Elsevier

Microbial Pathogenesis

Volume 114, January 2018, Pages 476-482
Microbial Pathogenesis

Zika virus: The transboundary pathogen from mosquito and updates

https://doi.org/10.1016/j.micpath.2017.12.031Get rights and content

Highlights

  • ZIKV is reemerging transboundary pathogen which causes public health concern.

  • New molecular determinants of ZIKV revealed how ZIKV caused microcephaly and other diseases, and enhanced ZIKV virulence.

  • Potent anti-ZIKV inhibitor and vaccine showed high efficacy to suppress ZIKV infection.

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus that was relatively obscure until outbreaks started in 2013. ZIKV is associated with neurological manifestations such as Guillan-Barrè Syndrome in adult and microcephaly in the newborn population. Although the majority of disease mechanisms of ZIKV is unclear, some information was updated with new scientific evidence. Currently, there are no approved drugs or vaccine that can be used for therapy during ZIKV infection. Based on the transmission mechanism of ZIKV, vector control and safe sex seem to be the most effective available preventive measures against ZIKV spread. This study summarized the current ZIKV epidemiology, the status of the existing pathogenic mechanism of ZIKV, the development of potential compounds and vaccines against ZIKV, and the control efforts against ZIKV.

Introduction

The most recent emerging disease is derived from a mosquito-borne agent, ZIKV, which is a member of the Flavivirus genus of the Flaviviridae family [1]. This virus was old, but reemerging and is not a well-defined transboundary arbovirus. Due to its mild clinical manifestations and limited spread in restricted geographical regions, ZIKV did not step into the spotlight in the past 70 years. For half a century, ZIKV was described as causing sporadic human infections only in Africa and Asia. Since 2007, ZIKV spread to Micronesia in Oceania, accompanied by a number of patients with rashes, conjunctivitis, subjective fever, arthralgia, and arthritis [2]. This outbreak has led to almost three-quarters of the population of Yap being infected, which was caused by the Asian lineage of ZIKV. Six years later, ZIKV had spread to French Polynesia by 2013-14 and other South Pacific islands by 2014-15 [3], which resulted in an estimate of 28,000 people infected with ZIKV in this outbreak [4]. The ZIKV which caused this outbreak originated from Yap Island. They have an identical 99.9% nucleotide and amino acid sequence [5], [6]. In early 2015, ZIKV was introduced into Brazil, and an estimate of 440,000 to 1,300,000 ZIKV infections have occurred in Brazil [7]. Other studies indicated the introduction of ZIKV to Brazil was possibly associated with the infected travelers during the World Cup football tournament hosted by Brazil [8], [9], [10]. Less than 20 sporadic cases of human ZIKV infection were confirmed before 2007, however, as of March 2016, this virus spread to over 50 countries and territories in the world. It is worth noting that imported cases of ZIKV by travelers from countries with outbreaks have been discovered worldwide since the outbreak in Brazil. This continuous infection and spread of ZIKV has become a global health problem. Although the virus was isolated in the Zika Forest of Uganda since 1947 during an intensive search for yellow fever virus [11], the biological significance of ZIKV still remains elusive due to genetic evolution and increased number of cases associated with congenital disabilities and neurological complications. This review summarizes the recent progress of ZIKV, to help us further understand the potential threats of the newly emerging virus to humans.

