Flaviviruses, such as dengue, Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and Zika viruses, are critically important human pathogens that sicken a staggeringly high ...number of humans every year. Most of these pathogens are transmitted by mosquitos, and not surprisingly, as the earth warms and human populations grow and move, their geographic reach is increasing. Flaviviruses are simple RNA–protein machines that carry out protein synthesis, genome replication, and virion packaging in close association with cellular lipid membranes. In this review, we examine the molecular biology of flaviviruses touching on the structure and function of viral components and how these interact with host factors. The latter are functionally divided into pro-viral and antiviral factors, both of which, not surprisingly, include many RNA binding proteins. In the interface between the virus and the hosts we highlight the role of a noncoding RNA produced by flaviviruses to impair antiviral host immune responses. Throughout the review, we highlight areas of intense investigation, or a need for it, and potential targets and tools to consider in the important battle against pathogenic flaviviruses.
In response to the outbreak of Zika virus (ZIKV) infection in the Western Hemisphere and the recognition of a causal association with fetal malformations, the Global Virus Network (GVN) assembled an ...international taskforce of virologists to promote basic research, recommend public health measures and encourage the rapid development of vaccines, antiviral therapies and new diagnostic tests. In this article, taskforce members and other experts review what has been learned about ZIKV-induced disease in humans, its modes of transmission and the cause and nature of associated congenital manifestations. After describing the make-up of the taskforce, we summarize the emergence of ZIKV in the Americas, Africa and Asia, its spread by mosquitoes, and current control measures. We then review the spectrum of primary ZIKV-induced disease in adults and children, sites of persistent infection and sexual transmission, then examine what has been learned about maternal-fetal transmission and the congenital Zika syndrome, including knowledge obtained from studies in laboratory animals. Subsequent sections focus on vaccine development, antiviral therapeutics and new diagnostic tests. After reviewing current understanding of the mechanisms of emergence of Zika virus, we consider the likely future of the pandemic.
•The Global Virus Network assembled a task force to respond to the outbreak of Zika virus infection in the New World.•This report summarizes what has been learned about ZIKV disease in humans to date.•Progress has been made in developing animal models, vaccines and therapeutics, with some Phase I trials completed.•Critical questions remain regarding the cause of congenital abnormalities in infants of mothers infected with ZIKV.•Novel strategies are needed to contain ZIKV spread in the Americas and around the world.
Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is ...the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5′ UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.
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•DDX39B is a potent activator of IL7R exon 6 splicing and a repressor of sIL7R•DDX39B genetic variants are significantly associated with MS risk•The 5′ UTR DDX39B variant reduces protein levels by decreasing translation efficiency•This variant shows strong genetic and functional epistasis with IL7R rs6897932
Two genes interact epistatically in multiple sclerosis risk in humans.
Currently there are no approved vaccines or specific therapies to prevent or treat Zika virus (ZIKV) infection. We interrogated a library of FDA-approved drugs for their ability to block infection of ...human HuH-7 cells by a newly isolated ZIKV strain (ZIKV MEX_I_7). More than 20 out of 774 tested compounds decreased ZIKV infection in our in vitro screening assay. Selected compounds were further validated for inhibition of ZIKV infection in human cervical, placental, and neural stem cell lines, as well as primary human amnion cells. Established anti-flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known antiviral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Several drugs reduced ZIKV infection across multiple cell types. This study identifies drugs that could be tested in clinical studies of ZIKV infection and provides a resource of small molecules to study ZIKV pathogenesis.
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•774 FDA-approved drugs screened for anti-Zika virus activity in a human hepatoma cell line•Over 20 compounds showed anti-Zika virus activity•Selected compounds validated in human neural stem cells and primary amnion cells
Currently there is no approved therapy to treat Zika virus (ZIKV) infection. Barrows et al. present a screen of FDA-approved drugs for anti-ZIKV activity in a hepatoma cell line. Selected compounds from the more than 20 identified candidates were validated in human neural stem cells and primary amnion cells.
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