Impact of gene-drive systems for population modification on malaria vector mosquitoes

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Project Summary While significant progress has been made in reducing the malaria burden since the turn of the century, the last few years have seen a deceleration of this success and the World Health Organization (WHO) in its 2020 World Malaria Reportestimates ~229 million cases (morbidity) and 409,000 deaths (mortality) in 2019. Approximately 95% of the global malaria deaths occurred in only 31 countries with seven in sub-Saharan Africa accounting for ~51% of all the deaths. Furthermore, the WHO predicts no further significant decreases without greater use of the existing technologies and the necessary development of new tools. The challenges of the continued demand for new drugs and the slow roll-out of an efficacious vaccine makes urgent the need for new, cost-effective and efficacious disease-control tools that are safe for people and the environment. This need justifies efforts to develop genetic approaches for controlling malaria parasite transmission. Long-term, sustainable genetic control will require the deployment of strategies designed to be resilient to the immigration of susceptible mosquitoes and parasite-infected people. Genetically-engineered mosquito strains for population modification have the appropriate performance features for this purpose. Wild mosquitoes immigrating into a region populated by engineered, parasite-resistant mosquitoes will acquire beneficial genes by mating with the local insects, and persons with malaria moving into the same region will not be able to infect the resident vectors, and therefore are not a source for infection of other people. We have exploited the molecular mechanisms of CRISPR/Cas biology to develop autonomous gene-drive systems for site-specific, transgene copy number amplification in the mosquito germline. These drive systems carry a cargo of anti-parasite effector genes that prevent transmission of the parasites by the mosquitoes carrying them. The working hypothesis is that these systems will be able to impact transmission dynamics even if they confer a genetic load that impacts reproductive fitness. We shall investigate the impact of gene-drive system insertions on the recipient mosquitoes to determine effects on reproductive success and drive and effector gene efficacy and stability. Towards these ends, our Specific Aims are: 1) evaluate the impact of autonomous gene-drive systems on the reproductive success of Anopheles gambiae ss. and An. coluzzii and 2) evaluate the multigenerational stability of autonomous gene-drive systems in Anopheles gambiae ss. and An. coluzzii in laboratory cage trials. The successful completion of these Specific Aims will inform plans and modelling for the future use of this technology in malaria control.