ZIKV is an emerging mosquito-borne human-pathogenic Flavivirus of the Flaviviridae family, which contains several other global human pathogens such as dengue, yellow fever, West Nile, Japanese encephalitis and tick-borne encephalitis viruses [12]. ZIKV was first discovered in 1947 from a febrile sentinel rhesus monkey in the Zika forest and refound from Aedes africanus mosquitoes in the same forest. ZIKV is a 50-nm enveloped, spherical partial with an approximately 10.7 kb single positive-sense RNA genome. Similar to other flaviviruses, the genomic RNA comprises a single open reading frame (ORF) which is flanked by 5′ and 3′ untranslated regions (UTRs). The ORF encodes a large polyprotein of 3423 amino acids (aa) which is cleaved post-translationally by host and viral proteases into three structural proteins (capsid (C), pre-membrane (prM), and envelope (E)) and seven non-structural proteins (NS1, NS2A, NS2B,NS3, NS4A NS4B, and NS5) [13] (Fig. 1). The three structural proteins are necessary for the formation of infectious virions [14]. The E protein is the major protein which is involved in receptor binding and fusion. The crystal structures showed that E contains a unique, positively charged patch, which may influence host attachment [15]. In addition, the E protein is also a major target for antibodies via recognition of the ZIKV E protein fusion loop region. M protein is a small protein that is hidden under the E protein layer. The surface proteins (E and M) are arranged in an icosahedral-like symmetry consisting of 60 repeating units [14]. C protein binds to the viral RNA to form a nucleocapsid, prM prevents premature fusion with host membranes [16]. The viral nonstructural proteins are involved in replication, assembly, and antagonizing the host innate response to infection [17]. Two important viral nonstructural proteins play a key role in catalyzing viral RNA replication. Viral serine protease is embedded in the N-terminal domain of NS3, which required NS2 as cofactor for its activity. C-terminal portion of NS3 comprising the RNA triphosphatase (NS3RTPase) and RNA helicase (NS3Hel) activities involves in capping and viral RNA synthesis [18]. The N-terminal portion of NS5 contains a methyltransferase (MT) for RNA capping, followed by a short linker that connects to the RNA-dependent RNA polymerase (RdRp) for viral RNA synthesis [19].

Prior to 2007, ZIKV generally caused mild symptoms or asymptomatic infections, and patients might not seek medical care since they were in poverty and without proper medical facilities. In general, when symptoms are present following ZIKV infection, it is a mild illness including a short duration, self-limiting, mild febrile illness accompanied by a maculopapular rash [20]. Most infected people recover without any long-term sequelae. ZIKV has shown more rapid transmission among human beings since 2007. During the Brazilian epidemic, some patients had new symptoms including Guillain-Barré syndrome (GBS) which is an acute, immune-mediated polyradiculoneuropathy typically occurring after minor viral and bacterial infections may be associated with the outbreak of ZIKV [21]. Clinical presentations at hospital admission were manifested by generalized muscle weakness, with incapacity to walk and even with breathless [22]. Another major concern associated with this infection is the apparent increased incidence of microcephaly [23]. This hypothesis was strongly supported in November 2015 by laboratory evidence of the amniotic fluid of women with microcephalic fetuses [24]. According to radiological analysis of newborns, the most frequently observed findings were microcephaly and decreased brain parenchymal volume associated with lissencephaly, ventriculomegaly secondary to the lack of brain tissue, and coarse and anarchic calcifications mainly involving the subcortical cortical transition, and the basal ganglia [25]. Recently, a new case was reported in Colombia that a 15-year-old girl with sickle cell disease who acquired a ZIKV infection died. Although sickle cell disease is considered as a risk factor for development of severe dengue [26], no cases have been reported in association with ZIKV. In addition, cardiovascular complication, uveitis, severe liver injury and coagulation disorders are also discovered in people infected with ZIKV [27], [28], [29], [30]. Later studies confirmed the ZIKV-induced uveitis in human by causing severe chorioretinitis in eyes of mouse during ZIKV infection [31]. Due to detection of ZIKV in semen of human [32], [33], in vivo experiment proved that ZIKV could cause testis damage in mice [34], [35], [36]. Because ZIKV is spreading rapidly recently, as a risk factor for other diseases, it is essential to take necessary measures to control this epidemic.

According to the results of bioinformatic analyses, ZIKV can be divided into two lineages including African and Asian lineage, the latter is responsible for the recent epidemics [37]. Recently some important genetic diversity between pre-epidemic Asian lineage and epidemic ZIKVs were discovered [38], [39]. They comprehensively compared the genome sequences of pre-epidemic Asian lineage and epidemic ZIKV strains with complete genome or complete polyprotein sequences available in GenBank. There were 15 amino acid substitutions existed in structure (C; prM; E) and non-structure(NS) (NS1; NS2A; NS2B; NS3; NS4A; NS4B; NS5) proteins in epidemic strains and not pre-2007 Asian lineage strains. Also, some amino acid substitutions throughout the genome and a conformational change in the SLI structure at the 3ʹ-UTR of the epidemic ZIKV strain were detected. A similar study also found that six amino acid substitutions in prM (I110V, K143E, A148P, V153M, H157Y, and V158I) resulted in a dramatic predicted structural change of prM between the African and Asian strains [40]. These mutations may be associated with changes in virulence, replication efficiency, antigenic epitopes and host tropism, which need to be verified under experiment.

