Over two hundred million cases of malaria occur annually worldwide. Limiting malaria transmission has been a major public health goal for many years; it's transmitted by mosquitoes, and most efforts target the insects. But the parasite itself also influences transmission, as having a malaria infection actually makes people more attractive to mosquitoes. A recent study published in Science shows that this attraction may be due to a specific malaria metabolite, knowledge of which could aid in future public health efforts.

While having malaria is bad enough, previous studies have shown that the parasite somehow arranges to make infected individuals more attractive to mosquitoes than healthy people are. This increased attraction is at least partially due to the fact that people infected with malaria smell more attractive to the mosquitoes. The researchers behind this Science study were interested in the chemical changes that occur during an infection with the malaria parasite, and how those changes could alter the odor profile of infected hosts.

The parasite in question is a single-celled protozoan that infects the red blood cells of hosts. The protozoans have their own metabolic pathways and cellular needs, many of them distinct from those of their hosts.

One of the important biosynthesis pathways in the malaria parasite produces an intermediate chemical known as HMBPP, an abbreviation for (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate. As an intermediate molecule, HMBPP is produced during the process of making complex molecules called "isoprenoids" that are essential to malaria parasite survival.

Critically for this work, HMBPP is not made by humans. This means that HMBPP is in the blood of humans infected with malaria, but not in the blood of healthy hosts, making it a good candidate for the molecule that made the “scent” of infected persons that brings all the mosquitoes to the yard.

The researchers found that female mosquitoes were significantly more likely to feed from a device filled with HMBPP-supplemented red blood cells, compared to a control of non-supplemented blood. They also repeated this experiment using blood serum and got the same result. Mosquitoes typically want to eat blood rich in red blood cells, so an experiment using only blood serum helped to confirm that the HMBPP really was attracting mosquitoes.

Next, the researchers looked at the gases that are released from red blood cells, with and without HMBPP. This experiment showed that the malaria parasite used HMBPP to make host red blood cells release volatile gasses that were extremely attractive to mosquitoes. So it's not the molecule itself, but the products of its metabolism in red blood cells that draw in the mosquitoes.

This interaction between the parasite, HMBPP, and the red blood cells of hosts also inspired mosquitoes to consume larger volumes of blood with each meal, increasing the chances that they'll take up a parasite. The scientists found that consumption of larger blood meals may help the mosquitoes to reproduce more effectively, therefore increasing the number of transmission vectors that may be available to spread the malaria parasite from host to host. Additionally, once ingested, the HMBPP changed the mosquitoes' gene expression in ways that made them more susceptible to infection.

This study shows that the HMBPP metabolite produced by malarial parasites may be a critical part of the parasite-mosquito cycle that spreads malaria. This discovery opens doors for many future antimalarial measures that could target the production of this molecule, since it doesn’t naturally occur in humans.

Science, 2017. DOI: 10.1126/science.aah4563 (About DOIs)