Analyzing the control of mosquito-borne diseases by a dominant lethal genetic system

Abstract

Motivated by the failure of current methods to control dengue fever, we formulate a mathematical model to assess the impact on the spread of a mosquito-borne viral disease of a strategy that releases adult male insects homozygous for a dominant, repressible, lethal genetic trait. A dynamic model for the female adult mosquito population, which incorporates the competition for female mating between released mosquitoes and wild mosquitoes, density-dependent competition during the larval stage, and realization of the lethal trait either before or after the larval stage, is embedded into a susceptible-exposed-infectious-susceptible human-vector epidemic model for the spread of the disease. For the special case in which the number of released mosquitoes is maintained in a fixed proportion to the number of adult female mosquitoes at each point in time, we derive mathematical formulas for the disease eradication condition and the approximate number of released mosquitoes necessary for eradication. Numerical results using data for dengue fever suggest that the proportional policy outperforms a release policy in which the released mosquito population is held constant, and that eradication in Ϸ1 year is feasible for affected human populations on the order of 10 5 to 10 6 , although the logistical considerations are daunting. We also construct a policy that achieves an exponential decay in the female mosquito population; this policy releases approximately the same number of mosquitoes as the proportional policy but achieves eradication nearly twice as fast.dengue fever ͉ genetically modified mosquitoes ͉ mathematical epidemiology W orldwide morbidity and mortality from mosquito-borne viral diseases are substantial and on the rise (1). No licensed vaccine exists for the most important of these viruses, the dengue virus, which each year causes 50-100 million cases of dengue fever and 250,000-500,000 cases of the potentially fatal dengue hemorrhagic fever (2). The Aedes aegypti mosquito (also known as Stegomyia aegypti), which is the main vector for dengue fever and yellow fever, is endemic in the southeastern U.S., and the West Nile virus spread easily through the U.S. in recent years, suggesting the U.S. could be vulnerable in coming years to both natural and deliberate outbreaks of mosquito-borne viral diseases. Given the failure of current methods to control the spread of these diseases, considerable effort has gone into novel population-suppression strategies. The sterile insect technique (SIT), which releases sterile (irradiated) male insects that mate with wild females, resulting in no progeny, has been used successfully for Ͼ50 years for control and eradication of several pests and disease vectors (3, 4). However, irradiated mosquitoes have difficulty competing with wild males for wild females (5-7) and there are no large-scale SIT mosquito programs currently in operation. A proposed alternative approach that is also environmentally benign is the release of insects carrying a dominant lethal (RIDL) strategy. In this ap...

Genetic elimination of dengue vector mosquitoes

“…Chemical control is increasingly restricted due to potential human toxicity, mortality in nontarget organisms, insecticide resistance, and other environmental impacts (7)(8)(9). Release of insects carrying a dominant lethal (RIDL) is a genetic control strategy derived from classical sterile insect technique (SIT) that provides a new solution to the challenges facing current control efforts (10)(11)(12)(13)(14).…”

Female-specific flightless phenotype for mosquito control

“…A system based on a lethal gene [release of insects carrying a dominant lethal (RIDL); (14)] that acts late in development would prevent mosquitoes from becoming adults, the only harmful life stage, yet enable them to survive and compete at the larval stage, when density-dependent competition occurs (17). Modeling this system predicts that fewer male mosquitoes of a late-lethal strain need to be released as compared to those carrying an early-lethal gene or irradiated strain to achieve an equivalent level of control of a target population (12,18). We reported previously the construction of repressible lethal strains of insects using the "tet-off" gene expression system based on a synthetic tetracycline-repressible transactivator (tTA) (12,14,16,19,20).…”

Genetics‐based methods for agricultural insect pest management

“…For example, modelling the effects of larval competition and exploring late‐acting lethal phenotypes in mosquitoes predicted that this could be substantially more effective at population control than an early‐acting (e.g. embryonic) lethality or radiation‐induced sterility (Atkinson et al ., 2007; Phuc et al ., 2007; Alphey & Bonsall, 2014a). Indeed, if density‐dependent juvenile competition were over‐compensatory, genetic lethality that occurred at an earlier stage, thereby freeing survivors from regulation by intense competition, could push adult insect numbers higher than in the natural uncontrolled population (Yakob et al ., 2008; Alphey & Bonsall, 2014a).…”

“…Indeed, if density‐dependent juvenile competition were over‐compensatory, genetic lethality that occurred at an earlier stage, thereby freeing survivors from regulation by intense competition, could push adult insect numbers higher than in the natural uncontrolled population (Yakob et al ., 2008; Alphey & Bonsall, 2014a). This multidisciplinary approach can be broad; population dynamic models incorporating density‐dependent competition were combined with epidemiological models to investigate the potential effect of releases on a mosquito‐borne disease in a human population (Atkinson et al ., 2007; Alphey et al ., 2011a) and linked with bio‐economic and health economic models to estimate the potential cost‐effectiveness of this novel vector control (Alphey et al ., 2011a). Similar multicomponent modelling approaches could be applied to plant pests, to explore potential for cost‐effective population control to limit crop yield losses.…”

“…The density dependence term in the formula is adjusted according to whether the genetically‐induced mortality occurs before or after the competition takes effect (Alphey & Bonsall, 2014b). Critical thresholds, or tipping points, are a common feature of models of genetic control (e.g., Atkinson et al ., 2007; Phuc et al ., 2007; Alphey et al ., 2009, 2011b; Alphey & Bonsall, 2014a,b). A ‘release ratio’ or ‘overflooding ratio’ can be defined in various ways, such as the ratio of engineered males to the number of wild males at natural equilibrium to be maintained at constant value through sustained ongoing releases balancing out mortality, or as a fixed proportion of released males to males emerging in the wild.…”