Until now there are limited published papers about the pathogenicity of ZIKV. Previously other groups used ZIKV to infect A549 cell in vitro [41]. The growth of ZIKV in A549 cells was highly efficient and stimulated the production of Type-I interferons (IFNs), ISGs, and pro-inflammatory cytokines. In addition, they also found that ZIKV replication resulted in a somewhat delayed mitochondrial apoptosis in human epithelial cells. Recently Lazear et al. used different mouse models which lacks components of the antiviral response to test the pathogenesis of ZIKV [42]. In their findings, viral burden analysis revealed that Ifnar1−/− mice lacking interferon α/β (IFN-α/β) signaling sustained high levels of ZIKV in all tissues tested, including serum, spleen, brain, spinal cord, and testes. That suggested that IFN-α/β signaling plays a crucial role in restricting ZIKV infection in mice. Similarly, another group employed AG129 mice lacking the IFN alpha receptor to be infected with a current Cambodian isolate [43]. Viremia peaked at 107PFU/mL on day two postinfection and reached high titers in the spleen on day one. On day three postinfection, ZIKV was detected in the brain and caused signs of neurologic disease. Robust replication was also noted in the testis. In this model, all mice infected at younger age succumbed to illness by day seven postinfection. Older mice showed signs of disease, viremia, and weight loss but recovered since day eight. Those findings suggested that ZIKV caused age-dependent morbidity and mortality in AG129 mice. These results were confirmed by other people [44]. ZIKV produced significant histopathology in the brain from AG129 mice, potentially emulating hallmark features of human infection with ZIKV. This mouse model will be useful for numerous vaccines, antiviral and supportive therapy studies.

