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.
Highlights
The endosymbiont Wolbachia is being released into wild populations of the mosquito vector Aedes aegypti throughout the tropics as a strategy to reduce the transmission of viruses to humans (Hoffmann et al 2011; Walker et al 2011)
To verify that the Wolbachia-induced blocking phenotype was present throughout the experiment, cells used at each passage were challenged in parallel with an aliquot of P0 at multiplicity of infection (MOI) of 0.1, and the viral copy number present in the supernatant was quantified at five days post-inoculation (Fig. 1B)
The higher variation in viral load in Aag-2wMel-passaged isolates relative to those passaged in Wolbachia-free lines may reflect an underlying variation in fitness or random noise, which may in turn be linked to the substantial population bottlenecks during passage
Summary
The endosymbiont Wolbachia is being released into wild populations of the mosquito vector Aedes aegypti throughout the tropics as a strategy to reduce the transmission of viruses to humans (Hoffmann et al 2011; Walker et al 2011). In Ae. aegypti infected with Wolbachia, the replication of DENV—as well as other medically important positive single-stranded RNA viruses such as chikungunya, Zika, and yellow fever—is reduced, leading to the potential interruption in pathogen transmission (Walker et al 2011; Van den Hurk et al 2012; Dutra et al 2016). A successful deployment in Townsville, Australia, has so far resulted in persistently high Wolbachia infection frequencies across the local mosquito population and elimination of domestic dengue transmission (O’Neill et al 2018). Evolution of resistance either against Wolbachia or its effects in the viral or mosquito genomes could lead to reduced efficacy
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