Feasible Introgression of an Anti-pathogen Transgene into an Urban Mosquito Population without Using Gene-Drive

Abstract

BackgroundIntrogressing anti-pathogen constructs into wild vector populations could reduce disease transmission. It is generally assumed that such introgression would require linking an anti-pathogen gene with a selfish genetic element or similar technologies. Yet none of the proposed transgenic anti-pathogen gene-drive mechanisms are likely to be implemented as public health measures in the near future. Thus, much attention now focuses instead on transgenic strategies aimed at mosquito population suppression, an approach generally perceived to be practical. By contrast, aiming to replace vector competent mosquito populations with vector incompetent populations by releasing mosquitoes carrying a single anti-pathogen gene without a gene-drive mechanism is widely considered impractical.Methodology/Principal FindingsHere we use Skeeter Buster, a previously published stochastic, spatially explicit model of Aedes aegypti to investigate whether a number of approaches for releasing mosquitoes with only an anti-pathogen construct would be efficient and effective in the tropical city of Iquitos, Peru. To assess the performance of such releases using realistic release numbers, we compare the transient and long-term effects of this strategy with two other genetic control strategies that have been developed in Ae. aegypti: release of a strain with female-specific lethality, and a strain with both female-specific lethality and an anti-pathogen gene. We find that releasing mosquitoes carrying only an anti-pathogen construct can substantially decrease vector competence of a natural population, even at release ratios well below that required for the two currently feasible alternatives that rely on population reduction. Finally, although current genetic control strategies based on population reduction are compromised by immigration of wild-type mosquitoes, releasing mosquitoes carrying only an anti-pathogen gene is considerably more robust to such immigration.Conclusions/SignificanceContrary to the widely held view that transgenic control programs aimed at population replacement require linking an anti-pathogen gene to selfish genetic elements, we find releasing mosquitoes in numbers much smaller than those considered necessary for transgenic population reduction can result in comparatively rapid and robust population replacement. In light of this non-intuitive result, directing efforts to improve rearing capacity and logistical support for implementing releases, and reducing the fitness costs of existing recombinant technologies, may provide a viable, alternative route to introgressing anti-pathogen transgenes under field conditions.

Gene Drive Strategies for Population Replacement

“…In a recent modeling study, Okamoto et al demonstrated the economic feasibility of releasing large numbers of insects carrying a dengue-refractory gene without a gene drive system in order to reduce the dengue transmission potential of Aedes aegypti mosquitoes in Iquitos, Peru [19]. Wide-scale control of Anopheles malaria vectors in sub-Saharan Africa is less likely amenable to the mass release strategy; however, it is essential to assess this in terms of efficacy, safety, and cost-effectiveness prior to implementation.…”

“…ToxinÀantidote-based underdominant systems would be an obvious choice if the goal were to test the concept of population replacement prior to a release of toxinÀantidote-based Medea elements. The bistable nature of these systems makes them particularly amenable to confinement; however, killerrescue systems and a mass release of transgenic insects with diseaserefractory genes [19,71] should also be considered, as these are significantly easier to engineer in a wide range of vector species and the spreading a disease-refractory gene into an isolated population will not always require gene drive.…”

Disruption of dengue virus transmission by mosquitoes

“…aegypti , may not be an absolute necessity as mathematical models generated with the recently developed Ae. aegypti population dynamics software, Skeeter Buster, suggest [50–51,52**,53,54,55**]. …”

Mosquito immune responses to arbovirus infections

“…aegypti [88]; however, gene drive approaches are not likely to be implemented as large-scale public health measures in the near future. Recently, Okamoto et al [89] used a stochastic, spatially explicit model of Ae. aegypti populations from Iquitos, Peru, to evaluate whether population replacement is feasible absent gene-drive.…”

“…aegypti populations from Iquitos, Peru, to evaluate whether population replacement is feasible absent gene-drive. The modeling indicated that releasing mosquitoes carrying only an anti-pathogen construct can negatively impact vector competence of a natural population at ratios well below those considered necessary for transgenic technologies involving population reduction [89-91]. Moreover, Okamoto and colleagues found that introgression of the effector gene could occur locally in a reasonable timeframe and releasing mosquitoes carrying only an anti-pathogen gene is considerably more robust for immigration into wild-type mosquito populations than other strategies modeled.…”