Population modification of Anopheline species to control malaria transmission

Abstract

Vector control strategies based on population modification of Anopheline mosquitoes may have a significant role in the malaria eradication agenda. They could consolidate elimination gains by providing barriers to the reintroduction of parasites and competent vectors, and allow resources to be allocated to new control sites while maintaining treated areas free of malaria. Synthetic biological approaches are being used to generate transgenic mosquitoes for population modification. Proofs-of-principle exist for mosquito transgenesis, the construction of anti-parasite effector genes and gene-drive systems for rapidly introgressing beneficial genes into wild populations. Key challenges now are to develop field-ready strains of mosquitoes that incorporate features that maximize safety and efficacy, and specify pathways from discovery to development. We propose three pathways and a framework for target product profiles that maximize safety and efficacy while meeting the demands of the complexity of malaria transmission, and the regulatory and social diversity of potential end-users and stakeholders.

Keywords: Population replacement; anti-parasite effector genes; gene drive; genetically-engineered mosquitoes; population alteration.

Figure 1.

Synthetic approach to making anti-parasite effector genes. A synthetic approach to making an anti-parasite effector gene starts with a simple model of a gene (A) comprising two parts. The control region contains cis-acting DNA that regulates when during development, where in the vector insect, and how much of a product is made. Constitutive and regulated endogenous mosquito genes with sex-, stage- and tissue-specific expression profiles have been used for the control regions (Table 2). The effector region is the expressed portion of the gene that kills or disables the parasite. This may result from a direct action such as a single-chain antibody that binds the parasite or toxin that kills it, or an indirect action that deprives the parasite of an essential host factor, blocks an important ligand or elevates a systemic immune response (Table 1). (B) Control regions can be selected to deliver effector molecules to specific compartments (midgut, hemolymph [open circulatory system] and salivary glands) in which specific parasite stages are found.

Figure 2.

Genotypic and phenotypic outcomes of gene-drive systems.

Figure 3.

Pathways for development of population modification technologies.