Using Wolbachia to Eliminate Dengue: Will the Virus Fight Back?

Abstract

Recent field trials have demonstrated that dengue incidence can be substantially reduced by introgressing strains of the endosymbiotic bacterium Wolbachia into Aedes aegypti mosquito populations. This strategy relies on Wolbachia reducing the susceptibility of Ae. aegypti to disseminated infection by positive-sense RNA viruses like dengue. However, RNA viruses are well known to adapt to antiviral pressures. Here, we review the viral infection stages where selection for Wolbachia-resistant virus variants could occur. We also consider the genetic constraints imposed on viruses that alternate between vertebrate and invertebrate hosts, and the likely selection pressures to which dengue virus might adapt in order to be effectively transmitted by Ae. aegypti that carry Wolbachia. While there are hurdles to dengue viruses developing resistance to Wolbachia, we suggest that long-term surveillance for resistant viruses should be an integral component of Wolbachia-introgression biocontrol programs.

Keywords: Aedes aegypti; Wolbachia; arbovirus; dengue virus; mechanisms of resistance.

FIG 1

Potential pathways for selection and removal of a Wolbachia-resistant variant through the DENV transmission cycle. This schematic highlights the population bottlenecks and fitness trade-offs that could prevent Wolbachia-resistant DENV variants from persisting throughout the transmission cycle. The DENV population in a blood meal is genetically diverse, but only a small proportion of variants establish infection in the mosquito midgut (1) and are able to disseminate to distal tissues (2). Variants that are more resistant to the antiviral properties of Wolbachia may be selected, allowing the virus to replicate in Wolbachia-infected and -uninfected cells. These variants may possess a replicative advantage in disseminated sites of the mosquito with high Wolbachia density, such as the salivary gland (3). DENV variants that replicate efficiently in the mosquito might not always be infectious for humans (4), such that if a Wolbachia-resistant variant did infect a human, it may replicate poorly or be outcompeted by other variants that are better adapted for replication in humans.

FIG 2

Proposed model of subcellular DENV restriction by Wolbachia. (1) Virus uptake occurs through clathrin-mediated endocytosis, and the viral genome is delivered following fusion of the viral and mature-endosomal membranes. (2) Replication of viral RNA (red) is restricted in Wolbachia-carrying cells and so is vesicle packet formation on ER membranes. This could be due to disturbance of ER and Golgi apparatus membranes due to (3) occupation/disruption by Wolbachia (green). (4) Altered cellular lipid content, e.g., increased cholesterol storage (yellow) or reduced acyl-carnitines, may restrict trafficking of membrane-bound vesicles and/or lower energy resources for virus production. Similarly, Wolbachia-induced alterations of the host cell cytoskeleton (5) may interfere with trafficking of endosomes and/or ER and Golgi vesicles required for movement of incoming virions and the maturation of daughter virions.