Researchers at Indiana University School of Medicine have identified a protein that plays a critical role in the survival of Plasmodium falciparum, the parasite that causes the most lethal form of malaria. The protein, called PfAnchor, is required to divide and inherit the apicoplast, a unique organelle necessary for the parasite’s replication during the blood stage.
In the first conversation of our three-part interview, researcher Sabrina Absalon, PhD, assistant professor of pharmacology and toxicology at Indiana University School of Medicine, said, “When we deplete that protein, the parasites don’t even egress properly, and they really die in the first cycle. Suddenly we were able to kill them right away and not afterwards.”
PfAnchor was discovered through work that began during Absalon’s postdoctoral research. She initially focused on nuclear division and identified a protein that disrupted chromatin structure when knocked down. Using biochemical approaches, her team identified PfAnchor as a highly expressed protein in the cytoplasm and nucleus. At first, its role was unclear.
“We didn’t have expansion microscopy then, so those dots made no sense in the cells,” Absalon said. “Then we realized it was associated with the apicoplast.”
The apicoplast is an organelle of prokaryotic origin, retained by the parasite for the synthesis of fatty acids and isoprenoids. It is inherited through endosymbiosis and has four membranes. While parasites can complete one replication cycle without a functioning apicoplast, they cannot survive beyond that without creating a new one.
“If they don’t have it, they die,” Absalon said. “We call it the delay of death. But with PfAnchor, they die in the first cycle.”
To study PfAnchor, the researchers used Ultrastructure Expansion Microscopy, which physically expands the biological sample and improves resolution. “Now the parasite is not one micron, it’s five,” Absalon said. “So suddenly we can have resolution and beautiful images of what is going on inside the parasite.”
The team found that PfAnchor localizes to the apicoplast and interacts with PfDyn2, a dynamin-related protein involved in membrane fission. It also associates with actin and chaperone proteins, suggesting that a larger network coordinates organelle inheritance and cytoskeletal remodeling.
Unexpectedly, the antibiotic azithromycin was able to rescue parasites lacking PfAnchor by collapsing the apicoplast’s branched structure into small vesicles, allowing cell division to proceed.
“This doesn’t mean azithromycin is a cure,” Absalon said. “But it shows a new vulnerability. If we can disrupt apicoplast morphology or fission, we may be able to kill parasites quickly, in just one replication cycle.”
PfAnchor has no known homologs outside of Plasmodium, making it a potential target for new antimalarial drugs. Absalon’s team plans to map the broader protein complex involved in apicoplast fission and study its integration with the parasite’s cytoskeleton.
“We’re just scratching the surface,” she said. “There’s an entire network we want to understand.”
