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Sustained Wolbachia-mediated blocking of dengue virus isolates following serial passage in Aedes aegypti cell culture.

ABSTRACT: Wolbachia is an intracellular endosymbiont of insects that inhibits the replication of a range of pathogens in its arthropod hosts. The release of Wolbachia into wild populations of mosquitoes is an innovative biocontrol effort to suppress the transmission of arthropod-borne viruses (arboviruses) to humans, most notably dengue virus. The success of the Wolbachia-based approach hinges upon the stable persistence of the 'pathogen blocking' effect, whose mechanistic basis is poorly understood. Evidence suggests that Wolbachia may affect viral replication via a combination of competition for host resources and activation of host immunity. The evolution of resistance against Wolbachia and pathogen blocking in the mosquito or the virus could reduce the public health impact of the symbiont releases. Here, we investigate if dengue 3 virus (DENV-3) is capable of accumulating adaptive mutations that improve its replicative capacity during serial passage in Wolbachia wMel-infected cells. During the passaging regime, viral isolates in Wolbachia-infected cells exhibited greater variation in viral loads compared to controls. The viral loads of these isolates declined rapidly during passaging due to the blocking effects of Wolbachia carriage, with several being lost all together and the remainder recovering to low but stable levels. We attempted to sequence the genomes of the surviving passaged isolates but, given their low abundance, were unable to obtain sufficient depth of coverage for evolutionary analysis. In contrast, viral loads in Wolbachia-free control cells were consistently high during passaging. The surviving isolates passaged in the presence of Wolbachia exhibited a reduced ability to replicate even in Wolbachia-free cells. These experiments demonstrate the challenge for dengue in evolving resistance to Wolbachia-mediated blocking.

SUBMITTER: Koh C

PROVIDER: S-EPMC6555872 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Sustained Wolbachia-mediated blocking of dengue virus isolates following serial passage in Aedes aegypti cell culture.

Koh Cassandra C Audsley Michelle D MD Di Giallonardo Francesca F Kerton Emily J EJ Young Paul R PR Holmes Edward C EC McGraw Elizabeth A EA

Virus evolution 20190101 1

Wolbachia is an intracellular endosymbiont of insects that inhibits the replication of a range of pathogens in its arthropod hosts. The release of Wolbachia into wild populations of mosquitoes is an innovative biocontrol effort to suppress the transmission of arthropod-borne viruses (arboviruses) to humans, most notably dengue virus. The success of the Wolbachia-based approach hinges upon the stable persistence of the 'pathogen blocking' effect, whose mechanistic basis is po ...[more]

PMID: 31191980

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Project description:BackgroundDengue viruses (DENV) are the causative agents of dengue, the world's most prevalent arthropod-borne disease with around 40% of the world's population at risk of infection annually. Wolbachia pipientis, an obligate intracellular bacterium, is being developed as a biocontrol strategy against dengue because it limits replication of the virus in the mosquito. The Wolbachia strain wMel, which has been introduced into the mosquito vector, Aedes aegypti, has been shown to invade and spread to near fixation in field releases. Standard measures of Wolbachia's efficacy for blocking virus replication focus on the detection and quantification of virus in mosquito tissues. Examining the saliva provides a more accurate measure of transmission potential and can reveal the extrinsic incubation period (EIP), that is, the time it takes virus to arrive in the saliva following the consumption of DENV viremic blood. EIP is a key determinant of a mosquito's ability to transmit DENVs, as the earlier the virus appears in the saliva the more opportunities the mosquito will have to infect humans on subsequent bites.Methodology/principal findingsWe used a non-destructive assay to repeatedly quantify DENV in saliva from wMel-infected and Wolbachia-free wild-type control mosquitoes following the consumption of a DENV-infected blood meal. We show that wMel lengthens the EIP, reduces the frequency at which the virus is expectorated and decreases the dengue copy number in mosquito saliva as compared to wild-type mosquitoes. These observations can at least be partially explained by an overall reduction in saliva produced by wMel mosquitoes. More generally, we found that the concentration of DENV in a blood meal is a determinant of the length of EIP, saliva virus titer and mosquito survival.Conclusions/significanceThe saliva-based traits reported here offer more disease-relevant measures of Wolbachia's effects on the vector and the virus. The lengthening of EIP highlights another means, in addition to the reduction of infection frequencies and DENV titers in mosquitoes, by which Wolbachia should operate to reduce DENV transmission in the field.

Dataset Information

Sustained Wolbachia-mediated blocking of dengue virus isolates following serial passage in Aedes aegypti cell culture.

Publications

Sustained <i>Wolbachia</i>-mediated blocking of dengue virus isolates following serial passage in <i>Aedes aegypti</i> cell culture.

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