RxPG News : Malaria

Disease control with current interventions has greater impact on malaria than global warming

Wed, 19 May 2010 14:45:20 PST

( from http://www.rxpgnews.com ) A study published today in the journal Nature casts doubt on the widely held notion that warming global temperatures will lead to a future intensification of malaria and an expansion of its global range.

The research, conducted by the Malaria Atlas Project (MAP), a multinational team of researchers funded mainly by the Wellcome Trust, suggests that current interventions could have a far more dramatic – and positive – effect on reducing the spread of malaria than any negative effects caused by climate change.

A steady stream of modelling studies have predicted that malaria will worsen and its range will spread as the world gets warmer. Malaria already kills more than a million people each year, mainly young children and pregnant women, with some 2.4 billion people at risk from its most deadly form.

Last year the Malaria Atlas Project produced a new map of modern-day malaria risk, giving researchers a unique opportunity to examine the effects that climate change may have had on the disease.

The new research compared this modern-day map with a historic reconstruction of malaria at its assumed peak, around 1900, and measured changes in the disease risk since that time. Although it is widely known that malaria has receded from many areas where it was previously endemic, such as the United States and much of Europe, the researchers were able to measure for the first time the extent of this recession and show that even in tropical areas the intensity of transmission has declined substantially this century.

The research was led by Dr Pete Gething from the Department of Zoology at the University of Oxford. He says: "The recession in malaria since 1900 is of little comfort to the billions of people still at serious risk, but it is important when thinking about the effects of climate on the future of the disease. We know that warming can boost malaria transmission but the major declines we've measured have happened during a century of rising temperatures, so clearly a changing climate doesn't tell the whole story."

The team compared the increases in malaria predicted by global warming scenarios with the actual declines of the twentieth century. Importantly, they also gauged the efficacy of different disease control measures when set against the possible adverse effects of rising temperatures and concluded that interventions such as insecticide-treated bed nets or modern antimalarial drugs can potentially outweigh the effects of global warming as much as tenfold.

Dr Simon Hay, who leads the MAP group in Oxford, explains: "When we looked at studies measuring the possible impact of bed nets or drugs, it was clear that they could massively reduce transmission and counteract the much smaller effects of rising temperatures.

"Malaria remains a huge public health problem and the international community has an unprecedented opportunity to relieve this burden with existing interventions. Any failure in meeting this challenge will be very difficult to attribute to climate change."

Target Site for Developing Mosquito Pesticides Discovered

Sun, 24 Dec 2006 19:30:39 PST

( from http://www.rxpgnews.com ) A Mayo Clinic researcher has discovered a target site within malaria-carrying mosquitoes that could be used to develop pesticides that are toxic to the Anopheles gambiae mosquito and other mosquito species. It would not affect humans and other mammals. If supported by further studies, the findings could offer a safer and more effective control of mosquito-borne diseases such as malaria.

Yuan-Ping Pang, Ph.D., a chemist and expert in computer-aided molecular design at Mayo Clinic, identified two unique amino acid residues called cysteine (286) and arginine (339). These exist in three mosquito species and the German cockroach

Dr. Pang's findings are significant because the residues could potentially be used as a target site for a pesticide that would incapacitate only insects that carry these residues, which do not exist in mammals. The findings appear in the current issue of PLoS ONE, a new, peer-reviewed, open-access journal published by the Public Library of Science.

"These findings suggest that new pesticides can be designed to target only the mosquito enzyme. Such pesticides could be used in small quantities to harm mosquitoes, but not mammals," Dr. Pang says. "We've developed a blueprint for a pesticide that could incapacitate malaria-carrying mosquitoes. We are currently making a prototype of the new pesticide."

Most pesticides today work by crippling the serine residue, which is another amino acid of the enzyme acetylcholinesterase and is located at the active site of the enzyme. This serine residue is present in both insects and mammals and therefore, any pesticide targeting this amino acid affects both insects and mammals.

Acetylcholinesterase is a vital enzyme to both insects and mammals. It breaks down the neurotransmitter acetylcholine, which is a primary neurotransmitter in the brain that is associated with memory and cognition.

