Vector biology meets disease control: using basic research to fight vector-borne diseases

Abstract

Human pathogens that are transmitted by insects are a global problem, particularly those vectored by mosquitoes; for example, malaria parasites transmitted by Anopheles species, and viruses such as dengue, Zika and chikungunya that are carried by Aedes mosquitoes. Over the past 15 years, the prevalence of malaria has been substantially reduced and virus outbreaks have been contained by controlling mosquito vectors using insecticide-based approaches. However, disease control is now threatened by alarming rates of insecticide resistance in insect populations, prompting the need to develop a new generation of specific strategies that can reduce vector-mediated transmission. Here, we review how increased knowledge in insect biology and insect-pathogen interactions is stimulating new concepts and tools for vector control. We focus on strategies that either interfere with the development of pathogens within their vectors or directly impact insect survival, including enhancement of vector-mediated immune control, manipulation of the insect microbiome, or use of powerful new genetic tools such as CRISPR-Cas systems to edit vector genomes. Finally, we offer a perspective on the implementation hurdles as well as the knowledge gaps that must be filled in the coming years to safely realize the potential of these novel strategies to eliminate the scourge of vector-borne disease.

Fig. 1 |. The malaria and dengue transmission cycles.

The developmental stages of P. falciparum (left) and DENV (right) are shown in A. gambiae and A. aegypti, respectively. Anopheles mosquitoes take up Plasmodium parasites as female and male gametocytes, which rapidly convert to gametes. The male gamete exflagellates to produce eight microgametes, which can fertilize the single female macrogamete. The formed zygote becomes a motile ookinete, traverses the midgut epithelium, and develops into an oocyst on the basal lamina of the outer midgut. Over several days, sporozoites develop in the oocyst, burst out and spread to the mosquito salivary glands by the haemolymph. Sporozoites are injected into the next host when the mosquito bites again. Similarly, in Aedes mosquitoes, DENV is taken up into midgut cells and, over several days, replicates its genome and expresses viral proteins. New virions are assembled and released into the mosquito haemolymph and invade the salivary glands for transmission to the next host. PBM, post blood meal.

Fig. 2 |. Immune control strategies.

Illustrated are examples of how insect immunity can by modified at multiple life stages to combat parasite development. Increasing expression of anti-parasitic factors or antimicrobial peptides (AMPs) (1) when insects take a blood meal can induce lysis of ingested parasites. Ookinetes can be blocked from invasion by occluding ookinete ligands or midgut receptors required for successful invasion (2). Stronger, more effective immune responses to invading ookinetes (3), oocysts (4) and sporozoites (5) can be engineered by overexpressing immune effectors or reducing expression of negative regulators of mosquito immunity from the mosquito fat body and haemocytes circulating in the haemolymph. Invasion of sporozoites into the salivary glands can also be blocked by disrupting specific ligand–receptor interactions.

Fig. 3 |. Manipulating the microbiome.

Several avenues for vector control through manipulations to the vector microbiome are possible, some of which are highlighted here for malaria mosquitoes. On parasite uptake, naturally occurring or modified paratransgenic bacteria in the mosquito could block infection by the secretion of antiparasitic factors (1). Similarly, infecting species with Wolbachia bacteria (which populate the germline, and occasionally other tissues) can block infection against a variety of parasites although the precise mechanisms of how this is achieved are unknown (2). Such strategies rely on spread of these blocking or entomopathogenic agents (fungi or bacteria) through the vector population, for instance by adding them to baited sugar traps or larval breeding sites for vectors to pick up from the environment (3). Additionally, biological agents could be spread from parents to offspring through vertical transmission to the egg or larva (4).

Fig. 4 |. Gene drives bias inheritance to ensure their propagation.

In normal Mendelian inheritance (left), a non-driving transgene (purple) that is on one chromosome (highlighted yellow) will be inherited by 50% of the offspring. Outcrossing to natural wild-type populations will halve the frequency of the transgene in the population with every generation. A gene drive transgene (right) biases transmission to over 50% of its offspring. Through a self-driven copying mechanism within the germline of heterozygotes, a gene drive transgene (purple) on one chromosome (highlighted yellow) will be copied to the other by cutting the other chromosome at the location of the insertion, and the cell uses the original chromosome containing the gene drive transgene as a template for repair by homology-directed repair. All the offspring inherit a copy of the gene drive transgene. Outcrossing to natural wild-type populations will cause spread of the gene drive transgene throughout the population.