Focus |

Malaria

Malaria continues to claim a significant number of lives worldwide, estimated at ~ 1 million each year. The genome sequence of the most prominent human parasite, Plasmodium falciparum, was published in Nature in 2002. We are now proud to present the genome sequences of two additional human parasites, Plasmodium vivax and Plasmodium knowlesi, along with a Review article discussing the scientific discoveries that have been aided by this information. In addition, we present a collection of papers illustrating highlights in malaria research that were published in recent years.

Current research

Four distinct Plasmodium species are known to regularly infect humans: Plasmodium falciparum, P. vivax, P. malariae and P. ovale. The genome sequence of P. falciparum, the cause of the most severe type of human malaria, was completed in 2002 at the same time as the mosquito vector, Anopheles gambiae. In this week's Nature, which focuses on the malaria parasite, two further malaria genome sequences are described. First that of P. vivax, which contributes significant numbers to malaria incidence in humans, though in contrast to P. falciparum, the resulting disease is usually not fatal. The genome of this rather neglected species is presented together with a comparative analysis with the genomes of other Plasmodium species. Second, we publish the genome sequence of Plasmodium knowlesi. For long regarded as a monkey malaria parasite, it is increasingly becoming recognized as the fifth human-infecting Plasmodium species. In particular, it is prevalent in South East Asia where it is often misdiagnosed as another human malaria parasite P. malariae. As a model organism P. knowlesi stands out: not only is it a primate system, useful for work on vaccines, but it can be cultured in vitro and subjected to efficient transfection and gene knockouts. In a Review Article, Elizabeth Winzeler considers the progress made towards using the genome sequence to understand basic malaria parasite biology, and in particular the work on developing rational therapeutic approaches to combat P. falciparum infections. See also the Editorial. For a comprehensive collection of resources visit Nature's past malaria specials: Malaria killer blow ; Outlook on malaria ; Malaria web focus ; Malaria Insight ; Nature Medicine focus on malaria ; Focus on malaria

Review Article | | Nature

Four distinct Plasmodium species are known to regularly infect humans: Plasmodium falciparum, P. vivax, P. malariae and P. ovale. The genome sequence of P. falciparum, the cause of the most severe type of human malaria, was completed in 2002 at the same time as the mosquito vector, Anopheles gambiae. In this week's Nature, which focuses on the malaria parasite, two further malaria genome sequences are described. First that of P. vivax, which contributes significant numbers to malaria incidence in humans, though in contrast to P. falciparum, the resulting disease is usually not fatal. The genome of this rather neglected species is presented together with a comparative analysis with the genomes of other Plasmodium species. Second, we publish the genome sequence of Plasmodium knowlesi. For long regarded as a monkey malaria parasite, it is increasingly becoming recognized as the fifth human-infecting Plasmodium species. In particular, it is prevalent in South East Asia where it is often misdiagnosed as another human malaria parasite P. malariae. As a model organism P. knowlesi stands out: not only is it a primate system, useful for work on vaccines, but it can be cultured in vitro and subjected to efficient transfection and gene knockouts. In a Review Article, Elizabeth Winzeler considers the progress made towards using the genome sequence to understand basic malaria parasite biology, and in particular the work on developing rational therapeutic approaches to combat P. falciparum infections. See also the Editorial. For a comprehensive collection of resources visit Nature's past malaria specials: Malaria killer blow ; Outlook on malaria ; Malaria web focus ; Malaria Insight ; Nature Medicine focus on malaria ; Focus on malaria