Although the appearance of ZIKV is related to the increase of microcephaly in newborns and GBS in adults, it has not been scientifically proven yet. The previous study showed that ZIKV could infect and replicate in murine neurons and astroglia [45]. Similar results were also found in the current epidemic virus [42]. Recent studies showed that ZIKV impairs human brain cells by reducing their viability and growth as neurospheres and brain organoids [46]. However, the mechanism is not clear. To investigate the association between ZIKV and fetal microcephaly, the most recent study discovered that primary human trophoblasts cells from full-term placentas are refractory to ZIKV infection [47]. In addition, medium from uninfected primary human trophoblast (PHT) cells protects non-placental cells from ZIKV infection. PHT cells constitutively release the type III interferon IFNL1, which functions in both a paracrine and autocrine manner to protect trophoblast and non-trophoblast cells from ZIKV infection. However, it is still obscure how ZIKV evade restriction cross the placental barrier. Most recently, Qian et al. developed a new platform to investigate human brain development [48]. A miniaturized spinning bioreactor was developed to generate forebrain-specific organoids from human-induced pluripotent stem cells. A similar microcephaly was generated when the forebrain organoid platform was infected with ZIKV. These results provide strong evidence to verify the association between ZIKV and microcephaly. Similar evidence for a direct link between ZIKV infection and microcephaly is also found in mice model through targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment [49], [50], [51]. However, it is not clear which viral protein and host pathway plays a crucial role in inducing microcephaly or contributing to virulence. Liang et al. found that NS4A and NS4B of ZIKV play an important role in viral pathogenesis [52]. NS4A and NS4B cooperatively suppress the Akt-mTOR pathway and lead to cellular dysregulation and promote autophagy to support virus replication. This result may provide evidence that there is a causal association between ZIKV and microcephaly. ZIKV also block the stress response pathway through inhibiting stress granule protein to benefit virus replication. The viral protein NS3 and NS4A played a key role in suppressing stress granule formation [53]. It has reported that NS4A induced cell hypertrophy and growth delay mediated through the target of rapamycin-mediated cellular-stress response pathway [54]. ZIKV NS5 expression resulted in proteasomal degradation of the IFN-regulated transcriptional activator STAT2 from humans, but not mice, which may explain the requirement for IFN deficiency to observe ZIKV-induced disease in mice [55]. When STAT2 was knocked out in hamsters, which are lethally susceptible to ZIKV infection. This also proved that STAT2 plays an important role during ZIKV infection [56]. In addition, NS2A of ZIKV was found to disrupt mammalian cortical neurogenesis by degrading the adherens junction complex. NS2A interacted with adherens junction complex components resulting in impairing adherens junction formation and reducing radial glial cell proliferation [57]. NS1 is a multifunctional protein which benefits viral prevalence in mosquitoes. A key mutation A188V in NS1 increased viral infectivity, which may lead to viral transmission in humans and cause birth defects [58]. The structural protein also played a significant role in the development of microcephaly and increasing virulence. One important discovery showed that a single mutation S139N in prM protein contributed to enhancing ZIKV infectivity in both human and mouse neural progenitor cells and led to more significant microcephaly in infant mice [59]. The possibility is that the mutation might have some effect on the transition of ZIKV from the immature to the mature virion and improve the viral fitness as well as neurovirulence. Another group reported that N-linked glycosylation of E protein played a significant role in virulence and nuroinvasion [60]. Another study presented evidence that TLR3 activated multiple genetic hubs regulating axonogenesis, cell proliferation, and anti-apoptotic pathways within neural progenitor cells may strongly contribute to the ZIKV-mediated microcephaly phenotype [61]. P53 activation is a special event by ZIKV infection in hNPCs, and a small group of P53 effector proteins also act as critical mediators in Zika –induced microcephaly [62]. Capsid protein can induce apoptosis, it was found to bind with MDM2 to regulate p53-mediated apoptosis pathway [63]. N6-methyladenosine (m6A) is the most common internal messenger RNA (mRNA) modification in eukaryotic organisms and plays pivotal roles in post-transcriptional regulation of gene expression [64]. Recently, the m6A modification of HIV-1 RNA significantly affects viral replication and gene expression [65]. Similarly, the silence of m6A-binding proteins in cells increased ZIKV infection. Furthermore, the silence of the m6A writers or erasers decreased or increased ZIKV synthesis and virion release in virus-producing cells, respectively. These results demonstrated that the host RNA methyltransferase machinery acts as a negative post-transcriptional regulator of ZIKV [66]. ZIKV utilized non-structure proteins to block the two innate pathways that normally inhibit viral replication: interferon (IFN) and mTOR signaling, which also functions to inhibit neurogenesis and induce cell growth arrest (Fig. 2). Its structural proteins are involved in regulating maturity of virion to improve viral fitness and inducing apoptosis via a p53-mediated pathway. According to these results, antiviral compounds could be designed to target non-structural proteins or m6A writer to inhibit viral replication.

In the future, reverse genetics technology and host-virus interaction should be established to verify viral determinants which caused the microcephaly and GBS and affected virulence. Recently, a reverse genetics system was developed to generate ZIKV from cDNA clone, which can be used to develop a new vaccine and expand molecular biology and disease pathogenesis [67], [68], [69].

