Zika Virus: An Emerging Global Health Threat

Abstract

Zika virus (ZIKV) is an emerging healthcare threat. The presence of the mosquito Aedes species across South and Central America in combination with complementary climates have incited an epidemic of locally transmitted cases of ZIKV infection in Brazil. As one of the most significant current public health concerns in the Americas, ZIKV epidemic has been a cause of alarm due to its known and unknown complications. At this point, there has been a clear association between ZIKV infection and severe clinical manifestations in both adults and neonates, including but not limited to neurological deficits such as Guillain-Barré syndrome (GBS) and microcephaly, respectively. The gravity of the fetal anomalies linked to ZIKV vertical transmission from the mother has prompted a discussion on whether to include ZIKV as a formal member of the TORCH [Toxoplasma gondii, other, rubella virus, cytomegalovirus (CMV), and herpes] family of pathogens known to breach placental barriers and cause congenital disease in the fetus. The mechanisms of these complex phenotypes have yet to be fully described. As such, diagnostic tools are limited and no effective modalities are available to treat ZIKV. This article will review the recent advancements in understanding the pathogenesis of ZIKV infection as well as diagnostic tests available to detect the infection. Due to the increase in incidence of ZIKV infections, there is an immediate need to develop new diagnostic tools and novel preventive as well as therapeutic modalities based on understanding the molecular mechanisms underlying the disease.

Keywords: Zika virus; Zika virus proteins; animal models of Zika virus; pathogenesis.

Figure 1

Structure of Zika virus (ZIKV). (A) The structure of ZIKV is comparable to many other flaviviruses. The nucleocapsid's diameter is ~25–30 nm. The envelope proteins E and M and other surface proteins are arranged in an icosahedral pattern. (B) Surface dimers depict T3-like organization (adapted from http://viralzone.expasy.org/all_by_species/6756.html).

Figure 2

Three-dimensional structure of ZIKV envelope protein. Ribbon diagram of ZIKV Envelope Protein (ZIKV-E) dimer obtained from Protein data bank (PDB id: 5jhm). ZIKV-E has three distinct domains a central β-barrel (domain I; brown color), an elongated finger-like structure (domain II; yellow color), and a C-terminal immunoglobulin- like module (domain III; green color) (adapted from Dai et al., 2016). Protein structures were visualized and rendered with PyMOL 1.7.3 (The PyMOL Molecular Graphics System, Schrödinger, LLC).

Figure 3

Maternal-Fetal Zika Virus Transmission: (1) Mother is bitten by the mosquito infected with ZIKV. ZIKV is spread throughout the maternal vasculature. (2) ZIKV gains access to the placenta by infecting extravillous trophoblasts residing in decidua. (3) ZIKV moves further into the stroma of villous tree of placenta. (4) ZIKV then infects the placental macrophages, Hofbauer cells. (5) ZIKV replicates inside Hofbauer cells. (6) When new generation of ZIKV is released from the macrophages, it can further migrate to fetal blood vessels, infecting the fetus. (7) ZIKV released from Hofbauer cell can also migrate back to extravillous trophoblast. (8) Newly released ZIKV further infects and damages the trophoblast layer, granting an easy access to placenta by ZIKV. Adapted from Coyne and Lazear (2016).

Figure 4

Structure of ZIKV complexed with antibody Fab C10 from Cryo-EM at pH 6.5 (A) and 8.0 (B) obtained from Protein data bank (PDB ids: 5H30 and 5H37). Blue shade (light to dark blue) shows antibody Fab C10; Red shade (yellow to red) highlights ZIKV-E (Envelope Protein E). Protein structures were visualized and rendered with NGL viewer (Rose and Hildebrand, 2015).