Article | Open Access | | Nature

Four distinct Plasmodium species are known to regularly infect humans: Plasmodium falciparum, P. vivax, P. malariae and P. ovale. The genome sequence of P. falciparum, the cause of the most severe type of human malaria, was completed in 2002 at the same time as the mosquito vector, Anopheles gambiae. In this week's Nature, which focuses on the malaria parasite, two further malaria genome sequences are described. First that of P. vivax, which contributes significant numbers to malaria incidence in humans, though in contrast to P. falciparum, the resulting disease is usually not fatal. The genome of this rather neglected species is presented together with a comparative analysis with the genomes of other Plasmodium species. Second, we publish the genome sequence of Plasmodium knowlesi. For long regarded as a monkey malaria parasite, it is increasingly becoming recognized as the fifth human-infecting Plasmodium species. In particular, it is prevalent in South East Asia where it is often misdiagnosed as another human malaria parasite P. malariae. As a model organism P. knowlesi stands out: not only is it a primate system, useful for work on vaccines, but it can be cultured in vitro and subjected to efficient transfection and gene knockouts. In a Review Article, Elizabeth Winzeler considers the progress made towards using the genome sequence to understand basic malaria parasite biology, and in particular the work on developing rational therapeutic approaches to combat P. falciparum infections. See also the Editorial. For a comprehensive collection of resources visit Nature's past malaria specials: Malaria killer blow ; Outlook on malaria ; Malaria web focus ; Malaria Insight ; Nature Medicine focus on malaria ; Focus on malaria

Letter | Open Access | | Nature

Malaria parasites need to reproduce sexually before they can transmit to vectors, but despite extensive research on ways of blocking transmission, little is known about their reproductive strategies. Reece et al. use novel experiments to show that the assumptions of sex-allocation theory, previously controversial when used to explain sex ratios in malaria parasites, are in fact valid. As predicted by this plank of evolutionary theory, Plasmodium chabaudi parasites adjust their sex-allocation in response to the presence of unrelated conspecifics. By means of this kin discrimination they evaluate the genetic diversity of their infections, and adjust their behaviour in response to environmental cues.

Article | | Nature

Malaria parasites need to reproduce sexually before they can transmit to vectors, but despite extensive research on ways of blocking transmission, little is known about their reproductive strategies. Reece et al. use novel experiments to show that the assumptions of sex-allocation theory, previously controversial when used to explain sex ratios in malaria parasites, are in fact valid. As predicted by this plank of evolutionary theory, Plasmodium chabaudi parasites adjust their sex-allocation in response to the presence of unrelated conspecifics. By means of this kin discrimination they evaluate the genetic diversity of their infections, and adjust their behaviour in response to environmental cues.

News & Views | | Nature

A major puzzle in understanding malaria is the wide range of clinical conditions seen in infected children — from mild flu-like symptoms to coma and death. A large-scale transcriptional analysis of malaria parasites isolated from human patients has uncovered a possible clue to this variation: Plasmodium falciparum exists in its human host in three different physiological states. These can be described as active growth, a response to starvation, and an environmental stress response. This finding has important implications both for treatment with current drugs and for future drug and vaccine development.

Letter | | Nature

A major puzzle in understanding malaria is the wide range of clinical conditions seen in infected children — from mild flu-like symptoms to coma and death. A large-scale transcriptional analysis of malaria parasites isolated from human patients has uncovered a possible clue to this variation: Plasmodium falciparum exists in its human host in three different physiological states. These can be described as active growth, a response to starvation, and an environmental stress response. This finding has important implications both for treatment with current drugs and for future drug and vaccine development.

News & Views | | Nature

The mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum serves only one function, it seems. Its sole remaining purpose is to make ubiquinone, required as an electron acceptor for a pyrimidine biosynthesis enzyme. Many single-cell eukaryotes have lost their mitochondrial genomes during evolution, and P. falciparum seems to be close to that state. The parasite's electron transport system is of particular interest as a target for antimalarials such as proguanil

Letter | | Nature

The infectious form of the malaria parasite has thousands of proteins, making it tough to develop a vaccine for it. Narrowing down which proteins cause protective immune responses may help resolve the problem.

News & Views | | Nature

It's been known for some time that the malaria parasite induces or activates novel channels in the membrane of its host red blood cell, and that because of this, Na+ moves into the red cell cytosol, making it a high-Na+ environment. New work shows that the parasite takes advantage of this raised Na+ to energize the uptake of an essential nutrient, inorganic phosphate. Now the Na+-coupled transporter protein involved has been identified.

