ScienceWeek

PUBLIC HEALTH: GENOMICS AND MALARIA CONTROL

The following points are made by K.D. Vernick and A.P. Waters (New Engl. J. Med. 2004 351:1901):

1) Two thirds of the global population is at risk for malaria. However, approximately 90 percent of deaths from this disease occur in sub-Saharan Africa, where 1.5 million to 2.5 million of those who die of malaria each year are children. Also, the incidence of malaria is on the rise -- owing in part to the resistance of parasites and mosquitoes to drugs and insecticides, and in part to social factors such as migration and political instability. We now know the genomic sequences of the most important malaria parasite of humans (Plasmodium falciparum), the mosquito vector (Anopheles gambiae), and the human: three participants in a complex yet durable system of disease transmission.

2) Such knowledge offers new opportunities for intervention, but the use of existing low-technology tools, such as bed nets, surveillance, and health care, including the strategic application of drugs, can also be effective. Thus, we are not obliged to wait idly for new forms of technology, and the failure to implement existing tools consistently lies at the heart of the current situation. Malaria is a disease of economic underdevelopment, and the success of new measures will depend on their ability to surmount this obstacle.

3) It is against this background that the genomic sequences must be exploited. The challenge is to provide affordable, deliverable strategies and products that will protect and cure people in areas in which the disease is endemic. Study of the annotated genomes, fleshed out with global gene-expression and protein profiles, has begun to yield detailed insights into the basic biology of the system. Control strategies can be grouped into one of two categories -- vector-targeted and human-targeted approaches -- but in reality, malaria results from three intimately interacting organisms. Fortunately, genomics-based approaches to malaria offer the strategic advantage of considering all three participants through integrative data sets, allowing us to identify the molecules from the human host, vector, and parasite that are involved in the interaction at the organismal interfaces.

4) The mechanics of malaria: The female mosquito bites the host and injects sporozoites from its salivary glands into the host's bloodstream. The sporozoite enters a hepatocyte, where it differentiates and divides; a single sporozoite can yield 10,000 infectious merozoites. Merozoites are released into the bloodstream and invade erythrocytes by a receptor-ligand-mediated mechanism, where they differentiate, grow, and multiply in a vacuole to yield more merozoites. This cycle of erythrocyte consumption, with its parasite-induced sequestration of infected erythrocytes in capillaries deep within many organs, causes many of the pathological hallmarks of infection. Merozoites cannot be transmitted to another human host by a mosquito bite, but a small proportion of merozoites follow an alternative developmental pathway that yields a transmissible form, the gametocyte. These long-lived, nondividing cells circulate in the bloodstream, awaiting uptake by the mosquito during a blood meal. Once in the insect's stomach, gametocytes produce gametes that undergo sexual fertilization to generate first a zygote and then the motile ookinete, which invades the midgut epithelium of the mosquito, thereby infecting the insect. Ookinetes are transformed into oocysts; during a period of apparent latency lasting approximately 10 days, approximately 10,000 sporozoites are formed. The oocysts then rupture and release the sporozoites into the mosquito's body cavity, where they migrate to invade the salivary glands.[1-4]

References:

1. Justice RW, Biessmann H, Walter MF, Dimitratos SD, Woods DF. Genomics spawns novel approaches to mosquito control. Bioessays 2003;25(10):1011-20

2. Osta MA, Christophides GK, Vlachou D, Kafatos FC. Innate immunity in the malaria vector Anopheles gambiae: comparative and functional genomics. J Exp Biol 2004;207:2551-2563

3. Doolan DL, Aguiar JC, Weiss WR, et al. Utilization of genomic sequence information to develop malaria vaccines. J Exp Biol 2003;206:3789-3802

4. Rosenthal PJ. Antimalarial drug discovery: old and new approaches. J Exp Biol 2003;206:3735-3744

New Engl. J. Med. http://www.nejm.org

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MEDICAL BIOLOGY: ON THE CONTROL OF MALARIA

The following points are made by J. Hemingway and A. Craig (Science 2004 303:1984):

1) The Plasmodium parasite that causes malaria is transferred to its human host by a mosquito vector. Over centuries this relationship between insect, parasite, and mammalian host has been finely tuned, enabling the parasite to partially evade both human and insect immune systems, thus ensuring its own survival.

2) Control of malaria in developing countries remains a major public health issue. A principal strategy has been to reduce mortality by rapid treatment with antimalarial drugs, but drug resistance in many malaria-endemic countries has made this approach unsustainable. The emergence of drug-resistant parasites means that control of the insect vector is again the most cost-effective and practical way to reduce the burden of malaria.

3) Numerous control trials of both indoor residual spraying with insecticides and the use of pyrethroid-impregnated bednets have demonstrated that human morbidity and mortality can be dramatically reduced when these measures are applied effectively. But in endemic countries, where the poorest rural sectors of society are hardest hit by malaria, these control methods are rarely applied effectively and problems with insecticide resistance now outpace the introduction of new insecticides onto the market.

