Parasite, Mosquito Genomes Complete Malaria Picture

The sequencing of both P. falciparum and its insect vector heralds a new era in the fight against malaria. When joined with information we have about the human genome, a much fuller understanding of this disease and its transmission is now possible, says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is proud to have contributed to this extraordinary scientific achievement, which will speed efforts to investigate and develop control strategies for this devastating disease.

The medical, social and economic ravages of malaria are most keenly felt in Africa, where 90 percent of the up to 2.7 million annual deaths worldwide from the disease occur. Most victims are children less than 5 years old; on average, a child succumbs to malaria every 30 seconds. Malaria causes cycles of fever and chills that accompany cyclical destruction of parasite-infected red blood cells. Debilitating and life-threatening complications of malaria include severe anemia, cerebral malaria, and respiratory distress. The disease is caused by single-celled parasites of the genus Plasmodium, which are transmitted from person to person through the bite of an infected mosquito. The menace posed by malaria is increasing with the spread of drug-resistant parasite strains and insecticide-resistant mosquitoes. No vaccine exists.

The sequencing of P. falciparum resulted from an international collaboration established in 1996. Besides NIAID, consortium support came from the Wellcome Trust, the Burroughs Wellcome Fund and the U.S. Department of Defense. Sequencers worked at The Institute for Genomic Research (TIGR) in Rockville, MD, the Stanford Genome Center in Palo Alto, CA, and the Wellcome Trust Sanger Institute in the United Kingdom. The lead investigator, Malcolm Gardner, Ph.D., of TIGR, co-authored the Nature paper with 44 researchers working in sites in the United States, the United Kingdom and Australia.

Researchers overcame significant technical challenges on the way to this accomplishment. Perhaps because of its unusual composition, Plasmodiums genetic material cannot be separated into a mixture of long, medium, and short lengths. Rather, the parasites DNA breaks up into very short lengths only. Placing such tiny strips back into their original sequence is difficult, just as repairing a vase that has smashed into hundreds of bits is harder than fixing one broken into a few large pieces.

This detailed map of the parasites 5,300 genes and their predicted functions is a milestone in malaria research. The information it provides will enable investigators to design anti-malarial drugs targeted precisely to areas of genetic vulnerability, says Michael Gottlieb, Ph.D., chief of NIAIDs parasitology and international programs branch.

In 1999, NIAID joined the Anopheles Gambiae Genome Consortium (AGGC) to accelerate sequencing of Anopheles 14,000 genes. Sequencing was performed at Genoscope with funds from the French government and at the Celera Genomics Group in Rockville, MD. Other institutions contributing to the effort include World Health Organizations Special Program of Research on Tropical Diseases; Germanys European Molecular Biology Laboratory; the Institute of Molecular Biology and Biotechnology in Crete; the Institut Pasteur in Paris; TIGR; and the universities of Iowa, Rome, Notre Dame, and Texas A&M. In August 2001, NIAID expanded its support for Anopheles genome sequencing with a $9 million award to Celera Genomics Group of Rockville, MD. Celeras Robert A. Holt, Ph.D., heads a list of 123 authors on the Science paper, submitted on behalf of the AGGC.

Before this weeks publications, significant amounts of sequence data produced by both teams had been disseminated through publicly accessible databases. For example, P. falciparum genes were identified that allow the parasite to avoid detection by human immune response cells. Other genes involved in parasite metabolism have no counterparts in humans. Inhibitors of those genes products could be developed into anti-malarial drugs.

Information from the Anopheles genome is giving researchers new insights into mosquito physiology and behavior, including the insects ability to digest blood and its choice of humans as a blood source. Scientists can now begin to determine how Anopheles reacts, at a molecular level, to infection with the Plasmodium parasite. Ultimately, such a detailed understanding of host-parasite interactions could improve mosquito control efforts.

With the triad of genomes now complete, investigators have essentially all the genetic information they need to understand the complexity of the parasites life cycle in mosquitoes and humans, notes Dr. Gottlieb. We are hopeful that this wealth of information will translate into new drugs, vaccines, and insecticides that will more effectively control malaria and, ultimately, lift a burden of suffering from millions, he adds.

NIAIDs comprehensive program of research on malaria, which began 50 years ago, is conducted at its laboratories in Bethesda, MD, in dozens of institutions throughout the United States, and through collaboration with scientists from countries where malaria is endemic, such as Mali, Cameroon, Ghana, Thailand, Indonesia, and Brazil. The Institute was also founding member of the Multilateral Initiative on Malaria, which emphasizes strengthening research capacity in Africa. For more information on NIAIDs malaria research and research support, visit http://www.niaid.nih.gov/dmid/malaria.

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov. References: MJ Gardner et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419: 498-511. (2002).

RA Holt et al. The genome sequence of the malaria mosquito Anopheles gambiae. Science 297: 129-49 (2002).