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Fighting Drug-Resistant Malaria

Rick Fairhurst and Others at NIAID Go Global

By Kristofor Langlais, NICHD, for the NIH Catalyst

Malaria researcher Rick Fairhurst was only five years old when he first encountered smallpox, African river blindness, the Black Death, and other plagues—on the pages of his family's encyclopedia, that is. The grisly photographs fascinated him—and, once he could read, so did the written descriptions of the diseases. But it was his stamp-collecting hobby that triggered his interest in malaria. When he was seven, he came across the World Health Organization's 1962 stamps that depicted malaria-carrying mosquitoes. To date he has collected more than 100,000 stamps including about 2,000 commemorating the global effort to eradicate malaria.

Fairhurst has been studying malaria—and the parasites that cause it—at NIH since 2001. After earning M.D. and Ph.D. degrees at the University of California, Los Angeles (UCLA), he completed a residency in internal medicine and a clinical fellowship in infectious diseases at the UCLA Medical Center. Now a tenure-track investigator, he began his NIH career as a research fellow in NIAID's Laboratory of Parasitic Diseases. In 2003, he became a staff clinician in Thomas Wellems' Laboratory of Malaria and Vector Research (LMVR). There Fairhurst led a study that showed how people with a specific type of hemoglobin were less prone to developing severe malaria.

Malaria is caused by a parasite from the genus Plasmodium, a single-celled eukaryote with a complex, multistage life cycle. Several species of Anopheles mosquitoes transmit the parasites to people. As the infected mosquito bites into human flesh to obtain a blood meal, she injects spindle-shaped Plasmodium sporozoites into the victim's bloodstream. The sporozoites travel to the liver, invade liver cells, and during the next five to 16 days, reproduce asexually to form tens of thousands of merozoites per liver cell.

Over the next one to three days, the merozoites exit the liver and re-enter the bloodstream, where they begin invading erythrocytes (red blood cells) to avoid the host immune system, feed on cellular proteins, and reproduce asexually in safety. The infected erythrocytes rupture, releasing the merozoites to start repeated rounds of erythrocyte invasion. Thousands of parasite-infected cells in the host bloodstream trigger the illness and complications of malaria that can last for months if not treated.

The cycle continues as some merozoites develop into gametocytes, which mosquitoes ingest when they feed on infected hosts. The gametocytes enter a sexual reproduction phase in the insect gut and produce human-ready sporozoites that can infect anyone the mosquito bites. And the cycle goes on. Nearly one million people die of malaria each year, 85 percent of them children; most of the malaria-related deaths occur in Sub-Saharan Africa.

Discovery

 

micrograph of Plasmodium gallinaceum
This is a scanning electron micrograph of Plasmodium gallinaceum, which causes malaria in poultry, invading the midgut of the Aedes aegypti mosquito.
Credit: NIAID

Fairhurst's 2005 discovery, published in Nature, was that hemoglobin type C impairs the ability of malaria parasites to cause severe disease. Hemoglobin comes in several varieties, with type A being the most common. But in parts of West Africa, one-fourth of the population has at least one gene for hemoglobin C. Children with at least one hemoglobin C gene are less likely to develop the fatal cerebral form of malaria.

Fairhurst's team figured out how. The parasites produce proteins that make the surface of parasitized red blood cells sticky so the cells cling to blood vessel walls and avoid being cleared from the bloodstream. But C hemoglobin causes an abnormal distribution of the protein and thus makes the parasitized red blood cells less sticky (Nature 435:1117–1121, 2005).

By 2008, Fairhurst had become a tenure-track clinical investigator and chief of LMVR's Malaria Pathogenesis and Human Immunity Unit. Today he travels around the world as he continues to pry into the sinister pathogenic mechanisms of the several species of Plasmodium, especially the deadly Plasmodium falciparum, which is prominent in Sub-Saharan Africa, and Plasmodium vivax, which is common in Asia and South America.

P. falciparum has an exceptional talent for developing resistance to whatever drug it encounters. The first effective malaria treatment, known since the 17th century, was quinine, a compound derived from the bark of the cinchona tree. In the 1940s quinine was replaced by a more effective medication—the synthetic drug chloroquine. But by 1957, chloroquine-resistant Plasmodium had appeared along the Thailand-Cambodia border and spread to Africa, causing the deaths of millions of children. In 1972 Chinese scientists discovered artemisinin, which is derived from an herb that had been used in traditional Chinese medicine to treat malaria as early as 200 BC. But even artemisinin may be no match for the wily Plasmodium.

 

photo of a Anopheles gambiae mosquito
As she takes a blood meal, the female Anopheles gambiae mosquito can transmit malaria parasites.
Credit: NIAID

To prevent, or at least delay, the development of artemisinin-resistant Plasmodium, physicians administer artemisinin combination therapy (ACT), which combines the fast-acting drug with a slower-acting and longer-lasting one such as piperaquine. The piperaquine mops up any remaining parasites and perhaps artemisinin-resistant ones. Today ACT has become the standard weapon against malaria. But history appears to be repeating itself. Fairhurst and his colleagues have observed hints of P. falciparum artemisinin resistance in Cambodia's Pursat province, again near the Cambodia-Thailand border.

