Malaria
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Parasitic diseases are among the Third World's three great killers, along with tuberculosis and Aids. Malaria is caused by a single-celled parasite, Plasmodium. There are four species which infect humans, Plasmodium falciparum, P. vivax, P. malariae and P. ovale. The most important of these is P. falciparum, which is responsible for at least one million deaths worldwide each year, the majority being among African children. Control measures against the disease are aimed at both the mosquito vector and the parasite inside its human host.
> Research on anti-malarial drugs
Malaria parasites are transmitted from person to person through Anopheles mosquitoes. When a mosquito bites, blood containing the parasites is taken into the mosquito's gut. Over a period of 10 or more days, the parasites undergo a complex development, the mature parasite eventually coming to reside in the mosquito's salivary glands, ready for transmission to a new person when it bites again. In the next human host, the parasite first infects the liver, undergoes rapid replication in this site for at least five days, and then infects red blood cells. It is in the blood that the parasites causes the most serious symptoms of malaria, including cerebral malaria initiated by parasitised blood cells blocking blood capillaries in the brain.
The parasite readily undergoes mutation during its rapid growth in humans, allowing it to develop strains resistant to antimalarial drugs. In addition, it undergoes genetic recombination during the mosquito phase of its life-cycle, thereby producing strains with novel combinations of genes. These genetic processes present major obstacles to control measures based on drugs or future vaccines.
Research into the biology of malaria has relied largely on animal models, especially on species of Plasmodium affecting rodents. A culture system is available for the blood forms of P. falciparum, which has greatly assisted the testing of drugs and vaccines against these stages of this species. However, no culture methods are available for the stages of the parasite in the liver, or for any of the other human malaria species.
Research on antimalarial drugs
New safe and effective drugs are desperately needed. The majority of drugs are aimed at the fast-replicating stages of the parasite in the blood; only a few drugs kill the liver forms. The parasite has become resistant to most of the drugs used to treat it, the only exception being the most recently developed drug artemisinine and its derivatives3.
An ideal drug needs to be targeted at a biochemical pathway in the parasite which is not present in the human host. In this regard, the parasite contains a number of unique features in its cells, such as food vacuoles and a body called the apicoplast. These are of much current interest in the search for new drugs. For example, a promising new drug, fosmidomycin, is known to affect an enzyme pathway in the apicoplast4. A new antibiotic, azithromycin, has been shown to be effective in mice and monkeys, and has been successfully trialled as a malaria prophylaxis in humans5. An antibiotic called triclosan, used in mouthwashes, anti-acne preparations and deodorants, could be an effective treatment. It completely clears the parasite from infected mice6 by blocking a parasitic enzyme called Fab I. New antimalarial drugs may target the gene that produces this enzyme.
- anti-infection vaccines, which target the infective stages of the parasite, the sporozoites, injected by mosquitoes
- anti-disease vaccines, targeted principally against the blood forms responsible for this disease's pathogenicity
- transmission-blocking vaccines, aimed at preventing the development of the parasite in its mosquito host.
Numerous early studies in humans and in rodent models have provided information of fundamental importance on potential immune protective mechanisms. Individual proteins have been shown to be at least partially protective in vaccination tests in both human and animal trials7. Most progress has been using an antigenic protein of the sporozoite, the CSP protein, first demonstrated to be highly immunogenic in a rodent model over 20 years ago. A human vaccine based on this work, denoted RTS,S, has given encouraging results in field trials in African countries by providing partial protection of humans from infection8. Similarly, there are now numerous vaccine trials being undertaken based on a variety of antigens present in the blood stages, which had been originally examined for their immunogenic potential in animal models. Vaccines consisting of combinations of target proteins have also completely protected mice from malaria, and human trials have been started9.
Research is also being done on a different type of vaccine, which targets a toxin released by the parasite. Mice inoculated with the toxin GPI were protected against many of the signs of malaria, and did not die from the disease. The findings demonstrate the potential of synthetic GPI in anti-toxic vaccines, and suggest that GPI is responsible for some symptoms of malaria in humans10.
A cheap vaccine purified from the milk of genetically modified mice has protected monkeys against the disease. Only one of five immunised animals contracted the disease, compared with six out of seven unvaccinated monkeys. The mice were engineered to carry the gene for a surface protein from P. falciparum. The gene was designed to be switched on by cells lining mouse mammary glands, so the protein would be secreted into the milk. The same team also modified goats to produce the protein in their milk, raising the prospect that one herd of goats could produce enough vaccine for the whole of Africa. The next step will be to find out whether the vaccine produced in goats' milk also protects monkeys11.
In experimental work that would not be possible in humans, scientists have produced some disturbing evidence that vaccines may well lead to the evolution of more aggressive malaria parasites, unless every parasite is eliminated (this is the same principle as antibiotic resistance in bacteria). They found that parasites that survived in immunised mice were more virulent than those which developed in mice that had not been immunised12. Clearly, the search for a fully effective safe vaccine against this parasite will continue to be a long and difficult undertaking.
1. Hemingway J, Beaty BJ, Rowland M, Scott TW, Sharp BL (2006) The Innovative Vector Control Consortium: improved control of mosquito diseases. Trends Parasitol 22, 308
2. Moreira LA, Ghosh AK, Abraham EG, Jacos-Lorena M (2002) Genetic transformation of mosquitoes: a quest for malaria control. Int J Parasitol 32, 1599
3. Bathurst I, Hentschel C (2006) Medicines for Malaria Venture: sustaining antimalarial drug development. Trends Parasitol 22, 301
4. Jomaa H, Wiesner J, Sanderbrand S et al (1999) Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285, 1573
5. Taylor WR, Richie TL, Fryauff DJ et al (2003) Tolerability of Azithromycin as Malaria Prophylaxis in Adults in Northeast Papua, Indonesia. Antimicrob Agents Chemother 47(7), 2199
6. McLeod R, Muench SP, Rafferty JB, Kyle DE (2001) Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of Apicomplexan Fab I. Intl J Parasitol 31, 109
7. Richie TL, Saul A (2002) Progress and challenges for malaria vaccines. Nature 415, 694
8. Alonso PL, Sacarlal J, Aponte JJ et al (2005) Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 366, 2012
9. Shi YP, Hasnain SE, Sacci JB et al (1999) Immunogenicity and in vitro protective efficacy of a recombinant multistage Plasmodium falciparum candidate vaccine. Proc Nat Acad Sci 96, 1615
10. Schofield L, Hewitt MC, Evans K et al (2002) Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria. Nature 418, 785
11. Stowers AW, Li-how Chen L-h, Zhang Y et al (2002) A recombinant vaccine expressed in the milk of transgenic mice protects Aotus monkeys from a lethal challenge with Plasmodium falciparum. Proc Nat Acad Sci 99, 339
12. Mackinnon MJ, Read AF (2004) Immunity promotes virulence evolution in a malaria model. PloS Biology 2, e230
Tags
Research Fields: Disease characteristics, Drugs & toxins(yes - 2 items)Animals Used: Mouse, Goat, Mouse (knockout/GM), Primates(required - 4 items)
