Silencing a mysterious cellular passenger.

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

The Woods and Your Health

The opportunity to hike beneath the orange and red foliage of a deciduous forest in autumn is one of the greatest perks of living in New England. I spent a fair amount of time in the wooded margins of the Colby College campus, drawn out of bed at sunrise and enduring chilly mornings on the cusp of winter to collect field data. While studying the relative distribution and abundance of small mammals, I had several opportunities to walk beneath the fall foliage, wrapped in silence except for the sounds of our footsteps and our research subjects scurrying through discarded leaves. Despite the obvious ecological transition into dormancy, the New England woodland in autumn conjures feelings of freshness and vitality rather than decay. However, beneath the duff on the forest floor and within the variegated canopy lurks an invisible threat. Secretly, this serene setting could be a hotbed of disease.

Richard Preston’s The Hot Zone, painted a thrilling picture of an exotic disease festering in a remote jungle until it aggressively emerged into a vulnerable human population through an unconfirmed, but likely encounter with a reclusive animal. A more temperate, developed setting, however, is certainly not disease-free. Extremely virulent pathogens can lurk in your own backyard in natural reservoir species as common as the white-footed mouse. Zoonotic diseases, or those that can be transferred to humans from other vertebrate animals, are so common that the majority of the diseases that infect humans today originated in other animals. According to the CDC, approximately 75% of recently emerged infectious diseases, including West Nile virus, Eastern Equine Encephalitis, and Lyme disease, are zoonotic. The natural reservoir of these diseases is an animal that acts as a long-term host for the pathogen and for which an infection is non-lethal. The natural reservoir therefore acts as a continual source of a pathogen, which would otherwise eliminate itself by killing hosts too quickly to perpetuate the infection.

The emergence of new zoonotic pathogens in human populations has risen in recent years due to increased contact between humans and wildlife. As humans push back the margins of animal habitat for settlement and exploit animal resources through hunting and husbandry, we increase our contact with animals that may harbor pathogens, thereby increasing our exposure to zoonotic disease. Zoonotic pathogens do not require humans to complete their life cycle; under natural conditions the pathogen would stay within the animal population. If exposed to a disease reservoir or vector, however, humans can become an incidental host. Habitat destruction and resource exploitation increases our risk of infection by potentially deadly pathogens simply by accident.

My research partner and I were warned about disease exposure as we emptied Sherman traps, studying the relative abundance of the white-footed mouse (Peromyscus leucopus) and the deer mouse (P. maniculatus) in the margins of the woodland surrounding Colby College. Worldwide, rodents are natural reservoirs for over 35 diseases. The pathogens that cause these diseases can be spread to humans either directly through contact with saliva, urine, and feces; or indirectly via insect vectors. Lyme disease is a well-known and well-publicized disease that is caused by bacteria harbored in a mouse reservoir but spread by ticks as vectors. When summer ends and ticks overwinter on the forest floor, humans can still fall victim to the potentially deadly hantavirus pulmonary syndrome. Hantavirus is spread to humans by direct contact with the feces and urine of an infected mouse, causing renal failure and fatal hemorrhagic fever. While the symptoms sound like something straight out of The Hot Zone, there are no monkeys, fruit bats, or protective suits involved. Hantavirus can be contracted by inhaling aerosolized waste of common and abundant rodents, and hundreds of cases have been reported in the United States, especially in the western states.

While disease was not the primary focus of our research, it had very clear epidemiological implications. As humans encroach upon animal habitat, we upset the population balance of the ecological community by eliminating cover, introducing invasive species, and reducing food availability. Some species, such as the white-footed mouse, are generalists that can thrive in highly-disturbed, marginal habitat. Their populations tend to explode when specialist species populations decline. Therefore, as we push into deciduous and mixed forests, the white-footed mouse may benefit under the altered ecological conditions and increase in numbers, but overall biodiversity collapses. Incidentally, the white-footed mouse is a reservoir for both Lyme disease and hantavirus.

Zoonotic diseases are caused by pathogens that will readily infect a variety of different host species, but for which there are very few natural reservoir species. This means that only a few species can survive and spread the infection, thereby assisting the long-term survival of the pathogen. A high density of a natural reservoir species in a community would increase the presence of the pathogen and also increase the likelihood that the disease will be passed to another host or vector species. In contrast, high biodiversity would reduce the density of the natural reservoir species and increase the number of incompetent reservoirs that cannot spread the disease. It has therefore been hypothesized that biodiversity can prevent the spread of zoonotic disease and in this way protect human health.

In a ground-breaking 2000 paper in the journal Conservation Biology, Richard Ostfeld and Felicia Keesing applied this hypothesis to the spread of Lyme disease, calling it the “dilution effect.” They predicted that high species diversity within the host community would increase the likelihood that ticks would feed on animals that do not harbor the Lyme disease bacteria. As a result the infection power of the natural reservoir, the white-footed mouse, would be diluted. With a lower prevalence of infection in ticks, the vectors of the disease, Ostfeld and Keesing hypothesized that high species diversity would also reduce transmission of Lyme disease to humans. Sure enough, through analysis of state level ecological and epidemiological data, they found that states with a greater number of small mammal species in the host communities had fewer reported cases of Lyme disease per capita.

The work of Ostfeld and Keesling demonstrates that the dilution effect can apply to indirect infection through an insect vector. A recently published study in the journal PLoS One, however, took their theory one step further. While studying the relationship between small mammal biodiversity and the prevalence of hantavirus in Panama, scientists from the Museum of Southwestern Biology and the University of New Mexico found that the dilution effect holds up for direct infections as well. They theorized that when species diversity in a host community is reduced and the density of the natural reservoir species increases, infected reservoirs will have more encounters with uninfected reservoirs and therefore more opportunities to transmit the virus. In contrast, high species diversity would reduce the encounter rate and similarly reduce the transmission rate. After setting up experimental field plots, the researchers reduced species diversity within some of the plots by removing the non-reservoir species. When the number of species was reduced, both the density of the natural reservoir population and the prevalence of hantavirus among those individuals increased. From this finding one could hypothesize that high biodiversity would consequently reduce the rate of direct infection to humans who are exposed to the reservoir species.

The idea that biodiversity can offer a service to human health is not a new concept. In fact, when people mobilize to save large swaths of highly diverse habitat from destruction, human health is one of the most argued cases for its preservation. However, people usually argue that within these areas of high biodiversity may be un-studied organisms with compounds for potential pharmaceuticals or that can act as laboratory models. While certainly compelling, this case incentivizes the preservation of certain species of potential value, not necessarily biodiversity. The ability of a diverse community to dilute the presence of a zoonotic pathogen and reduce human exposure to some of the deadliest diseases is an even stronger correlation between high biodiversity and improved human health.



Ostfeld, Richard S. and Felicia Keesing. 2000. Biodiversity and Disease Risk: the Case of Lyme Disease. Conservation Biology. 14(3):722-278

Suzan, Gerardo, Erika Marce, J. Tomasz Giermakowski, James N. Mills, Gerardo Ceballos, Richard S. Ostfeld, Blas Armien, Juan M. Pascale, Terry L. Yates. 2009. Experimental Evidence for Reduced Rodent Diversity Causing Increased Hantavirus Prevalence. PLoS One. 4(5)

Photo: Peromyscus leucopus; Encyclopedia of Life