An Overview of Zika Virus and Zika Virus Induced Neuropathies

Abstract

Flaviviruses pose a major public health concern across the globe. Among them, Zika virus (ZIKV) is an emerging and reemerging arthropod-borne flavivirus that has become a major international public health problem following multiple large outbreaks over the past two decades. The majority of infections caused by ZIKV exhibit mild symptoms. However, the virus has been found to be associated with a variety of congenital neural abnormalities, including microcephaly in children and Guillain-Barre syndrome in adults. The exact prediction of the potential of ZIKV transmission is still enigmatic and underlines the significance of routine detection of the virus in suspected areas. ZIKV transmission from mother to fetus (including fetal abnormalities), viral presence in immune-privileged areas, and sexual transmission demonstrate the challenges in understanding the factors governing viral persistence and pathogenesis. This review illustrates the transmission patterns, epidemiology, control strategies (through vaccines, antivirals, and vectors), oncolytic aspects, molecular insights into neuro-immunopathogenesis, and other neuropathies caused by ZIKV. Additionally, we summarize in vivo and in vitro models that could provide an important platform to study ZIKV pathogenesis and the underlying governing cellular and molecular mechanisms.

Keywords: animal and cell models; antivirals; mosquito/vector control; neuropathies; neuropathogenesis; neurotropic flaviviruses; oncolytic; prevention; transmission; treatment; vaccines; zika virus.

Figure 1

Genome Organization of Zika Virus: The ZIKV genome is composed of 10,794 nucleotides in a single-stranded, positive-sense RNA that encodes a polyprotein of 3423 amino acids and 10 proteins essential for the viral life cycle. ZIKV RNA has two untranslated regions (UTRs) and a single open reading frame (ORF) comprising three structural (Cap, prM, and E) and seven non-structural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins [60,61,62].

Figure 2

Replication cycle of Zika Virus: The ZIKV replication in the cell is mediated through various steps. (1). The binding of the ZIKV to the host cell is mediated by the interaction of ZIKV E protein and host cell receptors (TIM, TAM, Axl, etc.). (2, 3) Following viral binding to the receptor, the internalization of viral particles inside the cells is mediated through clathrin-coated vesicles, which leads to the formation of endosomes. (4) Inside the endosome, viral E protein rearranges as trimmers that cause the release of ZIKV nucleocapsid in the host cells (5, 6). Viral RNA then produces ZIKV polyprotein, which then enters the ER for the biosynthesis of viral structural and non-structural proteins (NSPs) (7). The immature ZIKV particles then bud off from the ER and migrate towards the Golgi complex. In the Golgi complex, further necessary modifications (glycosylation and others) happen that result in viral maturation. ZIKV then migrates from the Golgi complex to the cell membrane where it leaves the cells through the process of budding (8, 9, 10) [72,73,74,75]. The figure was created at https://BioRender.com.

Figure 3

Transmission cycle of Zika Virus: This figure illustrates the transmission of ZIKV. There are two types of ZIKV transmission: Vertical and horizontal transmission. Vertical transmission has been observed both in mosquitoes as well as in humans. In humans, vertical transmission results in the infection of the fetus and results in fetal loss, microcephaly, and a variety of CNS disorders. Horizontal transmission can occur in many different ways. It can happen in the form of sylvatic cycles where ZIKV transmission occurs between non-human primates (NHPs) and mosquitoes, whereas in urban transmission, transmission occurs by contact of infected mosquitoes with humans. Human-to-human horizontal transmission of ZIKV occurs through body fluids, contaminated instruments and blood transfusion, etc. [76,77,78,79]. The figure was created at https://BioRender.com.

Figure 4

Neurological diseases associated with Zika virus infection. The figure was created at https://BioRender.com.

Figure 5

Cells susceptible to Zika Virus infection: ZIKV gains access to body through bite of an arthropod vector. Following bite, viremia occurs and in a pregnant mother, ZIKV infects the Hofbauer cells in placenta and in this way, it is transmitted to the fetus. In fetus, ZIKV is capable of infecting a myriad of cells, including neural progenitor cells, oligodendrocytes, astrocytes, and microglial cells. This may result in the causation of several congenital neural diseases as discussed in the paper. Furthermore, ZIKV has also been found to establish active infection in male reproductive tract and thus, is transmitted from male to female [204,205,206,207]. The Figure was created at https://BioRender.com.