Dr. Pang, director of Mayo Clinic's Computer-Aided Molecular Design Laboratory, studied the genetic makeup of all known acetylcholinesterases in 73 species, including humans. He identified residues that only exist in the mosquito version of the acetylcholinesterase. To identify which of these residues is susceptible to pesticides, he developed a three-dimensional model of mosquito acetylcholinesterase. With this three-dimensional model in hand, Dr. Pang learned how residues function in a way never before possible.

He found that the cysteine and arginine residues were located at the opening of the active site of the mosquito acetylcholinesterase. An active site is a pocket in an enzyme where a fast chemical reaction takes place to break down a molecule or build a new molecule.

Previous studies by Dr. Pang and researchers elsewhere found that the cysteine residue acts as a hook that could tether a small molecule in the active site of an enzyme and permanently damage the enzyme. This led Dr. Pang to believe the cysteine and arginine residues could be targeted by a pesticide that would not affect humans and other mammals.

"While a three-dimensional model of the mosquito enzyme acetylcholinesterase has been reported by other scientists, no mosquito-specific residue at the active site of acetylcholinesterase has been reported until now," Dr. Pang says. "These findings suggest that a chemically stable molecule (to be used as a safer pesticide) could be made to react with the cysteine residue in the mosquito enzyme acetylcholinesterase and irreversibly inhibit the enzyme."

The three-dimensional model Dr. Pang developed was created with a powerful computing system called a terascale system. He built the system with 590 personal computers. Terascale refers to computational power measured in the unit of teraflops, which is a processor capable of a speed of one trillion floating-point operations per second. A single teraflops computer is comparable to a computer that can search at least 50,000 Manhattan phonebooks in one second. Terascale systems are among the most powerful computers available today.

Dr. Pang published similar findings in October 2006 in which he described a potentially safer and more effective method for controlling crop-destroying aphids. The study was published in the journal Bioorganic & Medicinal Chemistry Letters.

Background on pesticides and malaria DDT has been banned in most parts of the world for decades, but approximately 20 countries currently use the pesticide to control malaria and others are considering its use. DDT use remains controversial, as some studies have linked its use to environmental and health problems. Still, it is largely believed to be among the most effective methods to kill malaria-carrying mosquitoes. Malaria continues to be the leading cause of death and morbidity in poor countries, according to the World Health Organization (WHO). More than one million deaths and up to 500 million clinical cases are reported each year. Most of the 3,000 deaths that occur each day worldwide are of children in Africa. More than one-third of the world's population lives in malaria-endemic areas. According to a 2006 report by the Centers for Disease Control and Prevention, there were outbreaks of locally acquired mosquito-transmitted malaria in the United States.

Retina can provide a very reliable way of diagnosing cerebral malaria

Tue, 07 Nov 2006 14:22:37 PST

( from http://www.rxpgnews.com ) The eye can provide a very reliable way of diagnosing cerebral malaria, researchers in Malawi have shown. By looking at the changes to the retina, doctors are able to determine whether an unconscious child is suffering from this severe form of malaria or another, unrelated illness, leading to the most appropriate treatment.

Because malaria is so common in Africa, children may have an incidental malaria infection whilst actually having another life-threatening illness. This can confuse the diagnosis in an unconscious child. Doctors hope that widespread use of eye examination could greatly reduce the number of children dying from this major childhood killer.

In research funded by the Wellcome Trust and the National Institutes of Health, a study led by Dr Nick Beare of the St Paul's Eye Unit, Liverpool, has shown that changes to the retina were the only clinical sign or laboratory test which could distinguish between patients who actually died from cerebral malaria and those with another cause of death. The results of their study are published in the latest edition of the American Journal of Tropical Medicine and Hygiene.

"Over a million people a year die from malaria, and most of these are African children," explains Dr Beare. "Death is usually caused by cerebral malaria, a severe complication of malaria in which the Plasmodium falciparum malaria parasite causes infection of the capillaries that flow through the tissues of the brain, affecting the brain and central nervous system. This can lead to convulsions, coma and death."

Cerebral malaria is accompanied by changes in the retina, the light-sensitive tissue at the back of the eye. These changes, known as malarial retinopathy, include white, opaque patches, whitening of the infected blood vessels, bleeding into the retina and swelling of the optic nerve, the nerve that transmits visual signals to the brain. The first two of these signs are unique to severe malaria, and not seen in any other disease.

