Disorient the malaria parasite to prevent it from causing harm

With almost 250 million cases per year, 621,000 of which are fatal, malaria remains a major public health problem, especially in sub-Saharan Africa. Malaria is a parasitic disease that is transmitted by mosquitoes and is caused by microbes from the genus Plasmodium. In its journey from mosquito to human, Plasmodium must adapt to the specificities of the many organs and cells it parasitizes. Microbes have no sense organs; instead, they have sensors made of proteins to detect molecules specific to the environment they occupy. While most living organisms have the same type of sensors, Plasmodium is an exception. Biologists at the University of Geneva (UNIGE) have identified a new type of sensor that lets Plasmodium know exactly where it is and what to do. This work, published in the journal Science Advancesopens up the possibility of scrambling the signals sensed by these sensors to confound the orientation of the parasite and thereby prevent its replication and transmission.

When a human is bitten by a Plasmodium-infected mosquito, the parasite enters the bloodstream and travels to the liver, where it develops for about ten days without causing any symptoms. After this period, Plasmodium reenters the bloodstream, where it parasitizes red blood cells. Once inside the red blood cells, the parasites reproduce in synchronous 48-hour cycles. At the end of each multiplication cycle, the newly formed parasite leaves its host’s red blood cells, destroys them and infects new ones. It is this destruction of red blood cells that causes the waves of fever associated with malaria. Severe forms of malaria are associated with blockage of blood vessels by infected red blood cells.

When a mosquito bites a human whose blood is infected with Plasmodium, the parasite changes its developmental program to colonize the intestines of its new host. After a period of further multiplication, Plasmodium returns to the mosquito’s salivary glands, ready to infect a new human.

Unknown communication channel

From the warmth of red blood cells to the depths of a mosquito’s gut through the liver, how does Plasmodium sense changes in its environment to change its developmental program? “Understanding these very specific biological mechanisms is an important step towards fighting parasites,” explains Mathieu Brochet, Associate Professor in the Department of Microbiology and Molecular Medicine at the UNIGE School of Medicine, who led the project. “At each stage of its life cycle, the parasite must logically pick up signals that allow it to react correctly, but which and how?”

There are small molecules that are not present in the blood but are present in mosquitoes that the parasites can detect. “Starting from this single known element, we have identified a sensor that allows the parasite to detect the presence of these molecules when ingested by a mosquito,” explain Ronja Kühnel and Emma Ganga, PhD students in Mathieu Brochet’s lab and first authors of the study. “This sensor consists of five proteins. In its absence, the parasite is not aware that it has left the bloodstream for the mosquito, and therefore cannot continue its development.

Surprisingly, this sensor is also present at other stages of the parasite’s life cycle, especially when the parasite has to leave the red blood cells. “We then observed exactly the same mechanism: without this sensor, Plasmodium is trapped in red blood cells, unable to continue its cycle of infection.” However, scientists have yet to identify any human molecules detectable by the parasite; identifying them can provide a better understanding of how fever waves are caused by Plasmodium.

Other parasites are also involved

The protein complex found here is absent in humans, but is found in the entire family of apicomplexan parasites that belong to Plasmodium, as well as Toxoplasma, an agent of toxoplasmosis. By identifying these sensors, scientists can now envision how it scrambles the signals sensed by the parasite at different stages of its development, thereby confusing it and blocking its multiplication and transmission.