Letter | | Nature

Drug-resistant strains of the malaria parasite are widespread, and as a result mortality due to malaria has increased significantly in recent years. Artemisinin, isolated from the herb Artemisia annua (sweet wormwood), is one drug that shows a high efficacy in killing multi-resistant strains of the parasite. The drug is extremely expensive, and high demand has led to a shortage of artemisinin, available only by extraction from the plant source. Ro et al. now report the development of a yeast strain engineered to carry a cytochrome P450 monooxygenase from A. annua that can produce the drug precursor, artemisinic acid. Artemisinin can be synthesized from this precursor. If the efficiency of this process can be improved, this engineered yeast strain has the potential to alleviate the drug shortage.

Letter | | Nature

The malaria parasite Plasmodium falciparum invades red blood cells and deposits the virulence factor PfEMP1 on their cell surface. This is the key to the parasite's ability to evade the immune system, since PfEMP1 is encoded by a family of 60 var genes, only one of which is transcribed at any one time. How Plasmodium brings about this antigenic variation is not clear. Voss et al. show that one active var promoter is sufficient to initiate the transcription of one gene while shutting off the others. This is explained by the existence of a unique, peri-nuclear compartment that aids in the transcription of a single var gene; switching var transcription, and thus changing PfEMP1 identity, would occur by competition of a silenced var promoter for occupancy of this space.

Letter | | Nature

The malaria parasite Plasmodium falciparum invades red blood cells and deposits the virulence factor PfEMP1 on their cell surface. This is the key to the parasite's ability to evade the immune system, since PfEMP1 is encoded by a family of 60 var genes, only one of which is transcribed at any one time. How Plasmodium brings about this antigenic variation is not clear. Voss et al. show that one active var promoter is sufficient to initiate the transcription of one gene while shutting off the others. This is explained by the existence of a unique, peri-nuclear compartment that aids in the transcription of a single var gene; switching var transcription, and thus changing PfEMP1 identity, would occur by competition of a silenced var promoter for occupancy of this space.

News & Views | | Nature

Botswana has compiled a continuous record of the incidence of malaria for the period 1982–2002, providing a unique data set for work on malaria epidemiology in a desert-fringe area. Climate fluctuations are known to be a major determinant of malaria transmission in parts of Africa where the disease is endemic. Based on established quantitative relationships between climate fluctuations and malaria incidence, a new system for predicting interannual climate fluctuations in epidemic-prone regions has now been developed. The DEMETER project, combining the leading European global climate prediction models, can successfully predict the probability of a malaria outbreak in Botswana up to five months ahead, providing an extra four months warning compared with current monitoring methods, during which time vital decisions about resource allocation can be made.

Letter | | Nature

A powerful approach for understanding protein function is to identify which proteins bind to each other, as protein complexes are at the heart of most biological processes. Protein–protein interactions have now been mapped for one quarter of the malaria parasite's proteins. This large data set sheds new light on how parasites infect red blood cells and will be a vital tool for the development of new antimalarial drugs and vaccines. The primary data are freely available on the PlasmoDB database. Suthram et al. have used this new resource and find that the Plasmodium network has significantly less cross-species similarity than other eukaryotes. Its novel life style is reflected in a novel protein network, which therefore has a good chance of providing drug targets unique to the malaria parasite.

Letter | | Nature

A powerful approach for understanding protein function is to identify which proteins bind to each other, as protein complexes are at the heart of most biological processes. Protein–protein interactions have now been mapped for one quarter of the malaria parasite's proteins. This large data set sheds new light on how parasites infect red blood cells and will be a vital tool for the development of new antimalarial drugs and vaccines. The primary data are freely available on the PlasmoDB database. Suthram et al. have used this new resource and find that the Plasmodium network has significantly less cross-species similarity than other eukaryotes. Its novel life style is reflected in a novel protein network, which therefore has a good chance of providing drug targets unique to the malaria parasite.

Letter | | Nature