Malaria parasites live in red blood cells and make them stick to the inside of small blood vessels, particularly in the brain and also the eye. It is thought that this causes the unique whitening of eye blood vessels. The light-sensitive tissue in the eye is also affected because the parasites disrupt the supply of oxygen and nutrients. However, once children recover, their vision does not seem to be affected.

"In cerebral malaria, the eye acts as a window onto the brain, providing valuable information for the doctors caring for the patients," says Dr Beare. "Our research demonstrates that the detection of malarial retinopathy is a much needed diagnostic tool in cerebral malaria, and can identify those children at most risk of death. Diagnosis requires special training in eye examination, but is relatively straightforward and cost effective, which is essential in resource-poor settings such as Africa."

Doctors are able to carry out this diagnosis using just an ophthalmoscope, an instrument through which the observer can see the retina at the back of the eye.

Researchers in Malawi have previously shown that up to a quarter of children apparently dying from cerebral malaria in fact had another cause of death. Dr Beare and his team hope that by confirming the diagnosis of cerebral malaria, appropriate care can be targeted at those most in need. By identifying children who might not have cerebral malaria other causes of coma can be searched for, and potentially treated.

Commenting on the research, Dr Sohaila Rastan, Director of Science Funding at the Wellcome Trust, said: "This work is impressive and if it can be effectively delivered in a resource-poor setting could have a significant impact on the diagnosis and subsequent treatment of cerebral malaria in children."

New findings could lead to vaccine for severe malaria

Mon, 04 Sep 2006 16:59:37 PST

( from http://www.rxpgnews.com ) The most severe form of malaria hits pregnant women and children the hardest. A joint study between Karolinska Institutet in Sweden and Makerere University in Uganda has now produced some important findings on how the malaria parasite conceals itself in the placenta.

Plasmodium falciparium is the name of by far the most virulent of the four malaria parasites that infect man. It is particularly dangerous in that it also infects the placenta of pregnant women, with fatal consequences for both her and the foetus. This, combined with the often feeble medical resources of malaria-stricken countries, can lead to such serous complications that the mother dies during delivery.

"For some reason, women in their first pregnancy lose the semi-immunity that is normally found in adults," explains Niloofar Rasti, a KI graduate student who has been working with the study. "The placenta seems to be an anatomically favourable environment for a subpopulation of the parasites."

The research group from Karolinska Institutet, under the leadership of Professor Mats Wahlgren, has been working with colleagues from KI's partner university in Uganda to study in detail how the parasite infects the placenta. Their results, which are published in the American scientific journal PNAS, can enable the development of vaccines and therapies to combat severe malarial infections.

During one particular phase of its lifecycle, the parasite enters human red blood cells, where it produces proteins that attach themselves to receptors in the wall of the blood vessels. This causes the red blood cells to accumulate in organ capillaries, and gives rise to life-threatening symptoms. Adults who have been infected several times can become partly immune as their defence system gradually starts to recognise the parasite's proteins. When the placenta is formed, however, a new environment is introduced with a different set of receptors. This means that a new growth niche is made available to a subpopulation of the parasites.

Earlier studies have suggested that each protein from the parasite attaches to only one specific protein, a receptor, in the placenta. Ms Rasti and her colleagues suspected, however, that the natural mechanisms are more complex than laboratory studies have shown. They therefore collected and analysed placentas on site in Uganda.

"Most of the parasites we studied could bind to three different receptors in the placenta," she says. "This would mean that a future vaccine cannot be based on the principle of one protein-one receptor, as was previously believed."

Now that scientists know that several placental receptors are involved in the binding mechanism, attention will be shifted to the parasite itself, and whether it produces many different surface proteins or if one and the same protein is able to bind to many host receptors.

AgDscam gene Holds the Key to Broad-Based Pathogen Recognition

Fri, 23 Jun 2006 00:23:37 PST

( from http://www.rxpgnews.com ) Anything that's alive runs the risk of infection. How you respond to infection, however, depends on where you sit on the evolutionary tree. Humans and other vertebrates can fend off billions of pathogens by routinely recombining bits of genes for surface molecules on the cells charged with pathogen recognition. Insects and other invertebrates rely to a large degree on the pathogen recognition molecules (called pattern recognition receptors) they were born with. When a pattern recognition receptor detects a pathogenbased on what's known as its pathogen-associated molecular patternthe receptor can launch a direct attack that either engulfs the invader, through encapsulation or phagocytosis, or triggers signaling pathways that regulate immune system genes involved in killing the pathogen.

