Anopheles gambiae mosquitoes can transmit the Plasmodium parasites that cause malaria when they feed on people with blood. Photo credit: Jim Gathany, CDC
Malaria is a deadly global burden
Female Anopheles mosquitoes transmit the Plasmodium parasites that cause malaria. Control methods against mosquito populations, such as bed nets treated with insecticides, have significantly reduced the malaria burden over the past few decades. Yet malaria remains a devastating cause of disease and death in tropical and subtropical regions, with over 400,000 deaths and 220 million cases in 2019. To make further progress in the fight against malaria, we need a deeper understanding of the factors influencing transmission. as mosquito populations become increasingly resistant to insecticides.
The development of plasmodium in mosquitoes is complex
An important determinant of malaria transmission is the time it takes parasites to develop into mosquitoes. After a mosquito ingests malaria parasites in a blood meal by biting an infected person, the parasites go through a series of developmental forms until they eventually invade the mosquito’s salivary glands and can then be transmitted in a new bite. The time between infection of the mosquito and the ability to pass on is known as the extrinsic incubation time (EIP, approx. 10-14 days for Plasmodium falciparum laboratory infections). The effects on transmission are related to mosquito mortality: in mosquitoes with the same lifespan, parasites with a short EIP can be transmitted earlier and over a longer period of time than parasites with a long EIP.
Plasmodium falciparum parasites that develop in the midgut of an Anopheles gambiae mosquito
Photo credit: W. Robert Shaw
It is known that like many growth processes, the EIP is influenced by the ambient temperature, but it is also related to the available nutrient resources within the mosquito. Our previous work has shown that reducing the number of eggs a female produces increases parasite size and shortens EIP, thereby speeding up the appearance of parasites in the salivary glands. Parasites were able to effectively utilize the accumulated lipid resources available after egg development.
Mosquitoes feed themselves several times, of course
Given the relationship between EIP and resources in the mosquito, our most recent study looked at the effects of a mosquito taking an extra blood meal on the rate at which the parasite develops. In natural populations, Anopheles gambiae females bite humans for nutrients for each round of egg development, of which there can be several. This multiple feeding behavior is difficult to reproduce in laboratory experiments with Plasmodium-infected mosquitoes, which limits our understanding of the possible effects on malaria transmission, and yet it is much more similar to the situation in field populations.
An additional blood feed accelerates the parasite development and increases the malaria transmission potential
In our study, providing female mosquitoes with a second blood meal 3 days after being infected with the malaria parasite Plasmodium falciparum dramatically increased the size of the developing parasites and accelerated the appearance of communicable forms in the salivary glands, reducing EIP by 2.3 days ( 21%) and make these mosquitoes infectious earlier. The increased available resources, in particular amino acids and lipids, which are provided by an additional blood meal, are apparently accessible to the parasite and may be ingested by it. Plasmodium therefore has a remarkable plasticity for using available mosquito nutrients to speed up its development. Indeed, similar double-feeding effects are reported on multiple mosquito-pathogen interactions, so this may be a more general mechanism for parasites to increase their chances of transmission to the nearest host.
Modeling of the malaria transmission potential (R0) in sub-Saharan Africa shows a relative increase in all areas where mosquito populations feed twice compared to those who feed once due to a shorter parasite EIP.
Incorporating our results into a mathematical model across sub-Saharan Africa shows that malaria transmission potential, a parameter known as R0 that includes multiple blood feeding, is likely to be higher than previously thought. Given that natural already feeding mosquito populations are multiplying, this suggests that the contribution of multiple blood feeding as a driver of transmission is currently underestimated and disposal in these endemic areas may be more difficult than expected.
What are the implications for fighting malaria?
Our data suggests that, first, parasites can be transmitted by younger mosquitoes that are known to be less prone to killing insecticides, potentially negatively impacting the effectiveness of currently available insecticide-based strategies (bed nets and indoor sprays) affects.
Second, strategies to encourage mosquitoes to eat nearby animals rather than humans (zooprophylaxis) may not be as effective as expected because animal blood, although nutritionally different from human blood, has accelerated development within mosquitoes which increases the likelihood that women will transmit parasites when feeding on humans.
Finally, control strategies that disrupt egg production to reduce Anopheles populations, such as genetically engineered gene drives to suppress the population, can increase the resources within the mosquito, increase the resources available to parasites, accelerate their development and inadvertently promote the transmission of malaria.