Wolbachia wStri Blocks Zika Virus Growth at Two Independent Stages of Viral Replication

ABSTRACTMosquito-transmitted viruses are spread globally and present a great risk to human health. Among the many approaches investigated to limit the diseases caused by these viruses are attempts to make mosquitos resistant to virus infection. Coinfection of mosquitos with the bacteriumWolbachia pipientisfrom supergroup A is a recent strategy employed to reduce the capacity for major vectors in theAedesmosquito genus to transmit viruses, including dengue virus (DENV), Chikungunya virus (CHIKV), and Zika virus (ZIKV). Recently, a supergroup BWolbachia wStri, isolated fromLaodelphax striatellus, was shown to inhibit multiple lineages of ZIKV inAedes albopictuscells. Here, we show thatwStri blocks the growth of positive-sense RNA viruses DENV, CHIKV, ZIKV, and yellow fever virus by greater than 99.9%.wStri presence did not affect the growth of the negative-sense RNA viruses LaCrosse virus or vesicular stomatitis virus. Investigation of the stages of the ZIKV life cycle inhibited bywStri identified two distinct blocks in viral replication. We found a reduction of ZIKV entry intowStri-infected cells. This was partially rescued by the addition of a cholesterol-lipid supplement. Independent of entry, transfected viral genome was unable to replicate inWolbachia-infected cells. RNA transfection and metabolic labeling studies suggested that this replication defect is at the level of RNA translation, where we saw a 66% reduction in mosquito protein synthesis inwStri-infected cells. This study’s findings increase the potential for application ofwStri to block additional arboviruses and also identify specific blocks in viral infection caused byWolbachiacoinfection.IMPORTANCEDengue, Zika, and yellow fever viruses are mosquito-transmitted diseases that have spread throughout the world, causing millions of infections and thousands of deaths each year. Existing programs that seek to contain these diseases through elimination of the mosquito population have so far failed, making it crucial to explore new ways of limiting the spread of these viruses. Here, we show that introduction of an insect symbiont,Wolbachia wStri, into mosquito cells is highly effective at reducing yellow fever virus, dengue virus, Zika virus, and Chikungunya virus production. Reduction of virus replication was attributable to decreases in entry and a strong block of virus gene expression at the translational level. These findings expand the potential use ofWolbachia wStri to block viruses and identify two separate steps for limiting virus replication in mosquitos that could be targeted via microbes or other means as an antiviral strategy.

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Simultaneous detection of Dengue virus, Chikungunya virus, Zika virus, Yellow fever virus and West Nile virus

Journal of Virological Methods ◽

10.1016/j.jviromet.2019.03.014 ◽

2019 ◽

Vol 268 ◽

pp. 53-55 ◽

Cited By ~ 3

Author(s):

José A. Boga ◽

Marta E. Alvarez-Arguelles ◽

Susana Rojo-Alba ◽

Mercedes Rodríguez ◽

María de Oña ◽

...

Keyword(s):

West Nile Virus ◽

Dengue Virus ◽

Yellow Fever ◽

Zika Virus ◽

Chikungunya Virus ◽

Yellow Fever Virus ◽

Simultaneous Detection ◽

Fever Virus ◽

West Nile ◽

Virus Zika

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Endemic and Emerging Arboviruses of Mosquitoes in Ecuador

Práctica Familiar Rural ◽

10.23936/pfr.v5i2.165 ◽

2020 ◽

Vol 5 (2) ◽

Author(s):

Rachel Sippy ◽

Cat Lippi ◽

Anna Stewart ◽

Sadie Ryan

Keyword(s):