4) Researchers (1) have identified three mosquito genes that control the immune response of Anopheles gambiae, the principal vector of the malaria parasite in Africa, and these three genes directly affect development of the rodent malaria parasite, Plasmodium berghei, within the insect gut.

5) This is an exciting time for the malaria research community. The genomes of both mosquito and parasite have been sequenced (2,3), insect vectors can be transformed in culture, and the power of RNA interference (RNAi) can be applied to silence the expression of single mosquito genes. Initial analysis of important insect gene families that are targets for parasite or vector control, and their comparison between Drosophila and A. gambiae, suggest that many of these gene families have undergone recent expansions (1,4). For example, CYP12, a member of the P450 gene family that detoxifies insecticides, has expanded independently in Drosophila and A. gambiae, giving rise to six and four genes, respectively, that have no obvious equivalent in the other species. The availability of the A. gambiae genome sequence allows detailed transcriptional analysis of the mosquito gut epithelium during development of the parasite's sexual stages, the ookinete and oocyst (5). The three mosquito immune genes identified by Osta et al (1) as having a direct effect on the malaria parasite do not have orthologs in Drosophila. This makes them ideal candidates for specifically blocking mosquito-parasite interactions without negatively impacting nontarget organisms.

References (abridged):

1. M. A. Osta et al., Science 303, 2030 (2004)

2. R. A. Holt et al., Science, 298, 129 (2002)

3. M. J. Gardener et al., Nature 419, 498 (2002)

4. H. Ranson et al., Science 298, 179 (2002)

5. E. G. Abraham et al., J. Biol. Chem. 279, 5573 (2004)

Science http://www.sciencemag.org

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MEDICAL BIOLOGY: CLIMATE AND MALARIA

The following points are made by Christopher Thomas (Nature 2004 427:690):

1) After decades of decline, malaria has been on the rise in many parts of Africa -- an estimate(1) by the World Health Organization is that in some parts of the continent malaria mortality in young children almost doubled from the 1980s to the 1990s. The disease causes some 3000 deaths each day and imposes huge losses in economic productivity(2).

2) Is this resurgence a sign of increased transmission caused by climate change? Probably not, according to results presented by Small et al(3). Several studies have projected that global climate change will increase future malaria transmission in Africa(4,5). However, the link between contemporary changes in malaria and climate is hotly disputed. Alternative explanations such as an increase in parasite resistance to the front-line drugs since the 1960s, poverty, and a decline in many African health services are cited as more likely causes. Undoubtedly, a mix of such reasons is behind the rise in malaria. But identifying the prime factors will help greatly in planning control measures.

3) One problem dogging the interpretation of changes in local disease patterns in relation to climate is that meteorological recording stations are sparsely distributed in many parts of the continent, so that long-term records from the same locality are rare. As an alternative, researchers have used so-called "climate surfaces" -- maps interpolated from these sparse data. But these surfaces often provide only a coarse representation of climate, and their usefulness in relation to the scale of the malaria data has been open to question. To eliminate this mismatch, Small et al(3) used a malaria transmission index calculated directly from the interpolated climate data. They then produced an 85-year "hindcast" against which observed trends in malaria could be compared.

4) The malaria transmission index used by Small et al(3) was formulated in an earlier study to map zones of malaria transmission across Africa. This index is based on the temperature and precipitation constraints within which the mosquito vector and malaria parasite can develop, and is quite simple. It has nonetheless proved remarkably effective for estimating the distribution of stable malaria (as opposed to epidemics at unstable fringes) at coarse scales and is in operational use throughout the continent.

5) As far as climate change is concerned, the main message from Small et al(3) is that malaria transmission needs to be understood in terms of precipitation as well as temperature. No doubt climate models will continue to improve and we can look forward to refinement in the projection of these parameters. Regrettably, however, knowledge of the basic ecology of malaria transmission lags behind -- for instance, we cannot yet relate absolute mosquito abundance to climate. The urgent need is for progress on the entomological front to guide future modelling work on transmission.

References (abridged):

1. World Health Organization The African Malaria Report, 2003 WHO/CDS/MAL/2003.1093 (WHO, Geneva, 2003)

2. Sachs, J. & Malaney, P. Nature 415, 680-685 (2002)

3. Small, J., Goetz, S. J. & Hay, S. I. Proc. Natl Acad. Sci. USA 100, 15341-15345 (2003)

4. Lindsay, S. W. & Martens, W. J. M. Bull. World Health Organ. 76, 33-45 (1998)

5. Martens, P. et al. Glob. Environ. Hum. Policy Dimensions 9, S89-S107 (1999)

Nature http://www.nature.com/nature

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