A theoretical approach to predicting the success of genetic manipulation of malaria mosquitoes in malaria control

BACKGROUND: Mosquitoes that have been genetically modified to better encapsulate the malaria parasite Plasmodium falciparum are being considered as a possible tool in the control of malaria. Hopes for this have been raised with the identification of genes involved in the encapsulation response and with advances in the tools required to transform mosquitoes. However, we have only very little understanding of the conditions that would allow such genes to spread in natural populations. METHODS: We present here a theoretical model that combines population genetical and epidemiological processes, thereby allowing one to predict not only these conditions (intensity of transmission, evolutionary cost of resistance, tools used to drive the genes) but also the impact of the spread of refractoriness on the prevalence of the disease. RESULTS: The main conclusions are 1) that efficient transposons will generally be able to drive genes that confer refractoriness through populations even if there is a substantial (evolutionary) cost of refractoriness, but 2) that this will decrease malaria prevalence in the human population substantially only if refractoriness is close to 100% effective. CONCLUSIONS: If refractoriness is less than 100% effective (because of, for example, environmentally induced variation in the effectiveness of the mosquito's immune response), control programmes based on genetic manipulation of mosquitoes will have very little impact on the epidemiology of malaria, at least in areas with intense transmission

The fine-scale genetic structure of the malaria vectors Anopheles funestus and Anopheles gambiae (Diptera: Culicidae) in the north-eastern part of Tanzania

AbstractUnderstanding the impact of altitude and ecological heterogeneity at a fine scale on the populations of malaria vectors is essential to better understand and anticipate eventual epidemiological changes. It could help to evaluate the spread of alleles conferring resistance to insecticides and also determine any increased entomological risk of transmission in highlands due to global warming. We used microsatellite markers to measure the effect of altitude and distance on the population genetic structure ofAnopheles funestusandAnopheles gambiae s.s. in the Muheza area in the north-eastern part of Tanzania (seven loci for each species). Our analysis reveals strong gene flow between the different populations ofAn. funestusfrom lowland and highland areas, as well as between populations ofAn. gambiaesampled in the lowland area. These results highlight forAn. funestusthe absence of a significant spatial subpopulation structuring at small-scale, despite a steep ecological and altitudinal cline. Our findings are important in the understanding of the possible spread of alleles conferring insecticide resistance through mosquito populations. Such information is essential for vector control programmes to avoid the rapid spread and fixation of resistance in mosquito populations.</jats:p

Thermal behaviour of Anopheles stephensi in response to infection with malaria and fungal entomopathogens

<p>Abstract</p> <p>Background</p> <p>Temperature is a critical determinant of the development of malaria parasites in mosquitoes, and hence the geographic distribution of malaria risk, but little is known about the thermal preferences of <it>Anopheles</it>. A number of other insects modify their thermal behaviour in response to infection. These alterations can be beneficial for the insect or for the infectious agent. Given current interest in developing fungal biopesticides for control of mosquitoes, <it>Anopheles stephensi </it>were examined to test whether mosquitoes showed thermally-mediated behaviour in response to infection with fungal entomopathogens and the rodent malaria, <it>Plasmodium yoelii</it>.</p> <p>Methods</p> <p>Over two experiments, groups of <it>An. stephensi </it>were infected with one of three entomopathogenic fungi, and/or <it>P. yoelii</it>. Infected and uninfected mosquitoes were released on to a thermal gradient (14 – 38°C) for "snapshot" assessments of thermal preference during the first five days post-infection. Mosquito survival was monitored for eight days and, where appropriate, oocyst prevalence and intensity was assessed.</p> <p>Results and conclusion</p> <p>Both infected and uninfected <it>An. stephensi </it>showed a non-random distribution on the gradient, indicating some capacity to behaviourally thermoregulate. However, chosen resting temperatures were not altered by any of the infections. There is thus no evidence that thermally-mediated behaviours play a role in determining malaria prevalence or that they will influence the performance of fungal biopesticides against adult <it>Anopheles</it>.</p

Inferring selection in the Anopheles gambiae species complex: an example from immune-related serine protease inhibitors

