MicrobiologyBytes

To control mosquito-borne diseases like dengue fever, researchers need to look at the behavior of people, not just the insect that transmits the disease. Vector-borne diseases constitute a largely neglected and enormous burden on public health in many resource-challenged environments, demanding efficient control strategies that could be developed through improved understanding of pathogen transmission. Human movement – which determines exposure to vectors – is a key behavioral component of vector-borne disease epidemiology that is poorly understood.

A new paper attempts to develop a conceptual framework to organize past studies by the scale of movement and then examine movements at fine-scale – i.e. people going through their regular, daily routine – that determine exposure to insect vectors for their role in the dynamics of pathogen transmission. The authors develop a model to quantify risk of vector contact across locations people visit, with emphasis on mosquito-borne dengue virus in the Amazonian city of Iquitos, Peru.

An example scenario illustrates how movement generates variation in exposure risk across individuals, how transmission rates within sites can be increased, and that risk within sites is not solely determined by vector density, as is commonly assumed. This analysis illustrates the importance of human movement for pathogen transmission, yet little is known – especially for populations most at risk to vector-borne diseases (e.g. dengue, leishmaniasis, etc.). The authors outline several important considerations for designing epidemiological studies to encourage investigation of individual human movement, based on this experience studying dengue.

The incidence of dengue fever in Iquitos has varied from around five percent to over 30 percent after new virus serotype introductions. There is no vaccine and no cure for dengue, which is transmitted by the tiger-striped, day-biting mosquito, Aedes aegypti. To track individual human movement, the research team used satellite-based global positioning system (GPS) and culturally-sensitive interviews that were developed by the team. The researchers developed a conceptual model showing that the relevance of human movement at a particular scale depends on vector behavior. Focusing on Aedes aegypti, they illustrated how vector-biting behavior combined with fine-scale movements of individual humans engaged in daily routines can influence transmission. They also outlined several considerations for designing epidemiological studies to encourage studies of individual human movement. They hope to arrive at a better notion of the spatial scale on which dengue transmission occurs and from an operational standpoint, at what scale to focus interventions. Another aim is to encourage researchers of other mosquito-borne diseases, such as malaria, to perform more incisive examination of individual movements.

The Role of Human Movement in the Transmission of Vector-Borne Pathogens. PLoS Negl Trop Dis 3(7): e481 doi:10.1371/journal.pntd.0000481
Human movement is a key behavioral factor in many vector-borne disease systems because it influences exposure to vectors and thus the transmission of pathogens. Human movement transcends spatial and temporal scales with different influences on disease dynamics. Here we develop a conceptual model to evaluate the importance of variation in exposure due to individual human movements for pathogen transmission, focusing on mosquito-borne dengue virus. We develop a model showing that the relevance of human movement at a particular scale depends on vector behavior. Focusing on the day-biting Aedes aegypti, we illustrate how vector biting behavior combined with fine-scale movements of individual humans engaged in their regular daily routine can influence transmission. Using a simple example, we estimate a transmission rate (R0) of 1.3 when exposure is assumed to occur only in the home versus 3.75 when exposure at multiple locations – e.g. market, friends – due to movement is considered. Movement also influences for which sites and individuals risk is greatest. For the example considered, intriguingly, our model predicts little correspondence between vector abundance in a site and estimated R0 for that site when movement is considered. This illustrates the importance of human movement for understanding and predicting the dynamics of a disease like dengue. To encourage investigation of human movement and disease, we review methods currently available to study human movement and, based on our experience studying dengue in Peru, discuss several important questions to address when designing a study. Human movement is a critical, understudied behavioral component underlying the transmission dynamics of many vector-borne pathogens. Understanding movement will facilitate identification of key individuals and sites in the transmission of pathogens such as dengue, which then may provide targets for surveillance, intervention, and improved disease prevention.