In a new study, Yuemei Dong, Harry Taylor, and George Dimopoulos found a mosquito gene that vastly boosts the ability of insect pattern recognition receptors to detect pathogens. Originally implicated in neuron development, the gene can create a plethora of receptors for the malaria vector Anopheles gambiae. The AgDscam geneshort for Anopheles gambiae Down syndrome cell adhesion molecule genehas 101 protein-coding regions (called exons) that can be mixed and matched after transcription to produce over 31,000 possible alternative splice forms with different properties. Thus, while B cell and T cell receptor diversity is generated largely at the gene sequence level before transcription, AgDscam diversity is produced by reshuffling sections of gene transcripts before translation into protein.

Dscam was first characterized in the fruitfly (Drosophila melanogaster), where it can generate about 38,000 splice forms with different recognition and binding specificities from 95 variable exons. It's been suggested that a diverse inventory of adhesion molecules may help olfactory nerves establish the proper connections during development. But the presence of high levels of Dscam in cells that function in the fly's innate immune system and evidence of involvement in phagocytosis raised the possibility that the gene also plays a diverse recognition role in immunity.

Dong et al. found that AgDscam, like the fly version, has three variable regions within a portion of the immunoglobulin (Ig) gene. Each region contains different numbers of alternative splicing exons: Ig4 has 14, Ig6 has 30, and Ig10 has 38, leading to a possible 31,920 alternative splice forms. The researchers worked with a mosquito immune cell line to investigate AgDscam's response to infection. Exposure to bacteria, fungi, and parasite surface molecules caused the cells to produce different AgDscam splice-form repertoires with different interaction properties. As with the cell lines, bacterial infection of adult mosquitoes also caused alternative splicing of AgDscam. Infecting mosquitoes with two different Plasmodium malaria parasites produced completely different AgDscam splice-form repertoires.

When the researchers cut AgDscam protein levels in half with a technique that silences a gene by degrading its transcript, they could link its function with phagocytosis of pathogens. Mosquitoes with a silenced AgDscam gene succumbed to bacterial infections (caused by two types of bacteria that produce different surface proteins) at much higher rates than did mosquitoes with a functioning AgDscam gene. Silencing AgDscam also resulted in a profound proliferation of opportunistic microbes, suggesting its essential role in defending the mosquito against bacterial infections. When gene-silenced mosquitoes fed on blood infected with malaria parasites, the researchers found a 65% increase of parasites on the insects' guts. The researchers confirmed the specificity of these associations between splice forms and particular pathogens by selectively silencing the exon transcripts induced by different bacteria. Disabling bacteria-specific exons reduced binding for the target bacteria but had no effect on other bacteria.

Altogether, these results show that infection-induced AgDscam splicing creates receptors better equipped to recognizeand defend againstthe invading pathogen. Cells generated different splice-form repertoires depending on the source of infection. Alternative splicing allows the insect to vastly increase its repertoire of pattern recognition receptors from one single gene and thereby fight infection more efficiently. This work suggests that a better understanding of how A. gambiae's hypervariable receptor AgDscam recognizes the Plasmodium parasite might suggest novel ways to control malaria by targeting the parasite inside its mosquito host.

Genes responsible for malaria parasite's survival pin pointed

Tue, 20 Jun 2006 19:11:37 PST

( from http://www.rxpgnews.com ) "While millions of dollars have been spent to develop a malaria vaccine, we still don't have a licensed product," says Associate Professor Elizabeth Winzeler of Scripps Research, who led the study. "Our findings may help in the vaccine-development effort, because they point to novel immunogens that could be targeted."

Winzeler adds the study also identified novel genes involved in the parasite's development of drug resistance-another critical issue in the fight against malaria.

Malaria is a nasty and often fatal disease, which may lead to kidney failure, seizures, permanent neurological damage, coma, and death. There are four types of Plasmodium parasites that cause the disease, of which falciparum, the subject of the recent study, is the most deadly.

