Probing Molecular Insights into Zika Virus⁻Host Interactions

Abstract

The recent Zika virus (ZIKV) outbreak in the Americas surprised all of us because of its rapid spread and association with neurologic disorders including fetal microcephaly, brain and ocular anomalies, and Guillain⁻Barré syndrome. In response to this global health crisis, unprecedented and world-wide efforts are taking place to study the ZIKV-related human diseases. Much has been learned about this virus in the areas of epidemiology, genetic diversity, protein structures, and clinical manifestations, such as consequences of ZIKV infection on fetal brain development. However, progress on understanding the molecular mechanism underlying ZIKV-associated neurologic disorders remains elusive. To date, we still lack a good understanding of; (1) what virologic factors are involved in the ZIKV-associated human diseases; (2) which ZIKV protein(s) contributes to the enhanced viral pathogenicity; and (3) how do the newly adapted and pandemic ZIKV strains alter their interactions with the host cells leading to neurologic defects? The goal of this review is to explore the molecular insights into the ZIKV⁻host interactions with an emphasis on host cell receptor usage for viral entry, cell innate immunity to ZIKV, and the ability of ZIKV to subvert antiviral responses and to cause cytopathic effects. We hope this literature review will inspire additional molecular studies focusing on ZIKV⁻host Interactions.

Keywords: ZIKV-associated neurologic disorders; ZIKV–host interactions; antiviral responses; cell surface receptors; cytopathic effects; microcephaly; viral counteraction; viral pathogenesis; zika virus.

Figure 1

Schematic structure of the Zika virus genome. Each of the viral proteins is drawn based on the relative orientation in the RNA genome. The ZIKV viral protease, host protease and Furin protease are represented by different arrows, as shown. Each arrow points to the specific protease cleavage site. The numbers shown above each protein product indicate the start/end position. Abbreviations: anaC, anchored capsid protein C; C, capsid protein C; prM, precursor membrane protein; M, membrane protein; Pr, protein pr; E, envelope protein; NS, nonstructural protein; *, protease consists of N-terminal of NS3 and C-terminal NS2B as described in the text. C-terminal of NS3 encodes helicase; 2K, signal peptide 2K; NS5 encodes methyltransferase at its N-terminal end and RNA-dependent RNA (RdR) polymerase at its C-terminal end. UTR, untranslated region. The structures of 5′ UTR and 3′ UTR are based on [21]. The information of ZIKV protein products is based on [9].

Figure 2

This figure illustrates Zika virus interactions with host cells. The Zika virus or proteins are colored in red. Cellular receptors or proteins that are affected by ZIKV are shown in blue. Cellular proteins shown in green are regulatory proteins such as kinases. Three Zika viruses are used here to show ZIKV-induced T-cell responses (left), ZIKV-mediated type I and type III IFNs productions (middle) and ZIKV-triggered autophagy (right). → indicates a positive interaction. ┤ denotes inhibitory action. Small red dots are used to indicate phosphorylation.