Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways

Rainey, Stephanie M.; Martinez, Julien; McFarlane, Melanie; Juneja, Punita; Sarkies, Peter; Lulla, Aleksei; Schnettler, Esther; Varjak, Margus; Merits, Andres; Miska, Eric A.; Jiggins, Francis M.; Kohl, Alain

doi:10.1371/journal.ppat.1005536

Cited by 81 publications

(108 citation statements)

References 58 publications

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“…It is likely that many flaviviruses are restricted at this step based on flavivirus similarities. One study suggested that the alphavirus Semliki Forest virus is inhibited by Wolbachia early in viral inhibition (40), consistent with our data. Thus, Wolbachia may block many positive RNA viruses by the same mechanism.…”

Section: Discussionsupporting

confidence: 92%

Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures

Schultz

Isern

Michael

et al. 2017

J Virol

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Mosquito-borne arboviruses are a major source of human disease. One strategy to reduce arbovirus disease is to reduce the mosquito's ability to transmit virus. Mosquito infection with the bacterial endosymbiont Wolbachia pipientis wMel is a novel strategy to reduce Aedes mosquito competency for flavivirus infection. However, experiments investigating cyclic environmental temperatures have shown a reduction in maternal transmission of wMel, potentially weakening the integration of this strain into a mosquito population relative to that of other Wolbachia strains. Consequently, it is important to investigate additional Wolbachia strains. All Zika virus (ZIKV) suppression studies are limited to the wMel Wolbachia strain. Here we show ZIKV inhibition by two different Wolbachia strains: wAlbB (isolated from Aedes albopictus mosquitoes) and wStri (isolated from the planthopper Laodelphax striatellus) in mosquito cells. Wolbachia strain wStri inhibited ZIKV most effectively. Singlecycle infection experiments showed that ZIKV RNA replication and nonstructural protein 5 translation were reduced below the limits of detection in wStri-containing cells, demonstrating early inhibition of virus replication. ZIKV replication was rescued when Wolbachia was inhibited with a bacteriostatic antibiotic. We observed a partial rescue of ZIKV growth when Wolbachia-infected cells were supplemented with cholesterol-lipid concentrate, suggesting competition for nutrients as one of the possible mechanisms of Wolbachia inhibition of ZIKV. Our data show that wAlbB and wStri infection causes inhibition of ZIKV, making them attractive candidates for further in vitro mechanistic and in vivo studies and future vector-centered approaches to limit ZIKV infection and spread.IMPORTANCE Zika virus (ZIKV) has swiftly spread throughout most of the Western Hemisphere. This is due in large part to its replication in and spread by a mosquito vector host. There is an urgent need for approaches that limit ZIKV replication in mosquitoes. One exciting approach for this is to use a bacterial endosymbiont called Wolbachia that can populate mosquito cells and inhibit ZIKV replication. Here we show that two different strains of Wolbachia, wAlbB and wStri, are effective at repressing ZIKV in mosquito cell lines. Repression of virus growth is through the inhibition of an early stage of infection and requires actively replicating Wolbachia. Our findings further the understanding of Wolbachia viral inhibition and provide novel tools that can be used in an effort to limit ZIKV replication in the mosquito vector, thereby interrupting the transmission and spread of the virus.KEYWORDS Wolbachia, Zika virus, arthropod vectors, vector biology

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Section: Discussionsupporting

confidence: 92%

Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures

Schultz

Isern

Michael

et al. 2017

J Virol

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“…As for the other RNA viruses, infections with arboviruses also result in the production of 21 nt vsiRNAs, indicative of processing by Dicer-2. For alphaviruses (SINV and SFV), vsiRNAs were equally distributed between genomic and antigenomic strands and therefore likely originate from replication intermediates with dsRNA structure [47,48]. Also VSV infections produce 21 nt vsiRNAs that are approximately evenly distributed between genomic and antigenomic strand [47,49].…”

Section: Arbovirus Infections In Drosophilamentioning

confidence: 99%

Defense Mechanisms against Viral Infection in <em>Drosophila</em>: RNAi versus Non-RNAi

