Living organisms often create from scratch what they need for life.
For humans, this process means the creation of most of the essential compounds necessary for survival. But not all living beings have this ability, such as the parasite that causes malaria, which affected about 249 million people in 2022.
Virginia Tech researchers in the College of Agriculture and Life Sciences found that by preventing the malaria parasite from removing fatty acids, a type of necessary nutrient, it could no longer grow.
“The key to this advance is that we were able to develop a method to detect the malaria parasite and block this process,” said Michael Klemba, associate professor of biochemistry and principal investigator on the project. “Although they are in their infancy, the results could open the door to a new way to combat malaria.”
Malaria occurs while the parasite replicates in human red blood cells and relies on collection, rather than creation, to meet its need for fatty acids. Many fatty acids are obtained by metabolizing a class of host lipids called lysophospholipids. However, scientists did not know how the parasite releases fatty acids from the host's lipids.
The Virginia Tech research team did experiments with infected red blood cells and found chemicals that may prevent the parasite from obtaining necessary fatty acids. The researchers discovered that two enzymes played a decisive role in breaking down the host's lipids to release fatty acids that the parasite needs. These enzymes work in different places: one works outside, in the red blood cell, and the other, inside the parasite.
When the scientists removed these two enzymes, they discovered that the parasite had difficulty obtaining the necessary fatty acids and could not grow well. This was especially true when that guest lipid was the only available fatty acid source. When both enzymes were stopped working, either by changing the parasite's genes or using drugs, the parasites were unable to grow in human blood.
This shows that breaking down the host lipid, called lysophosphatidylcholine, to obtain fatty acids is essential for the survival of the malaria parasite in our bodies and that targeting these two enzymes could be a new way to combat malaria.
The research was published today by proceedings of the National Academy of Sciences from the United States of America and was funded by a grant from the National Institutes of Health, Hatch funding from the United States Department of Agriculture, and through the Department of Biochemistry at Virginia Tech.
Laying the foundation
In 2017, a study came out that showed that when levels of lysophosphatidic acid drop in the host, the malaria parasite, known as Plasmodium falciparum, is converted into a form that mosquitoes can absorb. P. falciparum causes malaria while replicating in the host's erythrocytes or red blood cells, and relies on harvesting rather than synthesising or creating compounds to meet its need for fatty acids.
This appeared to be an important environmental signal, Klemba said, and there was also evidence that host lipids were a preferred source of fatty acids.
“There was no clarity about what the metabolic pathways were,” he said. “If we could show that these metabolic pathways are useful, then it would be an important contribution to the field.”
For Klemba, this was an important question to answer, and his lab (and his students) were uniquely positioned to do so. Two graduate students worked on the project: Jiapeng Liu '23, now a postdoctoral fellow at Rutgers University, and Christie Dapper, a former professor at Virginia Tech. Liu was the lead author and Katherine Fike helped with the project as a research specialist.
“There are two enzymes that are really important for this process: one is inside the parasite and the other is exported to the host cell,” Klemba said. “Which is not typical of metabolic processes, since they normally take place within the parasite. Why did the parasite find it useful to put one of these enzymes into the host? We have some ideas that that might be involved in the host modification, which could be that the parasite remodels red blood cells once it has taken up residence.”
The researchers found that removing just one of the two enzymes, which they called XL2 and XLH4, does nothing. Both must be removed to inhibit parasite growth.
Future work
The discovery has some limitations: the research was carried out only using a culture dish, commonly known as in vitro. Researchers are also unsure whether the compounds used to inhibit the two enzymes are toxic.
Some level of toxicity is expected, Klemba explained, and it may be possible to detoxify the compounds.
“But that could be a big challenge,” he said.
Meanwhile, this discovery could open the door to therapeutic treatments for malaria.