A parasite believed to have infected as much as one-third of the world’s population may have a metabolic weak point that researchers could exploit to develop safer and more effective treatments.
In a review published in PLOS Pathogens, Clemson University biologist Zhicheng Dou said there is growing evidence that Toxoplasma gondii depends on its ability to produce heme, an iron-containing molecule required by proteins that help cells generate energy.
The parasite’s heme production system differs in important ways from that found in humans. Those differences could allow scientists to interfere with the parasite’s metabolism without shutting down heme production in human cells.
“This pathway is essential in parasites,” said Dou, who reviewed several years of genetic, biochemical and drug-development studies conducted by his lab and other research groups.
Toxoplasma gondii causes toxoplasmosis. Humans can contract T. gondii in a number of ways, including eating certain undercooked, contaminated meats, especially pork, lamb and venison; contact with cat feces; and in the womb, if the mother is infected.
Most healthy people who become infected have no or mild symptoms, but the illness is more dangerous for people with weakened immune systems, including transplant recipients, those receiving chemotherapy and people with HIV or AIDS. Current frontline treatment for acute toxoplasmosis can produce significant side effects, Dou said.
Once the parasite establishes a chronic infection, it can form cysts in the brain and other tissues that commercially available drugs do not eliminate.
The parasite also infects livestock and other animals.
New strategy
The new strategy centers on heme. In humans, heme is best known as a component of hemoglobin, the protein that carries oxygen in the blood. It is also required by other proteins involved in mitochondrial respiration, the process cells use to produce much of their energy.
T. gondii needs heme for similar reasons. When researchers genetically disrupted enzymes involved in the parasite’s heme production, its heme levels fell, its mitochondrial activity declined and its growth slowed sharply.
The promise of the approach does not lie simply in the importance of heme, but the organization of the parasitic pathway. Humans and T. gondii each possess the eight basic enzymes needed to make heme. In human cells, the reactions are divided between the mitochondria and cytoplasm. In T. gondii, the intermediate reactions take place inside the apicoplast, a plant-like organelle that humans do not have. Another of the parasite’s enzymes, PPO, resembles the plant version more than the human version.
That led researchers to compounds originally developed as herbicides. Several commercial herbicides that target PPO slowed parasite growth in lab cultures, but at too high of a concentration for a useful medication.
In a study referred to in the review, Clemson chemist Daniel Whitehead and his students altered the composition of one of the compounds and found some of the resulting derivatives were 100 to 150 times more potent against the parasite than the original compound.
Can’t interfere with host
Potency is only one requirement. Researchers must determine whether a compound damages human cells. A molecule that kills the parasite but also interferes with the host’s heme production would not provide the selectivity needed for safe treatment.
There’s another obstacle as well: in treating chronic infection where cysts form in the brain, the drug would have to cross the blood-brain barrier, which protects the central nervous system from many toxins but also stops many useful drugs.
Dou said he plans to study how important heme production remains during chronic infection. While it is known that the parasite reduces the activity of its heme synthesis genes when it enters the cyst stage, it is not yet clear if this metabolic slowdown makes the pathway completely invulnerable. Discovering whether the dormant cysts still depend on this reduced heme production is a crucial next step in developing treatments that can clear the parasite entirely.
Potential vaccine
Dou said the weakened parasites created in the genetic studies could eventually be examined as live, attenuated vaccines that could be used in livestock.
He said any new treatments from the studies are years away.
“It provides a starting point,” Dou said.
The complete review is available here.