Related:

• Dengue Virus
• Pathogenic Flaviviruses
• Changing patterns of chikungunya virus

The asexual erythrocytic phase of the life cycle of Plasmodium falciparum produces the clinical symptoms, disease and pathology associated with malaria. During this phase, merozoites released from schizont-infected erythrocytes invade uninfected erythrocytes. Invasion depends on distinct molecular interactions between ligands on the merozoite, the invasive form of the parasite, and host receptors on the erythrocyte membrane. To avoid infection, humans have evolved to eliminate or modify erythrocyte surface proteins that serve as receptors for parasite invasion. Perhaps one of the best examples of this evolutionary process is the loss of the Duffy blood group in Africa. Plasmodium vivax depends on two ligands for erythrocyte invasion: the Duffy-binding protein (DBP) that binds the Duffy blood group antigen and the reticulocyte homology protein that binds to an unknown receptor on reticulocytes.

Unlike P. vivax, P. falciparum has highly redundant, alternate invasion pathways that use several different receptor families. P. vivax has only one gene, DBP, in the Duffybinding-like erythrocyte-binding protein (DBL-EBP) family, whereas P. falciparum has four DBL-EBP genes: erythrocytebinding antigen 175 (EBA-175), erythrocyte-binding antigen 140 (BAEBL/EBA-140), erythrocyte-binding antigen 181 (JESEBL/ EBA-181), and erythrocyte-binding ligand-1 (EBL-1). Consequently, no erythrocyte has been identified that is refractory to P. falciparum invasion. A recent paper provides evidence that the fourth DBL-EBP family member, EBL-1, binds to glycophorin B.

Theoretical studies indicate that a null allele of glycophorin B would need to afford only a modest level of protection against malaria in heterozygous to increase in frequency from a single mutant to an allele frequency of 0.59. Assuming a constant population of size 1,000–10,000 individuals, one need invoke a selective advantage of only 1% in homozygous-null genotypes to have a single copy of the null mutant allele increase to a frequency of 59% across an interval of 100,000 years (5,000 generations). A shorter time entails stronger selection, but even for 10,000 years (500 generations), a selective advantage of only 10% in homozygous-null genotypes is required. Both cases require partial dominance corresponding to 10–20% as much protection in heterozygous genotypes as in the homozygous-null.

Glycophorin B is the erythrocyte receptor of Plasmodium falciparum erythrocyte-binding ligand, EBL-1. PNAS USA March 11, 2009
In the war against Plasmodium, humans have evolved to eliminate or modify proteins on the erythrocyte surface that serve as receptors for parasite invasion, such as the Duffy blood group, a receptor for Plasmodium vivax, and the Gerbich-negative modification of glycophorin C for Plasmodium falciparum. In turn, the parasite counters with expansion and diversification of ligand families. The high degree of polymorphism in glycophorin B found in malaria-endemic regions suggests that it also may be a receptor for Plasmodium, but, to date, none has been identified. We provide evidence from erythrocyte-binding that glycophorin B is a receptor for the P. falciparum protein EBL-1, a member of the Duffy-binding-like erythrocyte-binding protein (DBL-EBP) receptor family. The erythrocyte-binding domain, region 2 of EBL-1, expressed on CHO-K1 cells, bound glycophorin B+ but not glycophorin B-null erythrocytes. In addition, glycophorin B+ but not glycophorin B-null erythrocytes adsorbed native EBL-1 from the P. falciparum culture supernatants. Interestingly, the Efe pygmies of the Ituri forest in the Democratic Republic of the Congo have the highest gene frequency of glycophorin B-null in the world, raising the possibility that the DBL-EBP family may have expanded in response to the high frequency of glycophorin B-null in the population.

Related:

• Malaria: now you see me, now you don’t
• New ways to beat malaria
• Researchers characterize potential protein targets for malaria vaccine

In 2002, the publication of the genome of Plasmodium falciparum, the most malignant agent of malaria, generated hope in the fight against this deadly disease by the opportunities it offered to discover new drug targets. Since then results have not lived up to the expectations. The development of comparative genomics to further understanding of P. falciparum has indeed been hindered by a lack of knowledge of closely related species’ genomes. Only one species, P. reichenowi, infecting chimpanzees, was previously known as a sister lineage of P. falciparum.