Despite a century of effort to globally control malaria, the disease remains endemic in many parts of the world. With some 40 percent of the world's population living in these areas, the need for more effective vaccines and treatments is profound. The spread of drug-resistance adds to the urgency.

In the study, the scientists used gene-chip technology to compare the genomes of 14 different field and laboratory strains of Plasmodium falciparum collected from four continents. Of the parasite's roughly 5,000 genes, about 500 were found to be highly variable across the different strains, indicating that these genes are evolving at a faster-than-neutral rate.

"These genes exhibit variability far above and beyond basic housekeeping genes," notes Winzeler. "Most genes in the malaria parasite are highly conserved, but these appear to be evolving rapidly."

Why? According to the study, "guilt by association" would indicate that the genes that are rapidly evolving are the very genes responding to our best attempts to eradicate the parasite. "The two largest forces exerting selection pressures on the parasite are our immune system and anti-malarial drugs, particularly chloroquine," says Winzeler.

Previous to this study, no systematic overview of these potential targets in the parasite's genome existed. The study's results include known drug and vaccine targets and intriguingly, areas of the genome not currently under investigation.

One example of a promising potential target highlighted by the research is the P. falciparum GTP cyclohydrolase gene, the first enzyme in the folate biosynthesis pathway. Downstream members of this pathway are targeted by several widely used antimalarials, and authors speculate that an amplification of the GTP cyclohydrolase enzyme facilitates parasite resistance to antifolate drugs.

"I'm super excited about the paper," says Winzeler. "It's going to have an impact on the research community."

Mosquito immune system examined

Fri, 09 Jun 2006 13:58:37 PST

( from http://www.rxpgnews.com ) Mosquitoes employ the same immune factors to fight off bacterial pathogens as they do to kill malaria-causing Plasmodium parasites, according to a study by researchers at the Johns Hopkins Bloomberg School of Public Health. The study identified several genes that encode proteins of the mosquito's immune system. All of the immune genes that were involved in limiting infection by the malaria parasites were also important for the resistance to bacterial infection. However, several immune genes that were essential for resistance to bacterial infection did not affect Plasmodium infection. According to the authors, the findings add to the understanding of mosquito immunity, and could contribute towards the development of malaria-control strategies based on blocking the parasite in the mosquito.

"Mosquitoes that transmit malaria can kill large portions of Plasmodium parasites, and some mosquito strains are totally resistant to Plasmodium. However, our observations suggest that mosquitoes have not evolved a highly-specific defense against malaria parasites. Instead, they employ factors of their antimicrobial defense system to combat the Plasmodium parasite," said George Dimopoulos, Ph.D., senior author of the study and assistant professor with the Bloomberg School's Malaria Research Institute. "The degree of mosquito susceptibility to Plasmodium, and thereby its capacity to transmit malaria, may therefore partly depend on the mosquito's microbial exposure, which can differ greatly between different geographic sites. Potentially, we could boost the mosquito's capacity to fight the malaria parasite by exposing it to certain microbes or compounds that resemble the microbe molecules responsible for immune activation."

In this study, the investigators also analyzed the immune responses of Anopheles gambiae mosquitoes to infection with different Plasmodium parasite species, one that causes malaria in humans and another that only infects rodents. The study revealed that mosquitoes mostly employ the same immune factors in defending against the two different Plasmodium species. Only a few immune genes were more important in the defense against either one of the two species.

"The mosquito's immune system appears to employ a variety of antimicrobial defense factors (genes) against the malaria parasite, and can therefore significantly limit infection. The parasite, on the other hand, is capable of evading these defenses to a degree that allows its transmission by the mosquito. Now we have to figure out how to make the mosquito's immune system more effective in killing malaria parasites at multiple stages that would render the development of evasive mechanisms impossible for the parasite," said Dimopoulos.

The Haptoglobin Genotype Connection with Childhood Anemia in a Malaria-Endemic Region

Thu, 04 May 2006 23:29:37 PST

( from http://www.rxpgnews.com ) The World Health Organization estimates that malaria kills an African child every 30 seconds. Many of these children die because they develop severe anemia (a deficiency of red blood cells). As many as 5 million cases of severe malarial anemia occur in African children every year, and 13% of these cases are fatal. Turning the statistics around, more than half of young children in African countries where malaria is endemic (constantly present) are anemic. Nutritional deficiencies and various infections account for some of this disease burden, but malaria is one of the most important factors contributing to anemia.

