Zika virus genome biology and molecular pathogenesis

OPEN Emerging Microbes & Infections (2017) 6, e13; doi:10.1038/emi.2016.141 www.nature.com/emi REVIEW Zika virus genome biology and molecular pathogenesis Anyou Wang1*, Stephanie Thurmond2,*, Leonel Islas1,2, Kingyung Hui2 and Rong Hai1,2 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. Emerging Microbes & Infections (2017) 6, e13; doi:10.1038/emi.2016.141; published online 22 March 2017 INTRODUCTION Zika virus (ZIKV) is a single-stranded positive-sense RNA arbovirus belonging to the Flavivirus genus of the Flaviviridae family, members of which cause widespread morbidity worldwide.1 Since the recent large outbreak in 2007, ZIKV has rapidly spread throughout South America, Central America and the Caribbean, and has been implicated in neurological disorders such as microcephaly, a condition in which the fetal brain does not properly develop.2,3 ZIKV has also been linked to Guillain–Barré syndrome (GBS), an autoimmune disease that causes paralysis.4 The severity of the diseases associated with Zika and its rapid spread have triggered an urgent need to understand this virus. ZIKV was first isolated in 1947 from a sentinel rhesus monkey in Uganda.5 In 1952, it was found in humans, and it was linked to Zika disease in 1964.6 However, little attention was paid to this virus until 2007, when an outbreak of ‘dengue-like illness’ was reported in the Yap State of Micronesia. It was estimated that 470% of Yap State residents were infected with ZIKV.7 Another outbreak occurred in 2013 in French Polynesia and subsequently in other Pacific Islands.8 Outbreaks also occurred in New Caledonia, the Cook Islands and Easter Island,9 and ZIKV circulation has been reported in other Pacific islands. To date, the ZIKV outbreak in Brazil is the largest ever recorded, with an estimated 165 000 suspected and confirmed cases as of August 2016.10 This rapid spread of ZIKV and its implication in severe disease have prompted the scientific community to develop interventions to combat Zika disease. However, the disease mechanism is not currently understood. Here we review and analyze emerging studies of ZIKV genome biology and pathogenesis to provide insight into ZIKV molecular pathogenesis to facilitate the development of Zika disease prevention strategies. However, this review does not provide a general overview of ZIKV; such overviews have recently been published.2,11–16 ZIKV GENOME BIOLOGY The entire genome of the African prototype ZIKV strain (MR 766) was sequenced for the first time in 2007, and epidemic ZIKV strains are currently being sequenced at a rapid pace. The ZIKV genome comprises a 10.8-kb single-stranded positive-sense RNA molecule that contains an ~ 100 nt 5′ untranslated region (UTR), a single open reading frame of ~ 10 kb, and an ~ 420 nt 3′ UTR.17 The open reading frame encodes a single polyprotein, which is later processed into the capsid (C); the precursor membrane (prM); the envelope protein (E); and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5; Figure 1A). We next discuss the ZIKV genome, its divergence from other Flavivirus members, and the genetic variations found among various ZIKV isolates. Genome evolution Flavivirus genus members have evolved rapidly and divergently. To understand the evolutionary relatedness of ZIKV to other members of the Flavivirus genus, we performed a phylogenetic analysis using the genome sequences of representative Flavivirus members (Figure 1B). The analysis confirmed that ZIKV clusters with dengue viruses (DENVs) at a higher hierarchical level; however, ZIKV is most closely related to Spondweni virus, resulting in an individual ZIKV cluster in the phylogenetic tree. This separation of the ZIKV cluster from other clusters at a similar hierarchical level (for example, DENV and West Nile virus (WNV)) suggested that ZIKV may have evolved disease 1 The Institute for Integrative Genome Biology, University of California at Riverside, Riverside, CA 92521, USA and 2Department of Microbiology and Plant Pathology, University of California at Riverside, Riverside, CA 92521, USA *These authors contributed equally to this work. Correspondence: A Wang; R Hai E-mail: ; Received 25 September 2016; revised 3 December 2016; accepted 19 December 2016 ZIKV genome biology and molecular pathogenesis A Wang et al 2 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. mechanisms distinct from these other viruses despite the similarity in disease symptoms exhibited by dengue, West Nile and ZIKV-infected individuals (Figure 1B). Another unique characteristic of ZIKV is its high homologous recombination activity. ZIKV appears to have undergone multiple recombination events between 1947 and 2007. Such active recombination is uncommon among flaviviruses and has been suggested as a mechanism for the adaptation of ZIKV to the Aedes dalzieli vector.18 Strains and isolates within the ZIKV species have also evolved rapidly. These strains can be clustered into two major lineages: African and Asian (Figure 1C). Some investigators further divide the African lineages into West African and East African lineages.18–20 Many of the African lineage ZIKV strains were isolated from mosquitoes (Figure 1C). The Asian lineage evolved from the Malaysia/1966 isolate. The Asian stra (...truncated)