Christophe Boëte

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

BackgroundMosquitoes 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.MethodsWe 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.ResultsThe 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.ConclusionsIf refractoriness is less than 100% effective (because of, for example, environmentally induced variation in the effectiveness of the mosquitos 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.

A genetic correlation between age at pupation and melanization immune response of the yellow fever mosquito Aedes aegypti.

Abstract To investigate the evolutionary cost of an immune response, we selected six lines of the mosquito Aedes aegypti for earlier or later pupation and measured the extent to which this selection procedure changed the mosquitos ability to encapsulate and melanize a negatively charged Sephadex bead. After 10 generations of selection, the age at pupation in the two selection regimes differed by about 0.7 days, accompanied by an increase of wing length of the mosquitoes selected for late pupation. Among the mosquitoes that had been selected for early pupation, only 6% had strongly or completely melanized the bead, while among the individuals that had been selected for late pupation, 32% had melanized the bead. Thus, our results suggest a genetic correlation between age at pupation and immuno‐competence. As a consequence, mosquitoes that respond to increased intense parasite pressure with more effective immunity are predicted to pay for the increased defense with slower development.

Evolutionary ideas about genetically manipulated mosquitoes and malaria control

The release of mosquitoes that are genetically manipulated to destroy the malaria parasite Plasmodium falciparum is being considered as a possible method for malaria control. Hopes for this have been raised by the identification of genes involved in the mosquitos immune response and by advances in the tools required to transform mosquitoes. But, will such genes be able to spread in natural populations? What will their impact be on epidemiology of the disease? This article attempts to give some answers to these questions by reviewing some theoretical and empirical considerations underlying the evolutionary epidemiology of genetic manipulation and refractoriness.

A model for the coevolution of immunity and immune evasion in vector - borne diseases with implications for the epidemiology of malaria

We describe a model of host‐parasite coevolution, where the interaction depends on the investments by the host in its immune response and by the parasite in its ability to suppress (or evade) its host’s immune response. We base our model on the interaction between malaria parasites and their mosquito hosts and thus describe the epidemiological dynamics with the Macdonald‐Ross equation of malaria epidemiology. The qualitative predictions of the model are most sensitive to the cost of the immune response and to the intensity of transmission. If transmission is weak or the cost of immunity is low, the system evolves to a coevolutionarily stable equilibrium at intermediate levels of investment (and, generally, at a low frequency of resistance). At a higher cost of immunity and as transmission intensifies, the system is not evolutionarily stable but rather cycles around intermediate levels of investment. At more intense transmission, neither host nor parasite invests any resources in dominating its partner so that no resistance is observed in the population. These results may help to explain the lack of encapsulated malaria parasites generally observed in natural populations of mosquito vectors, despite strong selection pressure for resistance in areas of very intense transmission.

Direct and indirect immunosuppression by a malaria parasite in its mosquito vector

Malaria parasites develop as oocysts within the haemocoel of their mosquito vector during a period that is longer than the average lifespan of many of their vectors. How can they escape from the mosquits immune responses during their long development? Whereas older oocysts might camouflage themselves by incorporating mosquito–derived proteins into their surface capsule, younger stages are susceptible to the mosquitos immune response and must rely on other methods of immune evasion. We show that the malaria parasite Plasmodium gallinaceum suppresses the encapsulation immune response of its mosquito vector, Aedes aegypti, and in particular that the parasite uses both an indirect and a direct strategy for immunosuppression. Thus, when we fed mosquitoes with the plasma of infected chickens, the efficacy of the mosquitoes to encapsulate negatively charged Sephadex beads was considerably reduced, whether the parasite was present in the blood meal or not. In addition, zygotes that were created ex vivo and added to the blood of uninfected chickens reduced the efficacy of the encapsulation response. As dead zygotes had no effect on encapsulation, this result demonstrates active suppression of the mosquits immune response by malaria parasites.

Can transgenic mosquitoes afford the fitness 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 transgenes fitness cost and the efficacy of the gene drive will be more crucial than any evolutionary advantage.

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

Although 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 parasites 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 vectors immune response or that it modifies the blood of its chicken host in away that reduces the efficacy of the mosquitos 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.

Strategies of host resistance to pathogens in spatially structured populations: An agent-based evaluation.

There is growing theoretical evidence that spatial structure can affect the ecological and evolutionary outcomes of host-parasite interactions. Locally restricted interactions have been shown in particular to affect host resistance and tolerance. In this study we investigate the evolution of several types of host disease resistance strategies, alone or in combination, in spatially structured populations. We construct a spatially explicit, individual-based stochastic model where hosts and parasites interact with each other in a spatial lattice, and interactions are restricted to a given neighbourhood of varying size. We investigate several host resistance strategies, including constitutive (expressed in all resistant hosts), induced (expressed only upon infection), and combinations thereof. We show that the specific resistance mechanism against a pathogen as well as the size of the neighbourhood both affect resistance spread and parasite dynamics, an effect modulated by the level of the cost of resistance. Our results shed new light on the dynamics of disease resistance in a spatially-structured host-pathogen system, and illustrate the conditions in which a variety of resistance mechanisms can be maintained, including when they are costly. Overall these results advance our theoretical understanding of the evolutionary dynamics of disease resistance, a necessary step to elaborate more efficient and sustainable strategies for disease management.