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Harnessing Immunity Genes Against Plasmodium: The Series

February 6, 2012 - 11:24 -- Mark Benedict

Another group has engineered an anopheline to have a degree of Plasmodium immunity. Some of us hope for a mosquito that is ready to take a trip to the field, but can this one go the distance? Is it advisable?


The George Dimopoulos team at Johns-Hopkins has scored a nice victory with creation of a refractory genetically modified mosquito (GMM), the performance of which was published in December in PLoS Pathogens: “Engineered Anopheles Immunity to Plasmodium Infection.” (Sorry I didn’t blog on this earlier, but the holidays and whatnot...).


What Dong et al have done is to harness an A. gambiae Rel2 (Rel2-S) transcription factor to the control of a blood meal-inducible carboxylpeptidase (Cp) or vitellogenin (Vg) promoter and transformed this into An. stephensi using piggyBac. Both heterozygotes and homozygotes were studied, though most of the infection experiments were performed on homozygotes and double homozygotes for both effectors. Highly significant levels of reduced infections with Plasmodium falciparum NF45 were observed in all cases. This parasite strain has unusually high levels of parasite numbers, so it’s a knowingly somewhat artificial situation, but experimentally a good choice since it likely strongly challenges the GMM effect.


While one would naturally hope for absolute absence of infections in the GMM, that has not yet been accomplished here (or elsewhere as far as I know). Reduced levels of parasites were observed and might be sufficient to have a significant impact on transmission, particularly if the degree of effect observed is also seen in naturally infected mosquitoes: I’d be looking for a lab in a disease endemic country that could do somewhat natural infections with infected blood. Based on longevity and egg numbers, the authors report that there was “only a weakly negative impact of transgene…” on fitness.


I’ve argued previously that it is neither wise nor necessary to wait for the creation of all of the components required for driving refractoriness into wild populations in order to begin assessing their potential. A prudent and effective way to test these mosquitoes is to proceed toward field testing by inundative release of fertile males carrying the transgene. This would almost certainly have an intentionally limited effect spatially and temporally as the transgene would be diluted and quickly disappear. I won’t reiterate that argument here, but suffice to say that I’d like to see efforts to move refractory mosquitoes to field testing in order to ensure that the epidemiological effects are as expected.


Of course this would begin in small contained studies in disease endemic countries to ensure that they are safe and effective in the local mosquito genetic background, but these are not prohibitively difficult studies. On the other hand, since there would be a deliberate effort to put a gene into a wild population, the biosafety considerations would be different from that of e.g. sterile males.


The complexion of genetic control of mosquitoes changes with every year. Technical developments that were formidable years ago are becoming routine. Early assessments that An. gambiae is difficult to transform have been revised, and drive systems that are also effectors are offering new possibilities for overcoming the rightly anticipated disassociation of drive and effect. Still, ideal strains for genetic control of malaria vectors do not exist in my estimation. The strains, or attendant technology for handling them, would provide highly-specific en masse female elimination for release purposes – an objective that is technically within reach if given enough effort. Now if we just had an easier way to keep all those strains.