Researchers based in Gabon and France have now reported the discovery of a new malaria agent infecting chimpanzees in Central Africa. To investigate the diversity of Plasmodium parasites circulating in chimpanzees in Africa, the team collected blood from 19 wild-borne animals kept as pets by villagers in Gabon. Two were found infected by a Plasmodium parasite. This new species, named Plasmodium gaboni, is a close relative of the most virulent human malaria agent, P. falciparum. Based on its whole mitochondrial genome, they demonstrate that this new species is a close relative of P. falciparum and P. reichenowi. The analysis of its genome should thus offer the opportunity to explore P. falciparum specific adaptations to humans. These results suggest that malaria may have been present in early hominoids and may have experienced a radiation along with that of its hosts. This discovery highlights the paucity of our knowledge on the richness of Plasmodium species infecting primates and suggests more research in this area is urgently needed.

A New Malaria Agent in African Hominids. 2009 PLoS Pathog 5(5): e1000446
Plasmodium falciparum is the major human malaria agent responsible for 200 to 300 million infections and one to three million deaths annually, mainly among African infants. The origin and evolution of this pathogen within the human lineage is still unresolved. A single species, P. reichenowi, which infects chimpanzees, is known to be a close sister lineage of P. falciparum. Here we report the discovery of a new Plasmodium species infecting Hominids. This new species has been isolated in two chimpanzees (Pan troglodytes) kept as pets by villagers in Gabon (Africa). Analysis of its complete mitochondrial genome (5529 nucleotides including Cyt b, Cox I and Cox III genes) reveals an older divergence of this lineage from the clade that includes P. falciparum and P. reichenowi (21+/-9 Myrs ago using Bayesian methods and considering that the divergence between P. falciparum and P. reichenowi occurred 4 to 7 million years ago as generally considered in the literature). This time frame would be congruent with the radiation of hominoids, suggesting that this Plasmodium lineage might have been present in early hominoids and that they may both have experienced a simultaneous diversification. Investigation of the nuclear genome of this new species will further the understanding of the genetic adaptations of P. falciparum to humans. The risk of transfer and emergence of this new species in humans must be now seriously considered given that it was found in two chimpanzees living in contact with humans and its close relatedness to the most virulent agent of malaria.

Related:

• Malaria: now you see me, now you don’t
• New ways to beat malaria
• Tracing resistance to antimalarial drugs across Africa

Malaria is a major global health problem responsible for more than one million deaths annually. Severity of malaria disease is associated with the inability of host immune cells to efficiently eliminate malaria parasites from the blood. Little is known about immune regulatory factors controlling the onset of severe and potentially fatal malaria. Regulatory T (Treg) cells are a small specialized subset of immune cells that suppress the activation and expansion of effector immune cells which partake in parasite elimination. Scientists have now investigated the relationship between Treg cells, parasite burden, and disease severity in adult malaria patients with either uncomplicated or severe malaria.

They were able to demonstrate that Treg cell frequency was elevated in malaria patients and associated with high parasite burden in severe malaria but not in uncomplicated malaria. This type of cell turns off the immune system and can allow the parasite to grow uncontrollably. Comparison of Treg cell characteristics allowed them to identify a new highly suppressive subset of Treg cells that was elevated in severe malaria patients. When comparing Treg cell characteristics, the team was able to identify elevated levels of a new highly suppressive subset of Treg cells in those patients with severe malaria. The regulatory (Treg) cell subset associated with severe disease in humans expresses a unique combination of surface markers, including TNFRII. Regulatory T (Treg) cells are a small specialized subset of immune cells that suppress the activation and expansion of effector immune cells, which partake in parasite elimination.