The rapid spread of ZIKV throughout the world which is associated with GBS in adults and microcephaly in newborns caused devastating consequences for public health. So far, more than one million people have been infected with ZIKV. The Ae. aegypti mosquito is the principal vector of transmission for most human arbovirus infections, including yellow fever, dengue, chikungunya viruses and ZIKV [70]. ZIKV was transmitted between monkeys and mosquitos in the forest. Once the infected mosquitos or monkeys bite people, ZIKV could infect people and generate a new urban cycle (Fig. 3). Up to now, there is no available treatment or vaccine for ZIKV control. The primary approach for prevention and control of ZIKV disease is vector control, which currently relies on either insecticides or the destruction of larval breeding sites. Recently, two new methods were advocated. One of them is the genetic control of Ae. aegypti mosquitoes. The OX513A strain of male mosquitoes expressing a repressible lethal gene are released and these compete with wild males to mate with wild females. Their offspring typically die before adulthood as a consequence of the transgenic modification because they are lack of dietary additive in the wild. The recent data showed this method achieved around 80–90% reduction in wild mosquito's population [71]. Due to the release of transgenic mosquitoes in wild, it may cause public concern. After assessment, recent research showed that release of the transgenic mosquitoes would still be both safe and of great potential value in the control of diseases spread by Ae. aegypti [72]. Another approach is the use of endosymbiotic bacteria, Wolbachia to prevent arboviruses replicating within the mosquito [73]. Recent research has shown that Wolbachia bacteria can confer Ae. aegypt mosquitoes against dengue virus and ZIKV [74], [75]. This strategy utilized endosymbiont successfully invading wild mosquito populations due to a sperm–egg incompatibility called cytoplasmic incompatibility. Wolbachia-infected offspring will be generated when the Wolbachia-infected males or females mate with both infected or uninfected females or males, passing the bacteria from generation to generation. Wolbachia-infected Ae. aegypti mosquitoes were released and successfully invaded wild populations in Australia [76].

Although ZIKV is transmitted to human mainly by mosquitoes, several evidence has shown sex transmission of ZIKV between humans [77], [78], which is confirmed by sex transmission model and detection of ZIKV in semen and prostate [33], [79], [80], [81]. ZIKV RNA was detected in 62–144 days after onset of the illness [32], [82]. Virus was isolated from semen, which was collected on day 11 after symptom onset and showed cytopathic effect in Vero cells [82]. Another study demonstrated that high loads of infectious virus particles were presented in semen up to 69 days after symptom onset [83]. Based on these findings, barrier protection during sex and other forms of contraception should be taken to prevent ZIKV infection, especially during pregnancy. WHO and CDC also recommend taking effective measures to prevent ZIKV infection during sex especially with people living in areas with risk of ZIKV.

There are no approved antiviral drugs against ZIKV. Recently, scientists performed large-scale compound screens and found some common hits against ZIKV. In order to accelerate drug development for targeting ZIKV, drug-repurposing studies, which have demonstrated a promising strategy for identifying therapeutics with novel activity, were performed using FDA-approved drugs for antiviral activity against ZIKV infection. A few small molecules were found to suppress ZIKV across multiple cell types [84], [85], [86]. NSC157058 inhibitors targeted NS2B-NS3 protease without significant cellular toxicity to inhibit its cleavage activity and repress ZIKV infection in both cultured hfNPCs and mice [87]. Another group reused HCV NS3/NS4A inhibitors to test the antiviral activity of ZIKV, three compounds were identified as the competitive inhibitor of NS2B-NS3 protease [88]. Antiviral compound that inhibited dengue virus also suppressed ZIKV in vitro and mouse model [89]. Based on structure-guided approach, molecular modeling was used to obtain the structure of ZIKV MTase, four compounds were identified from 28,341 compounds in Life Chemicals database to inhibit ZIKV by targeting MTase of NS5 [90]. Based on the structural data of NS5, NS5 is a promising target which can be used to develop new inhibitor. Most recently, a nuclear import inhibitor was found to block ZIKV replication by targeting NS5 [91]. Furthermore, a designed peptide inactivator derived from E protein has been shown to block ZIKV infection in pregnant mice and infants through inactivating ZIKV virions [92], [93]. These results demonstrated that development of peptide drugs could be a promising and safe therapeutic candidate against ZIKV. Because ZIKV uses autophagy pathway to promote viral replication and transmission during pregnancy, an autophagy inhibitor, hydroxychloroquine was shown to suppress ZIKV infection in both human trophoblast and autophagy gene-deficient mice by repressing autophagy pathway [94].