Dengue Virus ◽

Yellow Fever ◽

Zika Virus ◽

Chikungunya Virus ◽

Yellow Fever Virus ◽

Eastern Africa ◽

Health Concern ◽

Long Time ◽

Mayaro Virus ◽

The Tropics

Arboviruses are arthropod-borne viruses that include many viruses of public health concern found in Ecuador. Dengue virus, yellow fever virus and Zika virus are in the Flaviridae family (1), while chikungunya virus and Mayaro virus are in the Togaviridae family (1). Yellow fever has circulated throughout the tropics since at least the17th century, with the first recorded outbreak in Latin America in 1647 (2), with the virus being identified in 1927 (3). Dengue virus is also a long-time source of global outbreaks and was identified in 1943 (4). Dengue has four virus serotypes (DENV 1-4), allowing for repeated infection of individuals. Chikungunya, Zika and Mayaro were identified as causes of febrile disease more recently: the Zika virus was isolated from a monkey in 1947 in Uganda (5), chikungunya virus during an outbreak in south-eastern Africa in 1952 (1), and Mayaro virus from a patient in Trinidad in 1954 (6). Chikungunya has four genotypes: East/Central/South African, Western African, Indian Ocean and Asian (1), while Zika has two genetics lineages: Asian and African (7). Ecuador is susceptible to introductions of arboviruses transmitted by several mosquito vectors that are either well established or recently introduced and has thus experienced multiple and repeated introductions of these diseases. Of these, at present, only yellow fever has a widely available and licensed vaccine.

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Zika Virus: Diagnostics for an Emerging Pandemic Threat

Journal of Clinical Microbiology ◽

10.1128/jcm.00279-16 ◽

2016 ◽

Vol 54 (4) ◽

pp. 860-867 ◽

Cited By ~ 151

Author(s):

Jesse J. Waggoner ◽

Benjamin A. Pinsky

Keyword(s):

Dengue Virus ◽

Zika Virus ◽

Chikungunya Virus ◽

Febrile Illness ◽

Zikv Infection ◽

Content Type ◽

Clinical Criteria ◽

Virus Diagnostics ◽

Pandemic Threat

Zika virus (ZIKV) is anAedesmosquito-borne flavivirus that emerged in Brazil in 2015 and then rapidly spread throughout the tropical and subtropical Americas. Based on clinical criteria alone, ZIKV cannot be reliably distinguished from infections with other pathogens that cause an undifferentiated systemic febrile illness, including infections with two common arboviruses, dengue virus and chikungunya virus. This minireview details the methods that are available to diagnose ZIKV infection.

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Tombusviruses target a major crossroad in the endocytic and recycling pathways via co-opting Rab7 small GTPase

Journal of Virology ◽

10.1128/jvi.01076-21 ◽

2021 ◽

Author(s):

Zhike Feng ◽

Jun-ichi Inaba ◽

Peter D. Nagy

Keyword(s):

Viral Replication ◽

Virus Replication ◽

Rna Viruses ◽

Small Gtpase ◽

Replication Protein ◽

Positive Strand ◽

Sorting Nexin ◽

Retromer Complex ◽

Infected Cells ◽

Positive Strand Rna

Positive-strand RNA viruses induce the biogenesis of unique membranous organelles, called viral replication organelles (VROs), which perform virus replication in infected cells. Tombusviruses have been shown to rewire cellular trafficking and metabolic pathways, remodel host membranes and recruit multiple host factors to support viral replication. In this work, we demonstrate that tomato bushy stunt virus (TBSV) and the closely-related carnation Italian ringspot virus (CIRV) usurp Rab7 small GTPase to facilitate building VROs in the surrogate host yeast and in plants. Depletion of Rab7 small GTPase, which is needed for late endosome and retromer biogenesis, strongly inhibits TBSV and CIRV replication in yeast and in planta. The viral p33 replication protein interacts with Rab7 small GTPase, which results in relocalization of Rab7 into the large VROs. Similar to depletion of Rab7, deletion of either MON1 or CCZ1 heterodymeric GEFs (guanine nucleotide exchange factors) of Rab7, inhibited TBSV repRNA replication in yeast. This suggests that the activated Rab7 has pro-viral functions. We show that the pro-viral function of Rab7 is to facilitate the recruitment of the retromer complex and the endosomal sorting nexin-BAR proteins into VROs. We demonstrate that TBSV p33-driven retargeting Rab7 into VROs results in delivery of several retromer cargos with pro-viral functions. These proteins include lipid enzymes, such as Vps34 PI3K (phosphatidylinositol 3-kinase), PI4Kα-like Stt4 (phosphatidylinositol 4-kinase) and Psd2 phosphatidylserine decarboxylase. In summary, based on these and previous findings, we propose that subversion of Rab7 into VROs allows tombusviruses to reroute endocytic and recycling trafficking to support virus replication. Importance: Replication of positive-strand RNA viruses depends on the biogenesis of viral replication organelles (VROs). However, formation of membranous VROs is not well understood yet. Using tombusviruses and the model host yeast, the authors discovered that the endosomal Rab7 small GTPase is critical for the formation of VROs. Interaction between Rab7 and the TBSV p33 replication protein leads to the recruitment of Rab7 into VROs. TBSV-driven usurping of Rab7 has pro-viral functions through facilitating the delivery of co-opted retromer complex, sorting nexin-BAR proteins and lipid enzymes into VROs to create optimal milieu for virus replication. These results open up the possibility that controlling cellular Rab7 activities in infected cells could be a target for new antiviral strategies.