These results indicate that severe malaria is accompanied by the induction of highly suppressive Treg cells that can promote parasite growth and caution against the induction of these Treg cells when developing effective malaria vaccines. It is estimated that 500 million people live in areas where there is a risk of getting malaria. The severe form of the disease causes death in 1-3 million people each year. Until now it had been largely unknown what bodily factors enable some patients to fight and survive the disease, while other patients contract the severe form of the disease and sometimes die. Targeting this cell type may lead to new drugs and immunotherapeutics against malaria. Further studies are needed to determine if this new cell may also be promoting severe forms of other inflammatory diseases.

Parasite-Dependent Expansion of TNF Receptor II–Positive Regulatory T Cells with Enhanced Suppressive Activity in Adults with Severe Malaria. 2009 PLoS Pathog 5(4): e1000402
Severe Plasmodium falciparum malaria is a major cause of global mortality, yet the immunological factors underlying progression to severe disease remain unclear. CD4+CD25+ regulatory T cells (Treg cells) are associated with impaired T cell control of Plasmodium spp infection. We investigated the relationship between Treg cells, parasite biomass, and P. falciparum malaria disease severity in adults living in a malaria-endemic region of Indonesia. CD4+CD25+Foxp3+CD127lo Treg cells were significantly elevated in patients with uncomplicated and severe malaria relative to exposed asymptomatic controls. In patients with SM, Treg cell frequency correlated positively with parasitemia and total parasite biomass, both major determinants for the development of severe and fatal malaria, and Treg cells were significantly increased in hyperparasitemia. There was a further significant correlation between Treg cell frequency and plasma concentrations of soluble tumor necrosis factor receptor II (TNFRII) in SM. A subset of TNFRII+ Treg cells with high expression of Foxp3 was increased in severe relative to uncomplicated malaria. In vitro, P. falciparum–infected red blood cells dose dependently induced TNFRII+Foxp3hi Treg cells in PBMC from malaria-unexposed donors which showed greater suppressive activity than TNFRII2 Treg cells. The selective enrichment of the Treg cell compartment for a maximally suppressive TNFRII+Foxp3hi Treg subset in severe malaria provides a potential link between immune suppression, increased parasite biomass, and malaria disease severity. The findings caution against the induction of TNFRII+Foxp3hi Treg cells when developing effective malaria vaccines.

Related:

• Malaria: now you see me, now you don’t
• New ways to beat malaria
• Researchers characterize potential protein targets for malaria vaccine

Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year, mostly in sub-Saharan Africa. People become infected with P. falciparum when they are bitten by a mosquito that has acquired the parasite in a blood meal taken from an infected person. P. falciparum malaria, which is characterized by recurring fevers and chills, anemia (loss of red blood cells), and damage to vital organs, can be fatal within hours of symptom onset if untreated. Until recently, treatment in Africa relied on chloroquine and sulfadoxine–pyrimethamine. Unfortunately, parasites resistant to both these antimalarial drugs is now widespread. Consequently, the World Health Organization currently recommends artemisinin combination therapy for the treatment of P. falciparum malaria in Africa and other places where drugresistant malaria is common. In this therapy, artemisinin derivatives (new fast-acting antimalarial agents) are used in combination with another antimalarial to reduce the chances of P. falciparum becoming resistant to either drug.

P. falciparum becomes resistant to antimalarial drugs by acquiring “resistance mutations,” genetic changes that prevent these drugs from killing the parasite. A mutation in the gene encoding a protein called the chloroquine resistance transporter causes resistance to chloroquine, a specific group of mutations in the dihydrofolate reductase gene causes resistance to pyrimethamine, and several mutations in dhps, the gene that encodes dihydropteroate synthase, are associated with resistance to sulfadoxine. Scientists have discovered that the mutations causing chloroquine and pyrimethamine resistance originated in Asia and spread into Africa (probably multiple times) in the late 1970s and mid-1980s, respectively. These Asian-derived mutations are now common throughout Africa and, consequently, it is not possible to determine how they spread across the continent. Information of this sort would, however, help experts design effective measures to control the spread of drug-resistant P. falciparum. Because the mutations in dhps that cause sulfadoxine resistance only began to emerge in the mid- 1990s, they haven’t spread evenly across Africa yet. In this study, therefore, the researchers use genetic methods to characterize the geographical origins and contemporary distribution of dhps resistance mutations in Africa.

