Deadly malaria jumped to humans from wild chimps

An international research team led by evolutionary geneticist Stephen M. Rich of the University of Massachusetts Amherst has discovered that the parasite Plasmodium falciparum, which causes the deadliest form of malaria, jumped from wild chimpanzees to humans via bites by mosquitoes (the vector) in equatorial Africa perhaps as recently as 10,000 years ago. It's an unsuspected origin much more recent than previously thought possible.

Genetic detective work by Rich and colleagues is described in the current issue of Proceedings of the National Academy of Sciences, USA. The researchers used blood samples from wild and wild-born captive African chimpanzees to discover that malaria is apparently a zoonotic disease, that is, one that jumps from animals to infect humans. A similar story has been proposed for how HIV (Human Immunodeficiency Virus) arose from a chimpanzee counterpart SIV (Simian Immunodeficiency Virus). Other zoonoses such as West Nile virus and Lyme disease, while still threats to humans, remain primarily in wild animals.

Rich and colleagues reveal the true evolutionary history of two closely related parasites - P. reichenowi found in chimps, and P. falciparum which is so deadly to humans - and refute a widely held view that the two species derived from parasites of the human and chimpanzee common ancestor some 5 to 7 million years ago.

Rich says this breakthrough on the recent evolutionary origin of P. falciparum will allow his group to determine exactly what makes it so extremely virulent (quickly multiplying) and pathogenic (rapidly fatal) compared to the other three malaria types that infect humans. As many as 3 million people die each year of malaria, mostly children, while hundreds of millions suffer debilitating illness. 'Our discovery of the origin of malignant malaria derived from a chimpanzee is a watershed. It's akin to finding a living Neanderthal and getting the opportunity to study his biology and behaviours,' says Rich.

This new study caps more than a decade of investigation by Rich and a co-author, evolutionary biologist Francisco Ayala at UC Irvine, who together wrote a ground-breaking 1998 paper proposing that human malaria parasites shared common ancestry as recently as 10,000 years ago, not 5 to 7 million as always assumed. Rich recalls, 'Before our study in 1998, very little was known about genetic diversity among malaria parasites. When we proposed that all malaria parasites were originated from a very recent common ancestor, our colleagues thought we were surely mistaken,' he adds, because at the time it was well known that genes controlling the parasites' ability to infect hosts and evade the immune systems were very diverse.

But Rich and Ayala's work showed these genes were so diverse because they evolved by previously unknown mechanisms at rates that were not thought possible. From this, they proposed their Malaria's Eve hypothesis about malaria's foremother, which was later further supported by several independent research groups. Since the 1998 study, debate has persisted as to the exact age of Malaria's Eve, with estimates ranging from a few thousand to a couple of hundred thousand years. 'I didn't participate much in this debate, because I knew that there was a missing piece of the puzzle,' says Rich.

He knew the key to understanding human malaria's Eve depended on more thorough study of its chimpanzee counterpart. At the time, only one known isolate of chimpanzee malaria existed, from the 1960s. So Rich initiated a collaboration with current co-authors Fabian Leendertz of the Robert Koch Institute and Christoph Boesch of the Max Planck Institute, who were looking for new viral pathogens in chimps.

Using genetic tools, Rich screened blood samples from 10 chimps that had died of natural causes and found that two were infected with chimpanzee malaria parasites. As a follow-up, he collaborated with Nathan Wolfe of the Global Viral Forecasting Initiative, also a current co-author, and acquired 94 more blood samples from wild and wild-born captive chimpanzees in wildlife sanctuaries in Cameroon. In DNA studies at his UMass Amherst laboratory, Rich determined that these chimpanzee parasites are not only the closest known relative of our malaria parasites, but also that human malaria derives from a transfer of parasites from the chimp lineage into our human ancestors.

So why did P. falciparum develop such a deadly potency for killing humans while the closely-related chimpanzee disease does not appear to do nearly so much damage? Rich speculates that the answer lies in a key change in human society 8,000 to 10,000 years ago―from nomadic hunter-gathering to settled agrarian societies. When humans began to stay for long periods in a single place, and they started to irrigate fields and live in huts rather than travel daily, the change selected for what Rich calls 'vectorial promiscuity.' That is, a highly anthropophilic (human-loving) Anopheles mosquito got very good at spreading huge numbers of parasites by biting as many people sleeping in the same hut as quickly as possible. Our closest relative, chimpanzees, made no such behaviour change, and the P. reichenowi parasite never encountered a situation that would allow selection of a strain with increased virulence.

Rich says all the genetic material that has accumulated in the P. falciparum parasite since its divergence from P. reichenowi now becomes the investigation ground for parasitologists. With new knowledge, they may be able to learn how to control and subdue one of the most deadly organisms ever to make a human sick.

Rich is the lead author of this study, conducted in collaboration with investigators from the Global Viral Forecasting Initiative, San Francisco; University of California Irvine, Stanford University, Max Planck Institute, Leipzig; Robert Koch Institute, Berlin; US Department of Agriculture, Beltsville, Md. and the University of Yaounde, Cameroon.

This work was supported by grants from the National Institute of General Medical Sciences at NIH, the Google Foundation, and the Skoll Foundation.