Zika virus genome biology and molecular pathogenesis

Abstract

Zika virus (ZIKV) is an emerging RNA virus in the widespread Flavivirus genus. Recently, ZIKV has rapidly spread around the world and has been implicated in human disease, including neurological disorders, triggering public and scientific attention. Understanding how ZIKV causes disease is the highest priority, yet little is known about this virus. Here we examine the currently published data from ZIKV studies to provide the latest understanding of ZIKV genome biology and molecular pathogenesis. The ZIKV genome evolved rapidly from the Flavivirus genus and diverged from the members of this genus, even within the dengue virus cluster to which ZIKV belongs. Genome variations and divergences also exist among ZIKV strains/isolates. These genome divergences might account for the uniqueness of Zika disease. ZIKV infection activates not only the antiviral immune response but also the pro-inflammatory responses associated with disease symptoms. Strikingly, ZIKV activates protein complexes that are functionally associated with disease process, such as glial cell activation and proliferation (for example, Toll-like receptors), apoptosis and cell death, and inflammation. The activation of these complexes may critically contribute to Zika disease. The novel insights into ZIKV genome divergence and disease mechanisms summarized in this review will help accelerate the development of anti-ZIKV strategies.

Figure 1

ZIKV genome divergence. (A) The ZIKV genome. (B) The ZIKV genome diverges from Flavivirus members. A phylogenetic tree was constructed using all gap-free sites from whole-genome sequences aligned by MAFFT (http://mafft.cbrc.jp/alignment/software/) using a bootstrap of 1000 and neighbor joining. The same method was applied to C. (C) ZIKV strain evolution based on geographic area. Zika virus, ZIKA.

Figure 2

Immune response to ZIKV. (A) An immune response network was constructed using published RNA-seq data. The network was inferred from the systems network database as we previously described, including domains, co-localization, physical interaction and co-expression. Briefly, the protein–protein interactions were extracted from a database and subsequently enriched for significant genes derived from RNA-seq data, as described in our publication. The color of a node (gene) denotes the expression level; expression increases from light red to dark red when compared with mock controls. A line (linkage) represents the interaction type, yellow—common protein domain, blue—co-localization, green—physical interaction. For illustration, the other interactions are labeled as white as background. (B) A proposed scheme of the inflammation initiated by ZIKV infection leading to an antiviral response and an inflammatory response associated with diseases. Zika virus, ZIKV.