The researchers analyzed dhps mutations in P. falciparum DNA from blood samples collected from patients with malaria in various African countries and searched the scientific literature for other similar studies. Together, these data show that five major variant dhps sequences (three of which contain mutations that confer various degrees of resistance to sulphadoxine in laboratory tests) are currently present in Africa, each with a unique geographical distribution. In particular, the data show that P. falciparum parasites in east and west Africa carry different resistance mutations. Next, the researchers looked for microsatellite variants in the DNA flanking the dhps gene. Microsatellites are DNA regions that contain short, repeated sequences of nucleotides. Because the number of repeats can vary and because microsatellites are inherited together with nearby genes, the ancestry of various resistance mutations can be worked out by examining the microsatellites flanking different mutant dhps genes. This analysis revealed five regional clusters in which the same resistance lineage was present at all the sites examined within the region and also showed that the resistance mutations in east and west Africa have a different ancestry.

These findings show that sulfadoxine-resistant P. falciparum has recently emerged independently at multiple sites in Africa and that the molecular basis for sulfadoxine resistance is different in east and west Africa. This latter result may have clinical implications because it suggests that the effectiveness of sulfadoxine as an antimalarial drug may vary across the continent. Finally, although many more samples need to be analyzed to build a complete picture of the spread of antimalarial resistance across Africa, these findings suggest that economic and transport infrastructures may have played a role in governing recent parasite dispersal across this continent by affecting human migration. Thus, coordinated malaria control campaigns across socioeconomically linked areas in Africa may reduce the African malaria burden more effectively than campaigns that are confined to national territories.

Multiple Origins and Regional Dispersal of Resistant dhps in African Plasmodium falciparum Malaria. PLoS Med 6(4): e1000055
Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution. We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations. Resistant dhps has emerged independently in multiple sites in Africa during the past 10–20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

Related:

• Comprehensive map of global malaria
• Malaria, mosquitoes and the legacy of Ronald Ross
• New ways to beat malaria
• Researchers characterize potential protein targets for malaria vaccine

Killing only older mosquitoes could be a more sustainable way of controlling malaria, and has the potential to lead to evolution-proof insecticides that never become obsolete, according to a new article. Each year, malaria – spread through mosquito bites – kills around a million people, and many of the chemicals used to kill the insects become ineffective as the mosquito’s resistance to them evolves. New theoretical work predicts that simple changes to the way insecticides are used could prevent the evolution of resistance and reduce the burden of malaria.

The authors argue that insecticides – chemical or biological – which kill only older mosquitoes are a more sustainable way to fight the deadly disease. The development of biological or chemical insecticides that target older, malaria-infected mosquitoes could save millions dollars that would otherwise be spent endlessly looking for new insecticides to replace ones that have become ineffective. Done right, a one-off investment could create a single insecticide that would solve the problem of mosquito resistance forever. Insecticides sprayed on house walls or bed nets are some of the most successful ways of controlling malaria, but they work by killing the insects or denying them the human blood they use to make eggs. This imposes an enormous selection in favor of insecticide-resistant mosquitoes. However, once malaria parasites infect a mosquito, they need at least 10 to 14 days – or two to six cycles of egg production – to mature and migrate to the insect’s salivary glands. From there they can pass into humans when a mosquito bites. Most mosquitoes do not live long enough to transmit the disease. To stop malaria, we only need to kill the old mosquitoes.

