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doi: 10.1186/1741-7007年5月11日.

Late-acting dominant lethal genetic systems and mosquito control

Affiliations

Late-acting dominant lethal genetic systems and mosquito control

Hoang Kim Phuc et al. BMC Biol. .

Abstract

Background: Reduction or elimination of vector populations will tend to reduce or eliminate transmission of vector-borne diseases. One potential method for environmentally-friendly, species-specific population control is the Sterile Insect Technique (SIT). SIT has not been widely used against insect disease vectors such as mosquitoes, in part because of various practical difficulties in rearing, sterilization and distribution. Additionally, vector populations with strong density-dependent effects will tend to be resistant to SIT-based control as the population-reducing effect of induced sterility will tend to be offset by reduced density-dependent mortality.

Results: We investigated by mathematical modeling the effect of manipulating the stage of development at which death occurs (lethal phase) in an SIT program against a density-dependence-limited insect population. We found late-acting lethality to be considerably more effective than early-acting lethality. No such strains of a vector insect have been described, so as a proof-of-principle we constructed a strain of the principal vector of the dengue and yellow fever viruses, Aedes (Stegomyia) aegypti, with the necessary properties of dominant, repressible, highly penetrant, late-acting lethality.

Conclusion: Conventional SIT induces early-acting (embryonic) lethality, but genetic methods potentially allow the lethal phase to be tailored to the program. For insects with strong density-dependence, we show that lethality after the density-dependent phase would be a considerable improvement over conventional methods. For density-dependent parameters estimated from field data for Aedes aegypti, the critical release ratio for population elimination is modeled to be 27% to 540% greater for early-acting rather than late-acting lethality. Our success in developing a mosquito strain with the key features that the modeling indicated were desirable demonstrates the feasibility of this approach for improved SIT for disease control.

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Figures

Figure 1
Figure 1
Dynamics and equilibrium conditions of density-dependent-limited populations under RIDL/SIT control. We compared the effectiveness of SIT (blue line) and a late-acting lethal RIDL strategy (thick red line) in a mathematical model of a continuous breeding Ae. aegypti population limited by density-dependent mortality (for details of the model see Methods). The population is assumed to start at equilibrium carrying capacity, and will therefore remain at the initial level if there is no intervention (black line). All releases are assumed to be of males only; the input release ratio, I, is defined relative to the initial wild male population; this rate of release of males then remains constant through time. In panels A and B, we plotted examples of the variation over time, from the start of control, of the number of females in the population relative to the initial number, for two different release ratios. The RIDL insects are assumed to be homozygous for a construct lethal to males and females ("non-sex-specific") after the density-dependent phase. For conventional SIT, mortality is assumed to be early (at embryogenesis), before any density-dependent mortality operates. With a low release ratio (A), SIT can actually increase the equilibrium size of the adult female population while RIDL can result in eradication. With a sufficiently high release ratio (B), conventional SIT can control the population, but the RIDL strategy is more effective. In panels C, D, E and F, we plot the equilibrium number of female mosquitoes in the population, relative to the initial numbers, following control with a given input ratio. The critical input ratios required to achieve eradication are shown as broken lines for the conventional SIT (blue) and RIDL systems (red). β represents the intensity of the density-dependence; P is the maximum per capita daily egg production rate corrected for density-independent egg to adult survival (see Methods). Parameter values for β and P (indicated in the panels) represent the best-estimate ranges calculated by Dye for a natural Ae. aegypti population [25]. In all cases, T = 27 days and δ = 0.12 per day; parameter values again taken from Dye [25].
Figure 2
Figure 2
The structure and function of transposon LA513. LA513 is a non-autonomous piggyBac-based transposon of 8.4 kb. Transgenics are readily identified by red fluorescence due to expression of DsRed2. tTAV is a tetracycline-repressible transcriptional activator [28, 48]. Here, tTAV is under the control of its own binding site, tetO, a minimal promoter from Drosophila hsp70, and a 3' UTR sequence from Drosophila fs(1)K10 [49]. In the absence of tetracycline, tTAV binds to tetO and drives expression of more tTAV, in a positive feedback loop. In the presence of tetracycline, tTAV binds tetracycline; this tetracycline-bound form does not bind tetO and so does not lead to expression of more tTAV. Consequently, this construct gives very high levels of expression of tTAV in the absence of tetracycline, but only low, basal expression in the presence of tetracycline. High level expression of tTAV is toxic, possibly due to the interaction of the VP16 domain with key transcription factors, so this construct provides a tetracycline-repressible lethal system [28]. Construct LA882 is very similar to LA513; the principal difference is the use of the IE-2 promoter from the baculovirus OpNPV to drive expression of the DsRed2 marker, in place of Act5C.
Figure 3
Figure 3
Sensitivity to incomplete lethality or competitiveness. We examined the impact of varying levels of lethality (penetrance) of the late-acting lethal (RIDL) system (a, b) or reduced competitiveness of the RIDL larvae (c, d) at release ratios of 2 (panel a) or 7.5 (panel b) with β = 1 and P = 1.31, equivalent to Fig. 1a and b respectively. Apart from the new parameters L and C (below), all other parameter values and assumptions about density-dependent mortality, relative mating competitiveness and release ratios are as for Fig. 1. (a, b) In each case, the lethality, L, associated with inheritance of a single copy of the RIDL construct was examined at values of L = 1, 0.95, 0.9, 0.8, 0.7 and 0.5. At L = 1, the outcome is identical to that of shown in Fig. 1 (red lines in Fig 1a, b). (c, d) The contribution of larvae carrying RIDL constructs to the overall density-dependent mortality experienced by all larvae in the generation was examined by varying a competitiveness scaling factor, C, between 1 (i.e. RIDL larvae are as competitive as the wild type and contribute equally to density-dependent mortality) and 0 (i.e. RIDL larvae contribute nothing to density-dependent mortality – this scenario is equivalent to an early acting conventional SIT system). C = 1 and C = 0 therefore correspond to the red and blue lines, respectively, in Fig. 1a,b.

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