<p>Abstract</p> <p>Background</p> <p>Mosquitoes of the <it>Anopheles gambiae </it>species complex are the primary vectors of human malaria in sub-Saharan Africa. Many host genes have been shown to affect <it>Plasmodium </it>development in the mosquito, and so are expected to engage in an evolutionary arms race with the pathogen. However, there is little conclusive evidence that any of these mosquito genes evolve rapidly, or show other signatures of adaptive evolution.</p> <p>Methods</p> <p>Three serine protease inhibitors have previously been identified as candidate immune system genes mediating mosquito-Plasmodium interaction, and serine protease inhibitors have been identified as hot-spots of adaptive evolution in other taxa. Population-genetic tests for selection, including a recent multi-gene extension of the McDonald-Kreitman test, were applied to 16 serine protease inhibitors and 16 other genes sampled from the <it>An. gambiae </it>species complex in both East and West Africa.</p> <p>Results</p> <p>Serine protease inhibitors were found to show a marginally significant trend towards higher levels of amino acid diversity than other genes, and display extensive genetic structuring associated with the 2La chromosomal inversion. However, although serpins are candidate targets for strong parasite-mediated selection, no evidence was found for rapid adaptive evolution in these genes.</p> <p>Conclusion</p> <p>It is well known that phylogenetic and population history in the <it>An. gambiae </it>complex can present special problems for the application of standard population-genetic tests for selection, and this may explain the failure of this study to detect selection acting on serine protease inhibitors. The pitfalls of uncritically applying these tests in this species complex are highlighted, and the future prospects for detecting selection acting on the <it>An. gambiae </it>genome are discussed.</p

Reduced efficacy of the immune melanization response in mosquitoes infected by malaria parasites

International audienceAlthough the mosquito vectors of malaria have an effective immune system capable of encapsulating many foreign particles, they rarely encapsulate malaria parasites in natural populations. A possible reason for this apparent paradox is that infection by malaria reduces the capability of the mosquito to mount an effective immune response. To investigate this possibility, we blood-fed Aedes aegypti mosquitoes on an uninfected chicken or on one infected with Plasmodium gallinaceum , and compared the proportions of the infected and uninfected mosquitoes that melanized a negatively charged Sephadex bead injected into the thorax 1, 2 and 4 days after blood-feeding. About 40% of the uninfected mosquitoes, but less than 25% of the infected ones, melanized the bead. The difference between infected and uninfected mosquitoes was most obvious 1 day after infection (at the parasite's ookinete stage), while the difference diminished during the early oocyst stage (2 days after infection) and disappeared at the later oocyst stage (4 days after infection). These results suggest that the parasite can either actively suppress its vector's immune response or that it modifies the blood of its chicken host in a way that reduces the efficacy of the mosquito's immune system. In either case, the reduction of immunocompetence can have important consequences for malaria control, in particular for the current effort being invested into the genetic manipulation of mosquitoes

Impact of mating behaviour on the success of malaria control through a single inundative release of transgenic mosquitoes

Transgenic mosquitoes are a potential tool for the control or eradication of insect-vectored diseases. For malaria, one possible strategy relies on the introduction of malaria-refractory transgenes into wild Anopheles mosquito populations that would limit their capacity to transmit the disease. The success of such an approach obviously depends on a variety of factors. By developing a model that integrates both population genetics and epidemiology, we explore how mosquito mating preferences and the cost and efficacy of refractoriness affects the long-term prevalence of malaria in humans subsequent to a single generation inundative release of male transgenic mosquitoes. As may be intuitively expected, mating discrimination by wild-type individuals against transgenic ones generally reduces the probability that transgenes become stably established at a high frequency in mosquito populations. We also show that in circumstances where transgenic individuals exhibit some degree of discrimination against wild-type individuals, this can favour the spread of refractory alleles and lead to a significant reduction in malaria prevalence in the human population (if the efficacy of a dominant refractory mechanism exceeds at least 75%). The existence of such a non-intuitive outcome highlights the practical value of increasing the understanding of Anopheles mating preferences in the wild as a means to harness them in the implementation of population replacement approaches. Potential strategies by which previously described mating preferences of Anopheles gambiae populations could be exploited to manipulate the mate choice of transgenic release stocks are discussed

Can transgenic mosquitoes afford the fiftess cost ?

In a recent study, SM1-transgenic Anopheles stephensi, which are resistant partially to Plasmodium berghei, had higher fitness than non-transgenic mosquitoes when they were maintained on Plasmodium-infected blood. This result should be interpreted cautiously with respect to malaria control using transgenic mosquitoes because, despite the evolutionary advantage conferred by the transgene, a concomitant cost prevents it from invading the entire population. Indeed, for the spread of a resistance transgene in a natural situation, the transgene's fitness cost and the efficacy of the gene drive will be more crucial than any evolutionary advantage