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.

Ceruloplasmin (Cp) is an abundant multifunctional copper‐binding protein in the blood plasma best known for its ferroxidase activity. Using purified 64Cu‐labeled Cp, we have now established that it also delivers copper directly to cultured cells. Here, we further examined whether this process occurs at the cell surface, involving a reductase, and attempted to identify a new copper transporter and overexpress human Cp. Uptake of copper from 64Cu‐Cp (purified from mouse plasma) by mouse embryonic fibroblasts that do and do not express Ctr1, was not prevented by endocytosis inhibitors; and holoCp appeared to convert to apoCp during uptake. The only known copper reductase expressed was identified as Steap2 by qPCR. Successive siRNA treatments did not reduce cell surface reductase activity, and other approaches are being applied. Identification of copper uptake transporter in the Ctr1‐/‐ fibroblasts was sought using biotinylation‐targeting with mouse Cp, and cross‐linking with formaldehyde. No clear candidates have as yet emerged. To provide a reliable source of 64Cu‐Cp for future studies, attempts were made to clone and express human Cp in Sf9 insect cells using baculovirus (which did not succeed); overexpression in human cell lines using either a conventional or lentivirus construct is now in the process. We conclude that uptake of copper from Cp occurs at the cell surface and may require a reductase that delivers Cu1+ not just to Ctr1 but also to another transporter.

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