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Yellow Fever Virus, but Not Zika Virus or Dengue Virus, Inhibits T-Cell Receptor–Mediated T-Cell Function by an RNA-Based Mechanism

The Journal of Infectious Diseases ◽

10.1093/infdis/jix462 ◽

2017 ◽

Vol 216 (9) ◽

pp. 1164-1175 ◽

Cited By ~ 5

Author(s):

James H McLinden ◽

Nirjal Bhattarai ◽

Jack T Stapleton ◽

Qing Chang ◽

Thomas M Kaufman ◽

...

Keyword(s):

T Cell ◽

Dengue Virus ◽

T Cell Receptor ◽

Yellow Fever ◽

Zika Virus ◽

Cell Function ◽

Yellow Fever Virus ◽

Cell Receptor ◽

Fever Virus ◽

T Cell Function

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High specificity of a novel Zika virus ELISA in European patients after exposure to different flaviviruses

Eurosurveillance ◽

10.2807/1560-7917.es.2016.21.16.30203 ◽

2016 ◽

Vol 21 (16) ◽

Cited By ~ 88

Author(s):

Daniela Huzly ◽

Ingeborg Hanselmann ◽

Jonas Schmidt-Chanasit ◽

Marcus Panning

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Dengue Virus ◽

Yellow Fever ◽

Zika Virus ◽

Yellow Fever Virus ◽

High Specificity ◽

Tick Borne Encephalitis ◽

Igm Elisa ◽

Tick Borne Encephalitis Virus

The current Zika virus (ZIKV) epidemic in the Americas caused an increase in diagnostic requests in European countries. Here we demonstrate high specificity of the Euroimmun anti-ZIKV IgG and IgM ELISA tests using putative cross-reacting sera of European patients with antibodies against tick-borne encephalitis virus, dengue virus, yellow fever virus and hepatitis C virus. This test may aid in counselling European travellers returning from regions where ZIKV is endemic.

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Aedes Anphevirus: an Insect-Specific Virus Distributed Worldwide inAedes aegyptiMosquitoes That Has Complex Interplays withWolbachiaand Dengue Virus Infection in Cells

Journal of Virology ◽

10.1128/jvi.00224-18 ◽

2018 ◽

Vol 92 (17) ◽

Cited By ~ 19

Author(s):

Rhys Parry ◽

Sassan Asgari

Keyword(s):