To study the impact of late-acting insecticides on mosquito populations, the researchers constructed a mathematical model of malaria transmission using factors such as the egg laying cycle of the mosquito and the development of parasites within the insect. Analyses of the model using data on mosquito lifespan and malaria development from hotspots in Africa and Papua New Guinea reveal that insecticides killing only mosquitoes that have completed at least four cycles of egg production reduce the number of infectious bites by about 95 percent. Critically, the researchers also found that resistance to late-acting insecticides spreads much more slowly among mosquitoes, compared to conventional insecticides, and that in many cases, it never spreads at all. Aging mosquitoes are easier to kill with insecticides like DDT but new generation pesticides could do it too. Since most mosquitoes die before they become dangerous, late-acting insecticides will not have much impact on breeding, so there is much less pressure for the mosquitoes to evolve resistance. This means that late-life insecticides will be useful for much, much longer – maybe forever – than conventional insecticides. Insects usually have to pay a price for resistance, and if only a few older mosquitoes gain the benefits, evolutionary economics can stop resistance from ever spreading.

The researchers are working on fungal pesticide – a form of biological control – that kills mosquitoes late in life. This could be sprayed onto walls or onto treated materials such as bed nets, from where the mosquito would get infected by the fungal spores. The fungi take 10 to 12 days to kill the insects. This achieves the benefit of killing the old, dangerous mosquitoes, while dramatically reducing the selection for the evolution of resistance. The next step is to test the approach in the field. The main challenge to overcome might be human perception. Young mosquitoes aren’t dangerous, though they are a nuisance. Getting rid of all mosquitoes comes at a high price. Insecticides that kill indiscriminately impose maximal selection for mosquitoes that render those insecticides useless. Late-life acting insecticides would avoid that fate.

How to make evolution-proof insecticides for malaria control. 2009 PLoS Biol 7(4): e1000058
Insecticides are one of the cheapest, most effective, and best proven methods of controlling malaria, but mosquitoes can rapidly evolve resistance. Such evolution, first seen in the 1950s in areas of widespread DDT use, is a major challenge because attempts to comprehensively control and even eliminate malaria rely heavily on indoor house spraying and insecticide-treated bed nets. Current strategies for dealing with resistance evolution are expensive and open ended, and their sustainability has yet to be demonstrated. Here we show that if insecticides targeted old mosquitoes, and ideally old malaria-infected mosquitoes, they could provide effective malaria control while only weakly selecting for resistance. This alone would greatly enhance the useful life span of an insecticide. However, such weak selection for resistance can easily be overwhelmed if resistance is associated with fitness costs. In that case, late-life–acting insecticides would never be undermined by mosquito evolution. We discuss a number of practical ways to achieve this, including different use of existing chemical insecticides, biopesticides, and novel chemistry. Done right, a one-off investment in a single insecticide would solve the problem of mosquito resistance forever.

Related:

• Tough Choices – DDT or Malaria?
• Comprehensive map of global malaria
• Malaria: now you see me, now you don’t
• Malaria, mosquitoes and the legacy of Ronald Ross
• Nature Collections – Malaria

There’s a great collection of freely available resources On the Nature website under Nature Collections – Malaria (maybe NPG is finally getting the message about open access – hey Nature, it’s good to share :-)

The world is on the verge of making major inroads against malaria – a deadly disease that still claims the lives of more than 1 million people annually, mostly children less than 5 years of age. Over the past decade, scientists, large pharmaceutical companies and small biotechnology firms, governments and philanthropic organizations have come together to mount a full frontal attack on malaria, and there is now even talk of the ‘E word’ – that is, eradication. This collection highlights advances in the deployment of existing tools, and in the basic science of malaria – particularly those flowing from sequencing of the malaria parasite genomes – that will underpin the next generation of malaria-control tools, which will be needed if the scourge of malaria is to be eradicated.

Contents:

• Malaria: The end of the beginning – After decades of work, a pioneering malaria vaccine may soon reach the final phase of clinical trials. A vaccine that is far from perfect – but which may provide new direction and save thousands of lives.
• Malaria vaccine gets shot in the arm from tests – Promising results pave the way for a vaccine candidate to undergo full-blown trials across Africa.
• Malaria: The big push – Zambia, with help from partners around the world, is stepping up its battle against malaria.
• The billion-dollar malaria moment – For years the global malaria effort has been asking for more resources. Now the field needs to figure out a systematic strategy for spending the money effectively.
• Review: Malaria research in the post-genomic era