The malaria parasite destroys red blood cells (a process called hemolysis) as part of its life cycle, releasing hemoglobin (Hb)an iron-containing protein that carries oxygen around the bodyinto the circulation. Free Hb can cause oxidant stress, which is itself associated with anemia in malaria. An important modulator of such stress is a serum protein called haptoglobin (Hp), which captures Hb during hemolysis.

Hp exists in three molecular forms that are genetically determined by two variants (alleles) of a single gene. People who have two copies of the Hp1 allele make only Hp1-1, a homodimeric protein. People with two copies of the Hp2 allele (the Hp2/2 genotype) make Hp2-2, a large circular polymer, and those with one copy of each allele make the linear polymer Hp1-2 in addition to these two forms. The functional properties of the three Hp forms are somewhat different. In particular, Hp2-2 binds Hb much less tightly than the other forms. Sarah Atkinson and her colleagues reasoned, therefore, that the Hp2/2 genotype might be a risk factor for anemia in children in malaria-endemic areas. To test their hypothesis, they measured Hb levels in Gambian children at the start and end of the malaria season, and now report in a new study that, as predicted, the Hp2/2 genotype is associated with seasonal childhood anemia in this population.

Most cases of malaria in The Gambia occur between September and December, so the researchers recruited 780 children aged two to six years from ten Gambian villages in July 2001, determined their Hp genotypes, assessed their blood Hb and serum Hp concentrations and iron status, and determined whether they were infected with malaria parasites. These variables were re-measured at the end of the malaria season. In addition, the researchers determined two other genetic polymorphisms that might influence Hb levels over the malaria seasonan Hb variant that causes sickle cell anemia (HbS), and glucose-6 phosphate dehydrogenase (G6PD) gene variants associated with hemolytic anemia.

Atkinson and her colleagues first analyzed their study population in terms of their Hp genotype. This univariate (single) analysis included 671 childrena few children were not included because of incomplete data. Baseline hb levels were not affected by Hp genotype, but the average drop in hb was 8.9 g/l in the 17% of children with the Hp2/2 genotype compared with only 5.1 g/l in children with the other genotypes. By contrast, the magnitude of the drop in Hb levels over the season was not affected by HbS or G6PD genotypetwo other genetic traits that affect the red blood cells. Because multiple factors influence Hb concentrations (for example, recent infection with malarial parasites and iron status), the researchers also did a multiple regression analysis of their data to test the effect of all such factors on Hb levels at the end of the malaria season. There were 565 children who had data complete enough for this more detailed analysis, and, once again, the Hp genotype emerged as a risk factor for anemia, even after adjusting for other factors that affect Hb levels.

Atkinson and her colleagues suggest that the association between Hp genotype and seasonal childhood anemia may reflect the reduced ability of the Hp2-2 polymer to scavenge free Hb and its bound iron after malaria-induced hemolysis. They also discuss why Hp2, a potentially detrimental allele, should be common in The Gambia, where malaria is endemic. Hp2 arose from Hp1 about 2 million years ago, and its subsequent spread across the world seems to have been driven by a strong genetic pressure, such as exposure to a life-threatening disease. The authors suggest that malaria may be one of the diseases that helped to select for the Hp2 allele; it is possible that the Hp2 allele may provide protection from life-threatening malaria, albeit at the expense of impaired hematological recovery from mild and asymptomatic malaria. In a related Perspective (DOI: 10.1371/journal.pmed.0030200), Stephen Rogerson expands on the possible mechanisms of Hp-related anemia, and considers what the wider health implications of this study might be.

Mosquitoes that could help combat malaria!

Sun, 30 Apr 2006 23:06:37 PST

( from http://www.rxpgnews.com ) Scientists have found a particular type of mosquito in Mali in West Africa that is naturally resistant to malaria and could be helpful in combating the disease.

A team including researchers from the University of Bamako in West Africa and three top US-based institutes said they have also identified a gene that could be key to determining how resistant the mosquitoes are to infection by the parasite, reported the online edition of Science magazine.

The team found that many Anopheles gambiae mosquitoes -- Africa's most important malaria vector -- are already resistant to Plasmodium falciparum, the malaria parasite.