Vaccine is the best way to prevent ZIKV infection, the development of a safe and efficacious vaccine to reduce ZIKV infection disease is urgent. Recently, different strategies are under development to produce vaccines that provide better cross-protection to anti-virus. A purified inactivated virus (PIV) vaccine derived from the Puerto Rico strain offered complete protection against parenteral ZIKV challenges in mice and rhesus monkey models [95], [96]. A DNA vaccine expressing full-length ZIKV pre-membrane and envelope, not mutants lacking prM and/or lacking the transmembrane region (dTM) or the full stem of Env, induced ZIKV-specific neutralizing antibodies after a single immunization and offered protection against ZIKV challenges [95], [96], [97]. Live-attenuated ZIKV strain encoding an NS1 protein without glycosylation or containing deletions in the 3′UTR of the ZIKV genome could prevent viral transmission during pregnancy and testis damage in mice [98], [99]. Another subunit vaccine encoding E protein in adenoviral vector also elicited a humoral immune response in mice [100]. A recombinant vesicular stomatitis virus (rVSV) –based vector expressing E or prM induced high anti-ZENV IgG and neutralizing antibodies (NAbs) to protect mice against ZIKV [101]. mRNA has emerged as a promising vaccine modality that can elicit potent immune responses. Unlike plasmid DNA, RNA vaccine poses no danger of genomic integration, which suggests that a RNA vaccine is safer than DNA vaccine. Recently, a lipid nanoparticle encapsulated optimized mRNA encoding prM-E genes elicited potent and durable NAb responses, could stop ZIKV replication in mice and non-human primate model and protected mice against ZIKV-induced damages to testes [98], [102], [103]. Furthermore, modified mRNA with deletion of an immunodominant epitope within the E domain II fusion loop was showed to elicit serum antibody responses, the mRNA protected against ZIKV challenge in mice and also cause less antibody-dependent enhancement (ADE) of DENV1 infection [103]. Since monoclonal flavivirus NAbs map to conformational epitopes in domain III of the E protein, or to more complex quaternary epitopes that bridge between antiparallel E dimers or between dimer rafts arrayed on the virus surface [104], [105]. Moreover, preM, which is important for protein stability could increase the yield of E protein [106]. Although lots of compounds and old drugs were found to inhibit ZIKV replication and different vaccines showed great protective efficacy, clinical experiments should be accelerated to test for an urgent need.

Section snippets

Conclusion

Based on the growing discoveries of ZIKV contributions by the scientific research community, ZIKV has been characterized well in terms of gene function, structure of proteins, genetic evolution, and molecular pathogenesis. Lots of potent compounds and drugs were found to inhibit the ZIKV replication in some way. According to the crystal structure of important proteins, ideal antiviral inhibitors could be designed and tested, and that could accelerate the structure-based design of antiviral

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

We thank Mr. Joe for his careful and critical reading of our paper.

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      ZIKV infection can cause microcephaly in developing embryos and newborn infants, and it is associated with Guillian-Barre syndrome in adults (Avelino-Silva and Martin, 2016; Beckham et al., 2016; Brasil et al., 2016; Cao-Lormeau et al., 2016; Coyne and Lazear, 2016; Cugola et al., 2016; Driggers et al., 2016; Li et al., 2016; Melo et al., 2016; Miner and Diamond, 2017; Miner et al., 2016; Mlakar et al., 2016; Moron et al., 2016; Oehler et al., 2014; Parra et al., 2016; Rodrigues, 2016; Smith and Mackenzie, 2016). The presence of mosquito vector in many parts of the world and the enhanced transmissibility of ZIKV in humans have caused an urgent demand for effective intervention strategies (Attaway et al., 2017; Beckham, 2017; Dick et al., 1952; Epelboin et al., 2017; Frank et al., 2016; Goddard, 2016; Kauffman and Kramer, 2017; Kong et al., 2018; Ozkurt and Tanriverdi, 2017; Perez et al., 2016; Wikan and Smith, 2016; Yockey et al., 2016). ZIKV is a member of the flaviviridae family and shares considerable sequence and structural and functional properties with dengue (DENV), yellow fever (YFV), Japanese encephalitis (JEV), and West Nile (WNV) viruses (Barba-Spaeth et al., 2016; Gubler et al., 2007; Hasan et al., 2017, 2018; Hayes, 2009; Kuhn et al., 2002; Mukhopadhyay et al., 2003; Neufeldt et al., 2018; Nugent et al., 2017; Song et al., 2017; White et al., 2016; Wikan and Smith, 2016).

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