The researchers meticulously depicted the genetic changes that the malaria parasite undergoes as it prepares to infect humans. The atlas depicts in unprecedented cellular detail what happens when the malaria parasite Plasmodium falciparum develops in mosquitoes and prepares to infect humans through bites. Such detailed investigations may lead to new ways to stop critical stages of parasite development and prevent transmission through future drugs or vaccines.
Mosquitoes are becoming more resistant to pesticides, and parasites that cause malaria are becoming more resistant to anti-malaria drugs. New approaches are urgently needed to tackle malaria, which in 2019 caused an estimated 229 million cases and 409 000 deaths, most of them young children in sub-Saharan Africa.
To reinvigorate efforts in drug or vaccine discovery, a team from Professor Jack Baum's lab at Imperial College London and Dr Mara Launizak's lab at the Wellcome Sanger Institute conducted an unprecedentedly detailed study of the human malaria parasite Plasmodium falciparum. Their results were published today (May 27, 2021) in Nature Communications.
A three-dimensional map of the genetic activity of the human malaria parasite at different stages of its life cycle
Plasmodium falciparum develops in the midgut of mosquitoes and then enters the salivary glands of mosquitoes, ready to infect humans when mosquitoes bite. During these phases, the parasite goes through a number of stages that are important for its ability to develop and spread, including changing into different forms.
The team tracked how these stages were controlled by analyzing the activity of genes throughout the process. They isolated different forms of the parasite and produced 1467 "transcriptomes" — maps of which genes in a single cell were turned on or off at different stages.
When genes are turned on, they instruct cells to make different proteins and drive developmental changes, such as getting the parasite to leave the midgut and colonize the salivary glands of mosquitoes, or crossing human cells to reach the liver, where the parasite is ready to invade more human cells.
Understanding the detailed workings of these processes at the cellular level reveals new targets that can be blocked by researchers to stop development and prevent the spread of parasites.
In addition to investigating the entire transmission cycle of the parasite, the team also focused on the so-called spore stage: the form released into human skin during mosquito bites. They classified the parasites during the development of mosquitoes and isolated sporozoites after being infected with bites because they interacted with human skin cells. In doing so, they were able to find specific gene expression patterns that defined each of these critical stages in the process. This fine granularity allows the researchers to trace the developmental process of spores and propose new mechanistic targets necessary for each step and future vaccine targets to block malaria infections.
The team was also able to compare their data with a similar dataset from the related parasite Plasmodium Berger's, a rodent malaria parasite that is often used as a model for studying malaria disease in the laboratory. This suggests which genes are common between species and which are specific to the human version of the parasite.
The researchers have made all of their data available on an interactive website, where it is easy and free to view transcription of any gene at any stage of the malaria parasite's life cycle.