Plasmodium falciparum:
A painful malaria parasite Is being unveiled
Mats Wahlgren and Qijun ChenStockholm, Sweden
Malaria can be a deadly disease. Caused frequently by the protozoan parasite Plasmodium falciparum and transmitted by the Anopheles mosquito, this infection is frequently more fatal in children than in adults-producing respiratory distress, neurological problems and severe anemia, and leading to death in 5-35% of severe infections. Around one million children succumb to the disease each year in Africa alone. Malaria also poses a particular danger to pregnant woman and may lead to miscarriage or low birth weight of the child. In endemic regions, the disease is recognized as serous impediment to economic and social development.
Unfortunately, the prevalence of malaria has been increasing, and around 400 million people now suffer from the disease, with 130 million new cases occurring annually. This rise can be attributed to the development of resistance by P. falciparum to commonly used anti-malarial drugs, to the resistance of mosquitoes to insecticides, and possibly to climatic changes that have enlarged areas of disease transmission.
Still, there is renewed hope. Heads of state and funding agencies have increased their commitment to fight malaria, and the director general of the World Health Organization, Gro Harlem Brundtland, recently launched the Roll-Back Malaria program with the aim of decreasing mortality due to the disease by 50% by year 2010.
The genome of the Anopheles mosquito has been mapped and is now being sequenced, and the complete genome sequence of P.falciparum should be at hand within the next year. The sequence of chromosomes 2 and 3 have been published1,2, and the sequencing of chromosomes 1, 4, 10, 12 and 14 is nearing completion, plus there is a considerable amount of 'shot-gun' data available on the sequences of the remaining seven chromosomes. This information has already been used to identify a drug target unique to the parasite: an inhibitor of the non-malevonate pathway3. It will also help us to understand the biology of P. falciparum: how it invades the liver and the red cells, how it survives inside them and how it makes its way out.
Knowledge of the pathogenesis of the disease is improving. Recrudescing variants in chronic malaria infections are antigenically distinct from those of the parental parasite, indicating that P. falciparum has devised means to vary polypeptides exported to the infected erythrocyte surface, thus reflecting a fundamental element of parasitism: antigenic variation4. We now know that this variation is brought about by a family of highly changeable adhesive polypeptides, such as P. falciparum erythrocyte membrane protein 1, which is localised at the infected erythrocyte surface, and the RIFIINS which were recently identified with the help of the genome sequence project5,6. Yet others remain to be elucidate, including clag (cytoadherence-linked asexual gene) and CTP (conserved telomeric protein).
But there is still much work to be done, as there is at present no vaccine against the disease and anti-malarial drugs are failing. Although increased understanding the molecular makeup of the parasite may well lead to new pharmaceuticals, the lack of a good animal model in which to test potentially new therapeutics will hamper both drug and vaccine development. We also need adjunct treatment for severe malaria and less-complicated diagnostic methods, because early diagnosis and treatment would decrease the death toll.
REFERENCES
- Gardner, M.J. et al. Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum. Science 282, 1126-1132
- Bowman, S. et al. The complete nucleotide sequence of chromosome 3 of Plasmodium falciparum. Nature 400, 532-538 (1999).
- Jomaa, H. et al. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285, 1573-1576 (1999).
- Wahlgren, M., Fernandez, V., Chen, Q., Svärd, S. & Hagblom, P. Minireview. Waves of malarial variations. Cell 96, 603-606 (1999).
- Fernandez, V, Hommel, M., Chen, Q. & Wahlgren, M. Small, clonally-variant antigens expressed at the surface of P. falciparum infected erythrocytes are encoded by the rif-gene-family and are the target of human immune responses. J. Exp. Med. 190, 1393-1403 (1999).
- Kyes, S., Rowe, A., Kriek, N. & Newbold, C. I. Rifins: A second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum. Proc. Natl Acad. Sci. USA 96, 9333-9338 (1999).
As outlined above by Mats Wahlgren, the magnitude of the malaria problem is the reason that Nature Medicine has chosen to pay special attention to this disease and produce a website presenting the latest biomedical research directed at combating malaria.
We are pleased to present readers with a selection of the most-recent and best scientific papers and News & Views articles on malaria research published in our journal and in Nature. In addition, this website contains a new Commentary article setting out the reasons why the United Nations Environment Programme should re-think its proposed ban on the use of DDT insecticide in malaria-endemic countries, plus a status report on malaria vaccine development presented at the US National Institutes of Health this spring. An update on the effort to sequence the Plasmodium falciparum genome is available in the Research News section, along with summaries of malaria research papers appearing in other, non-Nature journals. The news section contains stories outlining the political and financial war being waged against the disease.
We hope you enjoy learning more about malaria from this site and we welcome your feedback via medicine@natureny.com
Microbiology and Tumor Biology Center,
Karolinska Institutet and
Swedish Institute for Infectious Disease Control,
Box 280, S-171 77 Stockholm, Sweden
Correspondence should be addressed to M.W.; email: mats.wahlgren@smi.ki.se.
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