Characterization of the Zika virus induced small RNA response in Aedes aegypti cells

Varjak, Margus; Donald, Claire L.; Mottram, Timothy J.; Sreenu, Vattipally B.; Merits, Andres; Maringer, Kevin; Schnettler, Esther; Kohl, Alain

doi:10.1371/journal.pntd.0006010

Cited by 80 publications

(158 citation statements)

References 55 publications

(81 reference statements)

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“…In many species, including insects, RNA interference (RNAi) serves as a system of adaptive antiviral immunity. The importance of RNAi-mediated immunity and viral evasion strategies is exemplified by insects that transmit a wide variety of viral infectious agents to humans including sandfly fever, Dengue, Chikungunya, and Zika virus (Blair, 2011; Nayak et al, 2013; Varjak et al, 2017). The insect antiviral RNAi response requires the Dicer-2 (Dcr2) and the Argonaute 2 (Ago-2) enzymes, which cleaves double-stranded (ds) viral RNA replication intermediates and single-stranded viral RNA genomes, respectively, to limit virus replication (Aliyari et al, 2008; Marques et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability

Nayak¹,

Kim²,

Trnka³

et al. 2018

Cell Host & Microbe

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Summary The dicistrovirus, Cricket paralysis virus (CrPV) encodes an RNA interference (RNAi) suppressor, 1A, which modulates viral virulence. Using the Drosophila model, we combined structural, biochemical, and virological approaches to elucidate the strategies by which CrPV-1A restricts RNAi immunity. The atomic resolution structure of CrPV-1A uncovered a flexible loop that interacts with Argonaute 2 (Ago-2), thereby inhibiting Ago-2 endonuclease-dependent immunity. Mutations disrupting Ago-2-binding attenuates viral pathogenesis in wild-type but not Ago-2-deficient flies. CrPV-1A also contains a BC-box motif that enables the virus to hijack a host Cul2-Rbx1-EloBC ubiquitin ligase complex, which promotes Ago-2 degradation and virus replication. Our study uncovers a viral-based dual regulatory program that restricts antiviral immunity by direct interaction with and modulation of host proteins. While the direct inhibition of Ago-2 activity provides an efficient mechanism to establish infection, the recruitment of a ubiquitin ligase complex, enables CrPV-1A to amplify Ago-2 inactivation to restrict further antiviral RNAi immunity.

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Section: Introductionmentioning

confidence: 99%

A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability

Nayak¹,

Kim²,

Trnka³

et al. 2018

Cell Host & Microbe

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“…The RNA interference pathway (RNAi) is a major antiviral defense initiated by the recognition of viral replication intermediates by the Dicer-2 protein [46]. This pathway inhibits the replication of DENV and ZIKV viruses in the midgut and salivary glands of mosquitoes [47–49]. Interestingly, Myles and colleagues recently showed that the YFV C protein counteracts the RNA interference pathway in Ae.…”

Section: Resultsmentioning

confidence: 99%

Midgut barriers prevent the replication and dissemination of the yellow fever vaccine inAedes aegypti

