(D2OL)™ - Pathogens

Malaria is a life-threatening parasitic disease transmitted by the female Anopheles mosquito, which requires blood to nurture her eggs. The origin of the name, Malaria, can be traced back to the perceived cause of the disease, viz. fetid marshes (mal aria = bad air). In 1880 scientist discovered that the single-cell parasite of the Plasmodium genus causes the disease.

Malaria causes or contributes 3 million deaths and up to 500 million acute clinical cases each year. At least 40% of the world population, or an estimated 2.5 billion people in over 90 countries are at risk of getting infected each year. The main risk areas are Africa, South East Asia, India and South America (Malaria is one of the leading causes of morbidity and mortality in the developing world).

Mefloquine (Lariam®) Risk groups include pregnant women, refugees, migrant workers, travelers to high risk areas and children. The majority of deaths are in children with a mortality rate of 4 children minute or 35,000 children a week. Malaria was once widespread but it was successfully eliminated or drastically reduced in 37 countries with temperate climates in the 1950’s (in large part due to the WHO insecticide spraying program 1956-69) but this situation has been rapidly reversing, especially over the last decade. This reversing trend can be attributed to the cost of sustaining programs, loss of motivation in the face of a seemingly declining threat, and the development of insecticide and drug resistance. Other reasons for the increase in numbers are:

1. Increased migration and immigration (both from high risk areas and to high risk areas)
2. Urbanization
3. Increased tourist and business travel
4. Deforestation and Mining
5. Change in climatic conditions (Mosquito friendly climates)

There are four species of Plasmodium that can cause Malaria but Plasmodium falciparum and Plasmodium vivax are most common with P. falciparum being the most lethal form of the parasite. Plasmodium falciparum is most common in Africa, south of the Sahara, accounting in large part for the extremely high mortality in this region. There are also worrying indications of the spread of P. falciparum malaria into new regions of the world and its reappearance in areas where it had been eliminated.

The malaria parasite enters the human host when an infected Anopheles mosquito takes a blood meal. Inside the human host, the parasite undergoes a series of changes as part of its complex life-cycle. Its various stages allow plasmodia to evade the immune system, infect the liver and red blood cells, and finally develop into a form that is able to infect a mosquito again when it bites an infected person. Inside the mosquito, the parasite matures until it reaches the sexual stage where it can again infect a human host when the mosquito takes her next blood meal, 10 to 14 or more days later.

Malaria symptoms appear about 9 to 14 days after the infectious mosquito bite, although this varies with different plasmodium species. Typically, malaria produces fever, headache, vomiting and other flu-like symptoms. If drugs are not available for treatment or the parasites are resistant to them, the infection can progress rapidly to become life-threatening. Malaria can kill by infecting and destroying red blood cells (anemia) and by clogging the capillaries that carry blood to the brain (cerebral malaria) or other vital organs.

Malaria parasites are developing unacceptable levels of resistance to one drug after another and many insecticides are no longer useful against mosquitoes transmitting the disease. Years of vaccine research have produced few hopeful candidates and although scientists are redoubling the search, an effective vaccine is at best years away.

TARGET - Plasmepsin II

Lifecycle of Plasmodium falciparum

The Malaria parasite Plasmodium falciparum invades erythrocytes (red blood cells) and feeds of the hemoglobin (oxygen transport protein) during growth and development in the red blood cell (see life cycle diagram – Erythrocytic Cycle). Hemoglobin is digested in an acidic digestive vacuole of the parasite. Many of the current antimalarial agents, such as chloroquine, are though to disrupt this digestive process one way or another. The digestion of hemoglobin is facilitated by several digestive enzymes. Several cysteine proteases have been identified to be essential for the digestion of hemoglobin. Plasmepsin II can be potently inhibited by pepstatin A, which in laboratory cultures has shown to block hemoglobin degradation and kill the parasite. The crystal structure of the Plasmepsin II / pepstatin A complex is known and will server as a basis for the design of new, potent and selective inhibitors of parasitic cysteine proteases

Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum

Proc. Natl. Acad. Sci. Vol 93, pp 10034-10039, September 1996

A. M. SILVA*, A. Y. LEE*, S. V. GULNIK*, P. MAJER*, J. COLLINS*, T. N. BHAT*, P. J. COLLINS*, R. E. CACHAU*, K. E. LUKER†, I. Y. GLUZMAN†, S. E. FRANCIS†, A.OKSMAN†, D. E. GOLDBERG†, AND J. W. ERICKSON*

*Structural Biochemistry Program, National Cancer InstituteySAIC, P.O. Box B, Frederick, MD 21702; and †Howard Hughes Medical Institute, Departments of Molecular Microbiology and Medicine, and The Jewish Hospital of St. Louis, Washington University School of Medicine, Box 8230, 660 South Euclid Avenue, St. Louis, MO 63110

this page last reviewed October 1, 2004