 2017)
The blood–brain barrier (BBB) comprises endothelial cells strongly adhered via tight junction proteins (TJP), which are associated with pericytes, astrocytes, and microglia (Abbott et al, 2010; Mustafa et al, 2019)
Actin cytoskeleton rearrangement was observed upon infection, suggesting possible changes in the morphology of the endothelium (Cle et al, 2020). These findings suggest that endothelial leakage and BBB disruption may not be essential for ZIKV to reach the brain, and ZIKV might utilize other mechanisms to invade the central nervous system (CNS) (Figure 1)
Summary
Zika virus (ZIKV) is a mosquito-vectored flavivirus, consisting of three structural proteins [capsid (C), pre-membrane/membrane (prM/M), and envelope (E)], seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) and a single-stranded RNA genome of positive polarity (Yun and Lee, 2017). ZIKV has been detected in saliva, tears, urine, semen, brain, female genital tract, and testes (Morrison and Diamond, 2017). Zika and the Brain neuroinvasive characteristics and are identified as neurotropic. ZIKV received global attention due to the association with more severe neurological manifestations, such as Guillain-Barre syndrome (GBS) in adults (Oehler et al, 2014; Cao-Lormeau et al, 2016; Watrin et al, 2016) as well as microcephaly in infants (Brasil et al, 2016; Schuler-Faccini et al, 2016). Recent studies have demonstrated the neuroinvasiveness, tropism, and virulence of ZIKV (Shao et al, 2016; Costa et al, 2017a; Zhang et al, 2019). Owing to these severe complications, an extensive understanding of ZIKV neuroinvasion mechanisms and the host molecules involved is vital for therapy development
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