Articles:

• Comparative genomics of the neglected human malaria parasite Plasmodium vivax
• Genome sequence of the human malaria parasite Plasmodium falciparum
• Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii
• The genome of the simian and human malaria parasite Plasmodium knowlesi

Related:

• MicrobiologyBytes: Malaria

Malaria is one of the most common infectious diseases in the world and one of the greatest global public health problems. The Plasmodium falciparum parasite causes approximately 500 million cases each year and over one million deaths in sub-Saharan Africa. More than 40% of the world’s population is at risk of malaria. The parasite is transmitted to people through the bites of infected mosquitoes. These insects inject a life stage of the parasite called sporozoites, which invade human liver cells where they reproduce briefly. The liver cells then release merozoites (another life stage of the parasite), which invade red blood cells. Here, they multiply again before bursting out and infecting more red blood cells, causing fever and damaging vital organs. The infected red blood cells also release gametocytes, which infect mosquitoes when they take a blood meal. In the mosquito, the gametocytes multiply and develop into sporozoites, thus completing the parasite’s life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Effective treatment with antimalarial drugs also helps to decrease malaria transmission.

In 1998, the World Health Organization and several other international agencies launched Roll Back Malaria, a global partnership that aims to reduce the human and socioeconomic costs of malaria. Targets have been continually raised since this time and have culminated in the Roll Back Malaria Global Malaria Action Plan of 2008, where universal coverage of locally appropriate interventions is called for by 2010 and the long-term goal of malaria eradication again tabled for the international community. For malaria control and elimination initiatives to be effective, financial resources must be concentrated in regions where they will have the most impact, so it is essential to have up-to-date and accurate maps to guide effort and expenditure. In 2008, researchers of the Malaria Atlas Project constructed a map that stratified the world into three levels of malaria risk: no risk, unstable transmission risk (occasional focal outbreaks), and stable transmission risk (endemic areas where the disease is always present). Now, researchers extend this work by describing a new evidence-based method for generating continuous maps of P. falciparum endemicity within the area of stable malaria risk over the entire world’s surface. They then use this method to produce a P. falciparum endemicity map for 2007. Endemicity is important as it is a guide to the level of morbidity and mortality a population will suffer, as well as the intensity of the interventions that that will be required to bring the disease under control or additionally to interrupt transmission.

The researchers identified nearly 8,000 surveys of P. falciparum parasite rates (Pf PR; the percentage of a population with parasites detectable in their blood) completed since 1985 that met predefined criteria for inclusion into a global database of PfPR data. They then used ‘‘model-based geostatistics’’ to build a world map of P. falciparum endemicity for 2007 that took into account where and, importantly, when and all these surveys were done. Predictions were comprehensive (for every area of stable transmission globally) and continuous (predicted as a endemicity value between 0% and 100%). The population at risk of three levels of malaria endemicity were identified to help summarize these findings: low endemicity, where PfPR is below 5% and where it should be technically feasible to eliminate malaria; intermediate endemicity where PfPR is between 5% and 40% and it should be theoretically possible to interrupt transmission with the universal coverage of bed nets; high endemicity is where PfPR is above 40% and suites of locally appropriate intervention will be needed to bring malaria under control. The global level of malaria endemicity is much reduced when compared with historical maps. Nevertheless, the resulting map indicates that in 2007 almost 60% of the 2.4 billion people at malaria risk were living in areas with a stable risk of P. falciparum transmission – 0.69 billion people in Central and South East Asia (CSE Asia), 0.66 billion in Africa, Yemen, and Saudi Arabia (Africaþ), and 0.04 billion in the Americas. The people of the Americas were all in the low endemicity class. Although most people exposed to stable risk in CSE Asia were also in the low endemicity class (88%), 11% were in the intermediate class, and 1% were in the high endemicity class. By contrast, high endemicity was most common and widespread in the Africaþ region (53%), but with significant numbers in the intermediate (30%), and low (17%) endemicity classes.