Aedes Aegypti ◽

Dengue Virus ◽

Cell Line ◽

Cell Lines ◽

Virus Replication ◽

Rna Viruses ◽

Asia Pacific ◽

Content Type ◽

Negative Strand ◽

Positive Sense

ABSTRACTInsect-specific viruses (ISVs) of the yellow fever mosquitoAedes aegyptihave been demonstrated to modulate transmission of arboviruses such as dengue virus (DENV) and West Nile virus by the mosquito. The diversity and composition of the virome ofA. aegypti, however, remains poorly understood. In this study, we characterized Aedes anphevirus (AeAV), a negative-sense RNA virus from the orderMononegavirales. AeAV identified fromAedescell lines was infectious to bothA. aegyptiandAedes albopictuscells but not to three mammalian cell lines. To understand the incidence and genetic diversity of AeAV, we assembled 17 coding-complete and two partial genomes of AeAV from available transcriptome sequencing (RNA-Seq) data. AeAV appears to transmit vertically and be present in laboratory colonies, wild-caught mosquitoes, and cell lines worldwide. Phylogenetic analysis of AeAV strains indicates that as theA. aegyptimosquito has expanded into the Americas and Asia-Pacific, AeAV has evolved into monophyletic African, American, and Asia-Pacific lineages. The endosymbiotic bacteriumWolbachia pipientisrestricts positive-sense RNA viruses inA. aegypti. Reanalysis of a small RNA library ofA. aegypticells coinfected with AeAV andWolbachiaproduces an abundant RNA interference (RNAi) response consistent with persistent virus replication. We foundWolbachiaenhances replication of AeAV compared to a tetracycline-cleared cell line, and AeAV modestly reduces DENV replicationin vitro. The results from our study improve understanding of the diversity and evolution of the virome ofA. aegyptiand adds to previous evidence that showsWolbachiadoes not restrict a range of negative-strand RNA viruses.IMPORTANCEThe mosquitoAedes aegyptitransmits a number of arthropod-borne viruses (arboviruses), such as dengue virus and Zika virus. Mosquitoes also harbor insect-specific viruses that may affect replication of pathogenic arboviruses in their body. Currently, however, there are only a few insect-specific viruses described fromA. aegyptiin the literature. Here, we characterize a novel negative-strand virus, AeAV. Meta-analysis ofA. aegyptisamples showed that it is present inA. aegyptimosquitoes worldwide and is vertically transmitted.Wolbachia-transinfected mosquitoes are currently being used in biocontrol, as they effectively block transmission of several positive-sense RNA viruses in mosquitoes. Our results demonstrate thatWolbachiaenhances the replication of AeAV and modestly reduces dengue virus replication in a cell line model. This study expands our understanding of the virome inA. aegyptias well as providing insight into the complexity of theWolbachiavirus restriction phenotype.

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IRAV (FLJ11286), an Interferon-Stimulated Gene with Antiviral Activity against Dengue Virus, Interacts with MOV10

Journal of Virology ◽

10.1128/jvi.01606-16 ◽

2016 ◽

Vol 91 (5) ◽

Cited By ~ 21

Author(s):

Corey A. Balinsky ◽

Hana Schmeisser ◽

Alexandra I. Wells ◽

Sundar Ganesan ◽

Tengchuan Jin ◽

...

Keyword(s):

Antiviral Activity ◽

Dengue Virus ◽

Viral Replication ◽

Virus Replication ◽

Viral Rna ◽

Type I ◽

Dependent Manner ◽

Content Type ◽

Replication Complex ◽

P Bodies

ABSTRACT Dengue virus (DENV) is a member of the genus Flavivirus and can cause severe febrile illness. Here, we show that FLJ11286, which we refer to as IRAV, is induced by DENV in an interferon-dependent manner, displays antiviral activity against DENV, and localizes to the DENV replication complex. IRAV is an RNA binding protein and localizes to cytoplasmic processing bodies (P bodies) in uninfected cells, where it interacts with the MOV10 RISC complex RNA helicase, suggesting a role for IRAV in the processing of viral RNA. After DENV infection, IRAV, along with MOV10 and Xrn1, localizes to the DENV replication complex and associates with DENV proteins. Depletion of IRAV or MOV10 results in an increase in viral RNA. These data serve to characterize an interferon-stimulated gene with antiviral activity against DENV, as well as to propose a mechanism of activity involving the processing of viral RNA. IMPORTANCE Dengue virus, a member of the family Flaviviridae, can result in a life-threatening illness and has a significant impact on global health. Dengue virus has been shown to be particularly sensitive to the effects of type I interferon; however, little is known about the mechanisms by which interferon-stimulated genes function to inhibit viral replication. A better understanding of the interferon-mediated antiviral response to dengue virus may aid in the development of novel therapeutics. Here, we examine the influence of the interferon-stimulated gene IRAV (FLJ11286) on dengue virus replication. We show that IRAV associates with P bodies in uninfected cells and with the dengue virus replication complex after infection. IRAV also interacts with MOV10, depletion of which is associated with increased viral replication. Our results provide insight into a newly identified antiviral gene, as well as broadening our understanding of the innate immune response to dengue virus infection.

