Of Parasites and Poop

One of the oldest malaria riddles may have been solved in 2014… by a team of researchers sorting through poop [1].

Of the malaria species that infect people, the two that cause the vast majority of human suffering have the catchy names of Plasmodium falciparum and Plasmodium vivax. P. falciparum is primarily responsible for infections in sub-Saharan Africa. It’s the more deadly of the pair, and is responsible for most malaria-related fatalities. On the other hand, P. vivax is more geographically widespread, causing infections across Asia and South America, but has been thought to be almost entirely absent from Africa. P. vivax causes fewer deaths but certainly causes a great deal of suffering and lost productivity. Plus, P. vivax also has an extra sneaky trick: it can hide in an infected person’s liver for months or years before reemerging to cause a relapse.

Why do these parasites live in such different parts of the world, and where did they come from?

As a general rule for human pathogens, when you’re looking for their origin, look first to great apes and monkeys, the animals most similar to us. Scientists theorize that sometime back along the evolutionary history of malaria and humans, a mosquito carrying parasites adapted to a great ape, or a monkey, bit a human, and the parasites that got into the human survived and eventually adapted to their new home. Early studies suggested that P. falciparum was most like parasites in African great apes, suggesting an African origin; while P. vivax appeared to be most like parasites in Asian monkeys, suggesting an Asian origin. But why was Africa so dominated by P. falciparum, while the rest of the world appeared to be open to the spread of parasites?

A big piece of the puzzle slotted into place when scientists discovered the relationship between a particular human red blood cell protein, the “Duffy antigen”, to P. vivax susceptibility. P. vivax needs the Duffy protein to invade red blood cells. Therefore, individuals with a Duffy-negative variant have red blood cells that are resistant to P. vivax. The Duffy-negative variant is nearly ubiquitous in populations from sub-Saharan Africa, which means that almost everyone there is resistant to P. vivax.

So part of the question was answered. P. vivax isn’t a problem in Africa because African populations are largely resistant to it. But this theory almost created more questions than it answered. Why would African human populations have developed near-complete immunity to a pathogen that was developing in Asia? Another element didn’t fit: there were rare, mystifying reports of visitors from other continents – who didn’t carry the Duffy-negative variant – who left Africa carrying a mysterious parasite infection that looked and behaved an awful lot like P. vivax.

Where were the P. vivax parasites coming from?  Were they passed from person-to-person in the minority of people living in sub-Sarahan Africa without the Duffy-negative variant, or was P. vivax evolving to be able to infect Duffy-negative individuals? Or was P. vivax circulating in wild great ape populations, and if so, had it come to them recently, carried by travellers, or had it always been there?

A possible way to resolve the controversy would be to take blood samples from wild ape populations and examine them for P. vivax parasites. However, wild apes are endangered, their populations terribly fragile. Getting a blood sample from a wild chimpanzee or a gorilla requires darting the animal, a messy, dangerous process both for the ape and for the team responsible. Large-scale blood sampling is impossible.

The apparently insoluble problem – how can you adequately study the evolution of malaria parasites, if you can’t test blood from apes? – was unexpectedly solved by a group of scientists far better known for their work on a very different human pathogen, HIV. Dr. Beatrice Hahn and her lab (University of Pennsylvania) had been working on trying to elucidate the origin of HIV, and had realized that they could analyze HIV-like viruses in apes… by looking at feces, not blood, and getting around the sample problem that way. The researchers found that little bits of the virus’s genome were excreted into the feces and, using sophisticated computational techniques, could be analyzed and reassembled into viral genomes for comparison with human samples. Why not try the same approach for malaria parasites?

It worked – beautifully. Taking feces from the habitat of an ape is far less invasive than sampling their blood, and if lab assistants sometimes joked that they had become glorified Pooper-Scoopers, the data came rolling in. Hahn’s group assembled a plethora of data looking at the origin of P. falciparum first, and was able to show that the human parasite grouped most closely with the parasites identified from gorilla samples, not chimpanzees, suggesting that the deadliest human parasite had crossed over from gorillas.

In a subsequent study, Hahn’s team examined wild apes across Africa, and produced a startling result: P. vivax was common in many wild ape populations. Even more surprisingly, the genetic diversity of P. vivax in the ape populations was greater than that in human populations. High diversity of a pathogen generally suggests that it’s been around a while in that host, low diversity usually indicates that the pathogen is newer in the host species. The data Hahn’s team was able to gather strongly suggested that P. vivax, like P. falciparum, had originated in African ape populations and crossed over to humans in Africa, getting to Asia with human migrations, and spreading to infect the monkey species there. Researchers theorized that the Duffy-negative variant became common in Africa in the face of evolutionary pressure from continuing P. vivax infections, and P. vivax became rare in African human populations, but still continued to circulate in its original hosts, African great apes.

Why does it matter that P. vivax came out of Africa, and still circulates in wild ape populations there?  At the most basic level, doctors know now to be alert for possible P. vivax, which requires different drug treatments than P. falciparum, in travellers to Africa. But more than that, solving the age-old riddle of P. vivax’s origin helps us to understand not only where these malaria species have come from, but perhaps where they are going. As growing human populations come more and more frequently into contact with wild ape populations, and as intercontinental travel rapidly globalizes once-local diseases, we need to understand what factors determine the possibility of pathogen host switches. Figuring out the saga of P. vivax is an important step in that direction.

Natasha Spottiswoode is a malaria scientist and a medical student. She recently finished her PhD through a joint program between the University of Oxford and the National Institutes of Health in Washington, DC, studying the interactions between iron metabolism and malaria infections. Now she is a first-year medical student at Columbia Physicians and Surgeons in New York, NY. In the long-term, Natasha hopes to combine research with clinical work on malaria and other neglected infectious diseases. In her spare time, she enjoys rock climbing, music, and writing. 

References:

1. Liu W, Li Y, Shaw KS, Learn GH, Plenderleith LJ, et al. (2014) African origin of the malaria parasite Plasmodium vivax. Nat Commun 5: 3346.