Malaria is an ancient killer. For millennia it has claimed the lives of the world’s most vulnerable populations - the youngest and the poorest. Despite the human species' long history with the disease, it remains a mystery to us in many ways. We really only know the basics. Plasmodium falciparum, the parasitic microorganism that causes malaria, has an incredibly complex lifecycle. It is transmitted to humans in the saliva of a tiny Anopheles mosquito. When the mosquito bites, the parasites flow into the bloodstream. Once inside a human, the parasite goes through multiple phases, taking residence in liver cells and red blood cells. In each phase it feeds on the resources within the human cell as it grows rapidly and replicates its cellular machinery many times. Then it suddenly divides into many new individuals, aggressively bursting out of the human cell. This parasitic amplification occurs once in a liver cell, and subsequent to its forceful exit from the liver, it will amplify many times in red blood cells.
Not only does the Plasmodium undergo a very complicated lifecycle, it also contains some unusual cellular equipment. The Plasmodium contains a plastid, an organelle like the chloroplasts found in plants, which is capable of photosynthesis. What could a plastid be doing inside a human parasite? This question has managed to elude researchers for twenty years. One thing we know for sure is that it’s not performing photosynthesis like its chloroplast brethren.
The plastid found in Plasmodium is called an apicoplast. It is believed that plastids were once free-living bacteria that were gobbled up by algae 1500 million years ago and harnessed for their photosynthetic ability. Like all complex plastids, the apicoplast found its way into the Plasmodium eons ago when a Plasmodium engulfed a single-celled red algae that contained plastids. Over millions of years of evolution, however, the Plasmodium’s plastid passenger has lost its photosynthetic power and shipped most of its genetic information to the nucleus of the Plasmodium. In many ways the apicoplast seems like nothing more than an evolutionary relict. However, if the apicoplast serves any critical functions for the Plasmodium, it could be a key target for anti-malarial treatments.
Scientists have high hopes for apicoplast-targeted malaria treatments for one very important reason. Even though it has resided in more complex organisms for ages, the apicoplast is still of bacterial origin. In contrast, the Plasmodium, like a human cell, is a eukaryote. Definitions aside, this means that Plasmodium metabolism is more similar to metabolism in human cells than it is to apicoplast metabolism. Therefore, treatments that interrupt metabolic pathways of the apicoplast are likely to leave human cells unharmed, whereas treatments that target the Plasmodium itself may have the same adverse effect on human cells. This leaves scientists left to ponder the role of the apicoplast in the Plasmodium. What essential functions does the apicoplast perform for the Plasmodium that the Plasmodium cannot do for itself?
Both apicoplasts and human cells produce important molecules called isoprenoid precursors. The human and apicoplast versions of these molecules may look identical after synthesis, but since human cells are eukaryotic and apicoplasts are more like bacteria, the metabolic pathways that produce them are completely different. After the isoprenoid precursors are made in the apicoplast, they are shipped out into the parasite where they are used to make isoprenoids, a diverse and biologically important class of molecules. This step occurs during the blood stage of the parasite’s life cycle. Scientists believe that the synthesis and export of these isoprenoid precursors may be the only function of the apicoplast that is actually essential for parasitic growth.
In a recent publication in PLoS Biology, Drs. Ellen Yeh of Stanford and Joseph DeRisi of UCSF were able to demonstrate just how important these isoprenoid precursors are to the Plasmodium. It is known that several antibiotics are effective at combating malaria. Antibiotics attack the bacteria-like apicoplast, not the Plasmodium itself. However, their effectiveness at killing the malaria parasite suggests that functions of the apicoplast must be essential to the survival of the Plasmodium. Yeh and DeRisi took this information one step further, attempting to understand the mechanism of these antibiotics that cause the parasite to die.
They grew Plasmodium in a laboratory culture and treated the culture with antibiotics. As expected, the parasites stopped growing or died. Next they treated the cultures with antibiotics but added isoprenoid precursor molecules. By doing this they found that one particular molecule, IPP, “rescued” the Plasmodium in the culture. Even though the antibiotics killed the apicoplast, the Plasmodium survived with the addition of IPP. From this simple experiment, they were able to deduce that the essential function that the apicoplast performs for the Plasmodium is the synthesis of IPP.
Now that scientists have discovered the role of the apicoplast, they can target this metabolic function when developing new anti-malarials. In addition to that, through their experiment Yeh and DeRisi were able to produce a Plasmodium strain that lacks the apicoplast. This strain will be a powerful tool for Plasmodium studies, especially for identifying apicoplast drug targets and more advanced vaccines. Well done Dr. Yeh and Dr. DeRisi!
Yeh E, DeRisi JL (2011) Chemical Rescue of Malaria Parasites Lacking an Apicoplast Defines Organelle Function in Blood-Stage Plasmodium falciparum. PLoS Biol 9(8): e1001138. doi:10.1371/journal.pbio.1001138
The image comes from work by Waller, et al. (2000). This image shows the apicoplast, stained green, inside a Plasmodium during its many cellular stages in the blood phase. Notice that the apicoplast is replicated many times before the parasite divides into several new individual cells. The EMBO Journal (2000) 19, 1794 - 1802 doi:10.1093/emboj/19.8.1794
