Nearly half of the world’s population is at risk of malaria infection, a mosquito-borne disease caused by the parasitic protozoan Plasmodium. Without an approved malaria vaccine, infection prevention has focused on controlling the populations of the malarial vector, the Anopheles mosquitoes. Current management relies heavily on pesticides and, with only one type of pesticide approved for mosquito control, the evolution of pesticide resistance is an imminent danger. Since there is a pressing need to develop combinatorial approaches for vector control before our only weapon fails, the search for new control strategies is underway. Two avenues are currently being explored: controlling mosquito populations without pesticides, and inhibiting Plasmodium survival in mosquitoes.

To reduce vector populations, trojan mosquito strains that pass lethal genes onto their progeny have been engineered for release into the wild. One strain engineered by Oxitec to curb the transmission of dengue and yellow fevers, Aedes aegypti OX513A, passes on a gene that kills progeny in the late larval or pupae stage. This late lethality has an added benefit; throughout their development, larvae compete with wildtype populations for resources. Brazil approved the release of these mosquitoes into more than five neighbourhoods in late 2014, and the U.S. Food and Drug Administration (FDA) has started evaluating their use in southern Florida to curb transmission of dengue and chikungunya. Since this approach specifically targets the species of mosquitoes that act as vectors, it should have fewer damaging off-target effects than pesticides, although it is difficult to anticipate what impact it may have on the delicate balance of the ecosystem.

When a mosquito bites a malaria-infected human individual, Plasmodium enters the insect and travels from the salivary gland to the midgut where its life cycle takes place. Plasmodium sporozoites eventually return to the salivary gland where it can be transmitted to more people through the mosquito’s bite. Image credit: Angela Zhou.

To avoid the ecological consequences of depleting entire insect species, researchers are asking: can we prevent Plasmodium colonization of Anopheles mosquitoes in the first place? When a mosquito feeds on a person infected with malaria, some Plasmodium gametocytes in the person’s blood make it into the mosquito mid-gut. There, the gametocytes mature into sporozoites, which travel from the hemolymph into the salivary gland. As such, the mid-gut and salivary glands are organs of interest in the prevention of parasitic transmission. Prevention of sporozoite survival within the mosquito or entry into the salivary glands can both abrogate disease transmission.

In 2007, entomologist Raymond St. Leger’s group from the University of Maryland inserted the insect-specific neurotoxin scorpine into Metarizium anisopliae, a fungus that naturally infects the malaria vector Anopheles mosquitoes, to make it a more efficient mosquito killer (Wang et al. 2007). However, this fast-acting insecticide approach applies a strong selective pressure for M. ansiopliae-resistant mosquitoes. In 2011, the same research team engineered a recombinant strain of M. anisopliae to express the protein SM1 when in the mosquito salivary gland (Fang et al.). SM1 prevents entry of malaria sporozoite into the salivary gland by competing with the parasite for binding of salivary gland surface molecules. When mosquitoes were infected with SM1-expressing M. anisopliae, sporozoite colonization was decreased by 71%. The transgenic combination of SM1 and scorpine in M. anisopliae decreased sporozoite counts by 98%. Since these transgenes are only expressed once the fungus enters the insect hemolymph, the authors believe it will be low risk to the human population. Unlike the 2007 study, this recombinant M. anisopliae strain does not kill the mosquito quicker than the non-modified fungus, thereby avoiding selective pressure as the insect survives past reproductive age. The drawback to this strategy is that fungal spores only survive a few months when applied to walls and other surfaces, therefore making it difficult to introduce widely into mosquito populations.

The mid-gut houses Plasmodium during important developmental stages, and is also where the mosquito’s microbiome resides. Scientists have begun searching for mid-gut resident bacteria that can be used as anti-parasitic agents and have found potential candidates in the genus Wolbachia, an abundant group of intracellular bacteria naturally infecting over 65% of insect species. While the Anopheles mosquito is not a natural host for Wolbachia, a group from Michigan State University recently succeeded in establishing a stable Wolbachia colonization in the mid-gut of Anopheles mosquitoes (Bian et al. 2013). Females of the infected Anopheles line passed on the Wolbachia infection to 100% of progeny. Infected mosquitoes had a lower survival rate, and survivors had fewer viable progeny. In addition to affecting vector health, Wolbachia influences the health of the parasite also housed in the mid-gut. Compared to controls, mosquitoes colonized by Wolbachia had a modest decrease in Plasmodium oocysts and a 3.7-fold decrease in sporozoites after a P. falciparum-infected blood meal. However, a very small number of sporozoites are needed to pass on a malaria infection, making it unclear if the observed decrease in sporozoites would result in decreased transmission.

Establishing Wolbachia colonization in the huge populations of wild mosquitoes will not be trivial. To confuse matters more, a mosquito species that carries natural Wolbachia infection, Aedes fluviatilis, shows higher numbers of Plasmodium gallinaceum than A. fluviatilis that have been cleared of Wolbachia infection. Most worryingly of all, some experiments show Wolbachia infection leading to an increase in malaria transmission rates despite in vitro indications to the contrary. With Wolbachia-infected Aedes aegypti mosquitoes entering field trials in Brazil to curb a dengue re-emergence, more research is needed regarding the impact this could have on other vector populations.

Whether engineering reproductive dead-end mosquitoes or manipulating their microbiota, both strategies aim to specifically target species acting as vectors. Unlike pesticides that poison a broad range of insect species and cause toxic repercussions further up the food chain, the new approaches target single mosquito species. Although this is expected to limit ecological disruption, it is difficult to predict with certainty what effects could arise downstream of stable perturbations in the ecosystem. Furthermore, these control strategies offer a versatility that is promising for the development of combinatorial approaches to vector control, reducing the danger of mosquitoes developing resistance. However, any control strategies that manipulate vector biology must take into account how the transmission of other vector-borne diseases could be affected.

References

1. Bian, G., Joshi, D., Dong, Y., Lu, P., Zhou, G., Pan, X., Xu, Y., Dimopoulos, G., Xi, Z. (2013). Wolbachia invades Anopheles stephensi populations and induces refractoriness to Plasmodium infection. Science. 340:748-51.

2. Fang, W., Vega-Rodriguez, J., Ghosh, AK., Jacobs-Lorena, M., Kang, A., St Leger, RJ. (2011). Development of transgenic fungi that kill human malaria parasites in mosquitoes. Science. 331:1074-1077.

3. Hughes, GL., Rivero, A., Rasgon, JL. (2014). Wolbachia can enhance Plasmodium infection in mosquitoes: implications of malaria. PLoS Pathogens. 10:e1004182.

4. (2013). Modulating malaria with WolbachiaNature Medicine. 19:974-975.

5. Wang, C., St Leger, RJ. (2007). A scorpion neurotoxin increases the potency of a fungal insecticide. Nature Biotechnology. 25(12):1455-1456.

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