The accuracy of this new world map of P. falciparum endemicity depends on the assumptions made in its construction and critically on the accuracy of the data fed into it, but because of the statistical methods used to construct this map, it is possible to quantify the uncertainty in the results for all users. Thus, this map (which, together with the data used in its construction, will be freely available) represents an important new resource that clearly indicates areas where malaria control can be improved (for example, Africa) and other areas where malaria elimination may be technically possible. In addition, planned annual updates of the global P. falciparum endemicity map and the PfPR database by the Malaria Atlas Project will help public health experts to monitor the progress of the malaria control community towards international control and elimination targets.

A world malaria map: Plasmodium falciparum endemicity in 2007. 2009 PLoS Med 6(3): e1000048
Efficient allocation of resources to intervene against malaria requires a detailed understanding of the contemporary spatial distribution of malaria risk. It is exactly 40 y since the last global map of malaria endemicity was published. This paper describes the generation of a new world map of Plasmodium falciparum malaria endemicity for the year 2007. A total of 8,938 P. falciparum parasite rate (PfPR) surveys were identified using a variety of exhaustive search strategies. Of these, 7,953 passed strict data fidelity tests for inclusion into a global database of PfPR data, age-standardized to 2–10 y for endemicity mapping. A model based geostatistical procedure was used to create a continuous surface of malaria endemicity within previously defined stable spatial limits of P. falciparum transmission. These procedures were implemented within a Bayesian statistical framework so that the uncertainty of these predictions could be evaluated robustly. The uncertainty was expressed as the probability of predicting correctly one of three endemicity classes; previously stratified to be an informative guide for malaria control. Population at risk estimates, adjusted for the transmission modifying effects of urbanization in Africa, were then derived with reference to human population surfaces in 2007. Of the 1.38 billion people at risk of stable P. falciparum malaria, 0.69 billion were found in Central and South East Asia (CSE Asia), 0.66 billion in Africa, Yemen, and Saudi Arabia (Africaþ), and 0.04 billion in the Americas. All those exposed to stable risk in the Americas were in the lowest endemicity class. The vast majority (88%) of those living under stable risk in CSE Asia were also in this low endemicity class; a small remainder(11%) were in the intermediate endemicity class; and the remaining fraction (1%) in high endemicity areas. High endemicity was widespread in the Africaþ region, where 0.35 billion people are at this level of risk. Most of the rest live at intermediate risk (0.20 billion), with a smaller number (0.11 billion) at low stable risk. High levels of P. falciparum malaria endemicity are common in Africa. Uniformly low endemic levels are found in the Americas. Low endemicity is also widespread in CSE Asia, but pockets of intermediate and very rarely high transmission remain. There are therefore significant opportunities for malaria control in Africa and for malaria elimination elsewhere. This 2007 global P. falciparum malaria endemicity map is the first of a series with which it will be possible to monitor and evaluate the progress of this intervention process.

Related:

• MicrobiologyBytes: Malaria
• Malaria, mosquitoes and the legacy of Ronald Ross
• New ways to beat malaria
• Researchers characterize potential protein targets for malaria vaccine
• Researchers Find Essential Proteins for Critical Stage of Malaria Transmission

Burkitt’s lymphoma (BL) was first described 50 years ago, and the first human tumour virus Epstein–Barr virus (EBV) was discovered in BL tumours soon after. Since then, the role of EBV in the development of BL has become more and more enigmatic. Only recently have we finally begun to understand, at the cellular and molecular levels, the complex and interesting interaction of EBV with B cells that creates a predisposition for the development of BL. This review discusses the intertwined histories of EBV and BL and their relationship to the cofactors in BL pathogenesis: malaria and the MYC translocation.

The curious case of the tumour virus: 50 years of Burkitt’s lymphoma. 2008 Nature Reviews Microbiology 6, 913-924

Related:

• DNA Viruses
• Viruses and Human Cancer
• Herpesvirus proteins that target key cellular processes
• Epstein-Barr Virus protein EBNA1 contributes to cancer
• Herpesviruses – not all bad?