"The appearance of artemisinin resistance is profoundly worrisome," said Fairhurst. "If our suspicion is correct—that parasites in Western Cambodia are becoming less susceptible to artemisinin—this finding could be a harbinger of worse things to come."

Resistance Is Spreading

 

photo of people standing under a tree
1,500 children are enrolled in a study in Kenieroba, Mali.
Credit: NIAID

Resistance to chloroquine and other anti-malarial drugs spread from Cambodia to India and Africa. Fairhurst fears that artemisinin-resistant parasites may follow the same path.

"It is a time bomb; it is ticking," veteran malaria researcher Nicholas White told Reuters recently. "It has the potential of killing millions of African children." White, a professor of tropical medicine at Mahidol University (Bangkok) was one of the first to identify the artemisinin-resistant strain.

Fairhurst is collaborating with physicians and scientists around the world to assess whether artemisinin-resistant parasites are spreading beyond Cambodia. They have established testing and treatment sites in that country, other parts of Southeast Asia, and Mali, in West Africa, where they treat malaria patients with ACT and test their blood regularly for the quantity of the malaria parasites in order to gauge the rate of parasite clearance. The study results, which are expected in about a year, may provide clues to how resistance has arisen and how it might spread.

Mapping the "extent of artemisinin resistance is important if we are to eliminate the drug-resistant parasites and prevent their spread," said Fairhurst. "The effort is likely to improve our chances of developing an in vitro [assay] . . . to test new drugs."

NIAID has had a 20-year partnership with the University of Bamako in Mali and in 2002 designated the Malaria Research and Training Center (MRTC) in Bamako as an International Center for Excellence in Research (ICER). The ICER program helps to build sustainable research capacity in regions with high levels of infectious disease. The Mali ICER provides in-country support for state-of-the-art laboratories at the university and clinics in several rural villages. In addition, the ICER program has trained dozens of young Malian scientists at academic institutions and laboratories in Mali and the United States.

Fairhurst's team is currently working with the Mali ICER on a large multiyear clinical study that will monitor the emergence of artemisinin resistance in Mali. Even though mosquito-proof bed nets and other measures are being used to protect people from infected mosquitoes, the number of malaria cases is on the rise. Researchers are not certain when artemisinin-resistant parasites will emerge in such settings.

Fairhurst and other NIAID researchers are also battling malaria in Cambodia. They have been collaborating with the National Center for Parasitology, Entomology, and Malaria Control (CNM), in Phnom Penh, since 2005. In 2008, NIAID and CNM opened a newly renovated malaria research laboratory, which can rapidly analyze samples. NIAID also supports training exchanges involving NIH Fellows and Cambodian staff and is helping the lab to become a self-sustaining, locally run research center.

NIH Trainees in Cambodia

 

photo of a family at a Cambodian clinic
1,100 people are enrolled in a study in Thmar Da, Cambodia.
Credit: NIAID

Fairhurst and his trainees regularly travel to the Cambodia lab and field sites to treat patients, conduct clinical studies, and train students and clinicians in laboratory techniques. He is also carrying out a five-year study that involves 1,100 people at risk of acquiring malaria.

Typically, Fairhurst's trainees work in a malaria-endemic country for three to four months before returning to NIH to analyze their field data. Chanaki Amaratunga, a visiting postdoctoral fellow and native Sri Lankan, came to the United States in 2007 to work with Fairhurst. "I realized after a two-year postdoc in India that I liked to work with people and do field work," she said. "Working with Fairhurst promised everything I wanted." Amaratunga enjoys working with Cambodian colleagues and is helping to facilitate a Cambodian-Chinese research collaboration.

Another trainee, Erika Phelps, assists with Amaratunga's work and is pursuing her own research project on parasite drug resistance. "An important part of my training has been in the ethical aspects of working with patients with different social and cultural norms," she said. "The only way to truly learn this is by working on site."

In Mali, patients get themselves to the clinics, but in Cambodia, Fairhurst's team must travel several hours into the countryside to reach people with malaria. Patients are transported to field sites for treatment and participation in clinical studies that entail blood testing for parasites. The team uses a truck that can handle the worst of road conditions in rough mountain terrain. Getting from one field site to another can take seven hours on a good day to more than 10 hours on days when heavy rains have damaged the winding roads. Laboratory work is also challenging. Equipment, reagents, and office supplies are frequently flown in with the team, so careful pretrip planning and packing is essential. There are no local repair services, so a malfunctioning centrifuge or even a blown fuse can delay work for weeks or months.

Establishing and maintaining overseas facilities can be difficult, but they are crucial to NIH's mission and a key part of the U.S. government's global health agenda.

"If the U.S. is committed to successfully battling drug-resistant malaria, it should invest significantly in clinicians and scientists who are willing and able to meet malaria in person," said Fairhurst. That means "establishing and staffing field sites in collaboration with local officials."

Of the "Big Three" infectious diseases—malaria, human immunodeficiency virus infection and AIDS, and tuberculosis—"malaria is the number one killer, preying mostly on innocent children who are simply trying to reach their fifth birthday in the village where they were born," said Fairhurst. "The disease continues to devastate the lives of countless people each year, sometimes affecting the same people over and over again for decades."

This article originally appeared in the March-April 2011 issue of The NIH Catalyst, volume 19 issue 2 (NIH PDF).

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Last Updated May 19, 2011

Last Reviewed May 18, 2011