Danet

Beauclair

Berthet

et al. 2019

Preprint

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20 Background 21 To be transmitted to vertebrate hosts via the saliva of their vectors, arthropod-borne viruses have 22 to cross several barriers in the mosquito body, including the midgut infection and escape barriers.23 Yellow fever virus (YFV) belongs to the genus Flavivirus, which includes human viruses transmitted 24 by Aedes mosquitoes, such as Dengue and Zika viruses. The live-attenuated YFV-17D vaccine has 25 been used safely and efficiently on a large scale since the end of World War II. Early studies have 26 shown, using viral titration from salivary glands of infected mosquitoes, that YFV-17D can infect 27 Aedes aegypti midgut, but does not disseminate to other tissues.28 Methodology/Principal Findings 29Here, we re-visited this issue using a panel of techniques, such as RT-qPCR, Western blot, 30 immunofluorescence and titration assays. We showed that YFV-17D replication was not efficient in 31Aedes aegypti midgut, as compared to the clinical isolate YFV-Dakar. Viruses that replicated in the 32 midgut failed to disseminate to secondary organs. When injected into the thorax of mosquitoes, 33 viruses succeeded in replicating into midgut-associated tissues, suggesting that, during natural 34 infection, the block for YFV-17D replication occurs at the basal membrane of the midgut. Our NGS 35 analysis revealed that YFV-Dakar genome exhibited a greater diversity than the vaccine strain; a trait 36 that may contribute to its ability to infect and disseminate efficiently in Ae. aegypti. 37 Conclusions/Significance 38The two barriers associated with Ae. aegypti midgut prevent YFV-17D replication. Our study 39 contributes to our basic understanding of vector-pathogen interactions and may also aid in the 40 development of non-transmissible live virus vaccines.41 42 3 43 Author summary 44 Most flaviviruses, including yellow fever virus (YFV), are transmitted between hosts by mosquito 45 bites. The yellow fever vaccine (YFV-17D) is one of the safest and most effective live virus vaccine 46 ever developed. It is also used as a platform for engineering vaccines against other health-threatening 47 flaviviruses, such as Japanese encephalitis, West Nile, Dengue and Zika viruses. We studied here the 48 replication and dissemination of YFV-17D in mosquitoes. Our data showed that YFV-17D replicates 49 poorly in mosquito midgut and is unable to disseminate to secondary organs, as compare to a YFV 50 clinical isolate. Our study contributes to our basic understanding of the interactions between viruses 51 and their vectors, which is key for conceiving new approaches in inhibiting virus transmission and 52 designing non-transmissible live virus vaccines. 53 54 Introduction 55 Arborviruses, which are transmitted among vertebrate hosts by blood-feeding arthropod vectors, 56 put billions of people at risk worldwide. Viral infection in arthropod is usually persistent. Following 57 uptake of an infectious blood meal by a female mosquito, arbovirus must initiate a productive 58 infection of the midgut epithelium, which consists of a ...

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“…aegypti cell line Aag2 using arboviruses. Gene silencing of Piwi5 and Ago3 decreased vpiRNA biogenesis without impacting replication of Semliki Forest virus (SFV), Sindbis virus (SINV) and dengue virus [26, 27, 29, 31, 36]. Further experiments suggested that Piwi4 was antiviral against SFV, but not through the piRNA pathway [27].…”

Section: Introductionmentioning

confidence: 99%

Differential small RNA responses against co-infecting insect-specific viruses inAedes albopictusmosquitoes

Frangeul

Blanc

Saleh

et al. 2020

Preprint

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AbstractThe mosquito antiviral response has been mainly studied in the case of arthropod-borne virus (arbovirus) infection in female mosquitoes. However, in nature, both female and male mosquitoes are abundantly infected with insect-specific viruses (ISVs). ISVs are capable of infecting the reproductive organs of both sexes and are maintained primarily by vertical transmission. Since the RNA interference (RNAi)-mediated antiviral response plays an important antiviral role in mosquitoes, ISVs constitute a relevant model to study sex-dependent antiviral responses. Using a naturally generated viral stock containing three distinct ISVs, Aedes flavivirus (AEFV), Menghai Rhabdovirus (MERV) and Shinobi tetra virus (SHTV), we infected adult Aedes albopictus females and males and generated small RNA libraries from ovaries, testes, and the remainder of the body. Overall, both female and male mosquitoes showed unique small RNA profiles to each co-infecting ISV regardless the sex or tissue tested. While all three ISVs generated virus-derived siRNAs, only MERV generated virus-derived piRNAs. We also studied the expression of PIWI genes in reproductive tissues and carcasses. Piwi1-4 were abundantly expressed in ovaries and testes in contrast to Piwi5-9, suggesting that Piwi 5-9 are involved in exogenous viral piRNA production. Together, our results show that ISV-infected Aedes albopictus produce viral small RNAs in a virus-specific manner and that male mosquitoes mount a similar small RNA-mediated antiviral response to that of females.

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Characterization of the Zika virus induced small RNA response in Aedes aegypti cells

Cited by 80 publications

References 55 publications

A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability

A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability

Midgut barriers prevent the replication and dissemination of the yellow fever vaccine inAedes aegypti

Differential small RNA responses against co-infecting insect-specific viruses inAedes albopictusmosquitoes

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