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Zika Virus Methyltransferase: Structure and Functions for Drug Design Perspectives

Journal of Virology ◽

10.1128/jvi.02202-16 ◽

2016 ◽

Vol 91 (5) ◽

Cited By ~ 63

Author(s):

Bruno Coutard ◽

Karine Barral ◽

Julie Lichière ◽

Barbara Selisko ◽

Baptiste Martin ◽

...

Keyword(s):

Drug Design ◽

Dengue Virus ◽

Viral Replication ◽

Binding Site ◽

Zika Virus ◽

Neurological Disorders ◽

Innate Immune ◽

Viral Mrna ◽

Structure Based Drug Design ◽

Content Type

ABSTRACT The Flavivirus Zika virus (ZIKV) is the causal agent of neurological disorders like microcephaly in newborns or Guillain-Barre syndrome. Its NS5 protein embeds a methyltransferase (MTase) domain involved in the formation of the viral mRNA cap. We investigated the structural and functional properties of the ZIKV MTase. We show that the ZIKV MTase can methylate RNA cap structures at the N-7 position of the cap, and at the 2′-O position on the ribose of the first nucleotide, yielding a cap-1 structure. In addition, the ZIKV MTase methylates the ribose 2′-O position of internal adenosines of RNA substrates. The crystal structure of the ZIKV MTase determined at a 2.01-Å resolution reveals a crystallographic homodimer. One chain is bound to the methyl donor (S-adenosyl-l-methionine [SAM]) and shows a high structural similarity to the dengue virus (DENV) MTase. The second chain lacks SAM and displays conformational changes in the αX α-helix contributing to the SAM and RNA binding. These conformational modifications reveal a possible molecular mechanism of the enzymatic turnover involving a conserved Ser/Arg motif. In the second chain, the SAM binding site accommodates a sulfate close to a glycerol that could serve as a basis for structure-based drug design. In addition, compounds known to inhibit the DENV MTase show similar inhibition potency on the ZIKV MTase. Altogether these results contribute to a better understanding of the ZIKV MTase, a central player in viral replication and host innate immune response, and lay the basis for the development of potential antiviral drugs. IMPORTANCE The Zika virus (ZIKV) is associated with microcephaly in newborns, and other neurological disorders such as Guillain-Barre syndrome. It is urgent to develop antiviral strategies inhibiting the viral replication. The ZIKV NS5 embeds a methyltransferase involved in the viral mRNA capping process, which is essential for viral replication and control of virus detection by innate immune mechanisms. We demonstrate that the ZIKV methyltransferase methylates the mRNA cap and adenosines located in RNA sequences. The structure of ZIKV methyltransferase shows high structural similarities to the dengue virus methyltransferase, but conformational specificities highlight the role of a conserved Ser/Arg motif, which participates in RNA and SAM recognition during the reaction turnover. In addition, the SAM binding site accommodates a sulfate and a glycerol, offering structural information to initiate structure-based drug design. Altogether, these results contribute to a better understanding of the Flavivirus methyltransferases, which are central players in the virus replication.

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Zika virus infection: a public health emergency!

International Journal of Scientific Reports ◽

10.18203/issn.2454-2156.intjscirep20170884 ◽

2017 ◽

Vol 3 (3) ◽

pp. 68

Author(s):

Muhammad Salman Haider Qureshi ◽

Bakhtawar Wajeeha Qureshi ◽

Ramsha Khan

Keyword(s):

Public Health ◽

West Nile Virus ◽

Virus Infection ◽

Dengue Virus ◽

Yellow Fever ◽

Zika Virus ◽

Yellow Fever Virus ◽

Public Health Emergency ◽

Human Pathogens ◽

The Family

Zika virus belongs to the family of Flaviviridae. The Flaviviridae family also includes other human pathogens like West Nile virus (WNV), Yellow fever virus (YFV), mosquito transmitted Dengue virus (DENV), Tick borne encephalitic virus (TBEV) and Japanese encephalitis virus (JEV). Zika virus is a mosquito-borne disease and is transmitted by Aedes aegypti mosquito.

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