Swevers¹,

Liu²,

Smagghe³

2018

Preprint

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RNAi is considered a major antiviral defense mechanism in insects but its relative importance compared to other antiviral pathways has not been evaluated comprehensively. Here, it is attempted to give an overview of the antiviral defense mechanisms in Drosophila that involve both RNAi and non-RNAi to acquire a sense of their relative importance. While RNAi is considered important in most viral infections, many other pathways can exist that confer antiviral resistance. It is noted that very few direct recognition mechanisms of virus infections have been identified in Drosophila and that the activation of immune pathways may be accomplished indirectly through cell damage incurred by viral replication. In several cases, protection against viral infection can be obtained in RNAi mutants by non-RNAi mechanisms, confirming the variability of the RNAi defense mechanism according to the type of infection and the physiological status of the host. This analysis invites to investigate more systematically the relative contribution of RNAi in the antiviral response and more specifically to ask whether RNAi efficiency is affected when other defense mechanisms predominate. While Drosophila can function as a useful model, this issue may be more critical for economically important insects that are either controlled (agricultural pests and vectors of diseases) or protected from parasite infection (beneficial insects as bees) by RNAi products.

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“…This may be particularly relevant for viruses that require lipids for attachment and entry into host cells and for replication (Lu, Cassese, & Kielian, 1999; Mackenzie, Khromykh, & Parton, 2007). Most recently, there is some evidence primarily from Drosophila that Wolbachia may be modifying host cellular structures or organelles rendering them less hospitable to viral replication (Rainey et al., 2016; White et al., 2017). A range of studies also point to a correlation between Wolbachia densities and the strength of blocking (Frentiu et al., 2010; Lu, Bian, Pan, & Xi, 2012; Osborne, Iturbe‐Ormaetxe, Brownlie, O'Neill, & Johnson, 2012), a trend that would be expected with any of the above explanations for blocking.…”

Section: Introductionmentioning

confidence: 99%

Wolbachia enhances insect‐specific flavivirus infection in Aedes aegypti mosquitoes

Amuzu

Tsyganov

Koh

et al. 2018

Ecology and Evolution

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Mosquitoes transmit a diverse group of human flaviviruses including West Nile, dengue, yellow fever, and Zika viruses. Mosquitoes are also naturally infected with insect‐specific flaviviruses (ISFs), a subgroup of the family not capable of infecting vertebrates. Although ISFs are not medically important, they are capable of altering the mosquito's susceptibility to flaviviruses and may alter host fitness. Wolbachia is an endosymbiotic bacterium of insects that when present in mosquitoes limits the replication of co‐infecting pathogens, including flaviviruses. Artificially created Wolbachia‐infected Aedes aegypti mosquitoes are being released into the wild in a series of trials around the globe with the hope of interrupting dengue and Zika virus transmission from mosquitoes to humans. Our work investigated the effect of Wolbachia on ISF infection in wild‐caught Ae. aegypti mosquitoes from field release zones. All field mosquitoes were screened for the presence of ISFs using general degenerate flavivirus primers and their PCR amplicons sequenced. ISFs were found to be common and widely distributed in Ae. aegypti populations. Field mosquitoes consistently had higher ISF infection rates and viral loads compared to laboratory colony material indicating that environmental conditions may modulate ISF infection in Ae. aegypti. Surprisingly, higher ISF infection rates and loads were found in Wolbachia‐infected mosquitoes compared to the Wolbachia‐free mosquitoes. Our findings demonstrate that the symbiont is capable of manipulating the mosquito virome and that Wolbachia‐mediated viral inhibition is not universal for flaviviruses. This may have implications for the Wolbachia‐based DENV control strategy if ISFs confer fitness effects or alter mosquito susceptibility to other flaviviruses.

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Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways

Cited by 81 publications

References 58 publications

Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures

Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures

Defense Mechanisms against Viral Infection in <em>Drosophila</em>: RNAi versus Non-RNAi

Wolbachia enhances insect‐specific flavivirus infection in Aedes aegypti mosquitoes

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