Although the asymptomatic liver stage of malaria is a crucial part of the parasite's development inside humans, it remains an unexplored black box. Until recently, scientists were convinced that malaria parasites were so adept at taking over liver cells that any attempt by the liver cell to attack the parasite would be futile. Now, researchers at Seattle BioMed are using systems biology to begin to unravel part of this mystery, with the finding that liver cells infected with malaria parasites are more vulnerable than previously thought, and that existing drugs can be leveraged to force those infected cells to self destruct while leaving the healthy cells intact. These results are published this month in Cell Death & Disease.
Malaria targets the liver
When a malaria-infected mosquito bites a human, parasites migrate from the mosquito's salivary glands to the human liver, where they find and occupy a cell. Over the next seven to ten days, the parasite multiplies hundreds of thousands of times over, dramatically expanding the size of the liver cell but causing no other symptoms. Finally, the parasites burst into the blood stream, causing symptoms that include fever, chills, and nausea, and in some cases death. Malaria kills nearly a million children every year, with a child dying of the disease every 43 seconds.
Conventional scientific wisdom regarding the "liver stage" of disease was that the malaria parasites make their host cells exceptionally resistant to death. This meant that bombarding the liver with drugs that cause cells to commit cell suicide, or apoptosis, would destroy healthy liver cells while allowing infected cells to escape unscathed. Now, new data collected by Alexis Kaushansky, Ph.D., and Stefan Kappe, Ph.D., of Seattle BioMed shift this paradigm.
Finding the vulnerabilities in malaria's defenses
The work published this month in Cell Death & Disease is the second major breakthrough in this area in recent months. In March, Kaushansky and Kappe demonstrated that malaria-infected cells were not the indestructible survivors as previously believed. By using drugs to stimulate p53, a classic tumor suppressor molecule, Kaushansky and Kappe were able to help liver cells fight off the malaria parasite. This piece of knowledge led them to wonder: How many other targets could make malaria-infected cells vulnerable? Is the pool of drugs that can effectively target malaria parasites before they cause symptoms larger than we imagined?
The goal was simple: find a pathway that, when activated, kills infected cells while leaving healthy cells unaffected, and eliminates malaria parasites before they cause disease. Kaushansky had noticed in the previous study that infected cells showed higher levels of survival molecules -- ones that suppressed apoptosis -- in the mitochondria. She wondered if stimulating cells to kill themselves using that particular pathway would result in more damage to infected cells, with little or none in healthy cells.
By administering chemotherapy sensitization agents that target a molecule called Bcl-2, Kaushansky was able to stimulate that cell death pathway, causing the parasite-infected cells to kill themselves while leaving healthy liver cells mostly intact. This finding represents a fundamentally new way to kill malaria parasites while in the liver.
Uncovering the range of weapons already at our disposal against malaria
"Malaria still threatens a quarter of the world's population despite decades of eradication efforts, and thus to effectively combat this disease a fresh approach must be taken," says Kaushansky. "Using systems biology, we were able to show the existence of additional pathways that can be used to fight infected cells, demonstrating that our previous research involving p53 was not an isolated case and that we have only begun to scratch the surface of how broad these kinds of host-based therapeutics can be."
The broader range of targets means that the drug possibilities for fighting off the liver stage of malaria are much larger than previously thought. "In this study, we looked at an entirely separate pathway, working by an entirely different mechanism, and it still worked to help kill infected cells," says Kappe. "This gives us hope that there are many other pathways that may also work as drug targets, and we look forward to conducting additional research into other potential pathways that may also hold potential for treating malaria."
Using existing drugs to target the liver stage of malaria also carries other potential benefits. Because the drugs tested have already been developed for other purposes, explains Kaushansky, there are substantial economic benefits in repurposing the drugs for malaria. Additionally, because the drugs target the host liver cell rather than the parasite, the potential for drug resistance to grow against these therapies is far lower. "This could fundamentally change the way we think about fighting the malaria parasite," she says.
The above story is based on materials provided by Seattle Biomedical Research Institute (Seattle BioMed). Note: Materials may be edited for content and length.
- A Kaushansky, P G Metzger, A N Douglass, S A Mikolajczak, V Lakshmanan, H S Kain, S HI Kappe. Malaria parasite liver stages render host hepatocytes susceptible to mitochondria-initiated apoptosis. Cell Death and Disease, 2013; 4 (8): e762 DOI: 10.1038/cddis.2013.286
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