Malaria is an infectious disease characterised by cycles of chill, fever and sweating caused by the parasitic infection of red blood cells by a protozoan that is transmitted by the bite of an infected female mosquito.

It affects approximately 300 million people worldwide and kills between one and 1.5 million people every year.

Previously extremely widespread, malaria is now mainly confined to Africa, Asia and Latin America. The situation has become even more complex over the last few years with the increase in resistance to drugs normally used to combat the parasite that causes the disease.

Malaria parasite plasmodium impairs key immune system cells

Wed, 12 Apr 2006 13:35:37 PST

( from http://www.rxpgnews.com ) Plasmodium, the parasite responsible for malaria, impairs the ability of key cells of the immune system to trigger an efficient immune response. This might explain why patients with malaria are susceptible to a wide range of other infections and fail to respond to several vaccines. In a study published today in the open access journal Journal of Biology, researchers show that if dendritic cells, the key cells involved in initiating immunity, are exposed to red blood cells infected with Plasmodium chabaudi, they initiate a sequence of events that result in compromised antibody responses. The researchers show that this is due to the presence of hemozoin, a by-product of the digestion of hemoglobin by Plasmodium, in infected red blood cells. These observations also explain why vaccines for many diseases are so ineffective during malaria infection, and suggest that the use of preventive anti-malarial drugs before vaccination may improve vaccine-induced protection.

In a study funded by the Wellcome Trust, Owain Millington and colleagues from the University of Strathclyde, UK, studied the effects of Plasmodium chabaudi, the mouse Plasmodium, on mice antigen-presenting dendritic cells in culture and confirmed their findings in live mice.

Millington et al.'s results show that dendritic cells exposed to P. chabaudiinfected red blood cells do not activate normally. They express lower levels of membrane molecules that stimulate other cells of the immune system, and their cytokine production is lower than that of normal dendritic cells. Millington et al. demonstrate that this is caused by exposure to hemozoin present in infected red blood cells.

Millington et al. then show that P.chabaudi-infected dendritic cells fail to activate helper T cells properly T cells are activated but show reduced proliferation and cytokine production in culture. Importantly, during malaria infection, T cells fail to migrate to B-cell areas of lymph nodes or spleen, and this results in the failure of B-cell activation and antibody production.

Modeling the Impact of Intermittent Preventative Treatment on the Spread of Drug-Resistant Malaria

Wed, 05 Apr 2006 19:18:37 PST

( from http://www.rxpgnews.com ) Until the mid-20th century, malaria occurred in most temperate, subtropical, and tropical countries of the world. Then, the introduction of powerful insecticides, including DDT, made it possible to eliminate this human parasitic disease in many temperate countries by controlling the mosquitoes that transmit malarial parasites between people. Elsewhere, eradication efforts were less successful, but the use of inexpensive antimalarial drugs such as chloroquine and sulfadoxine-pyrimethamine (SP) further reduced global morbidity and mortality from malaria. Sadly, the rapid spread of resistance to chloroquine (and more recently to SP) has resulted in a resurgence of malaria over the past three decades. Nowadays, 40% of the world's population is at risk of contracting malaria, and every year, it kills at least 1 million peoplemainly children. Pregnant women and their unborn children are particularly vulnerable to malaria, for whom it is a major cause of perinatal mortality, low birth weight, and maternal anemia.

One way to reduce malaria morbidity and mortality is to treat asymptomatic individuals, regardless of their infection status, with regular therapeutic doses of antimalarial drugs. Intermittent preventative (or presumptive) treatment (IPT) is currently used in pregnant women (IPTp) in malaria-endemic areas, and IPT for infants (IPTi) is also being considered. However, before an intervention of this type is widely introduced, its potential impact on the spread of drug-resistant parasites needs to be investigated. A badly designed intervention could increase the speed at which malaria parasites become resistant to new drugs, an outcome that public health officials want to avoid. Ideally, such information would come from field trials, but in practice such trials are rarely undertaken, so researchers, including Wendy Prudhomme O'Meara, David Smith, and Ellis McKenzie, have turned instead to mathematical modeling. O'Meara and colleagues now describes a model that has allowed them to evaluate the possible impact of IPTp and IPTi on the spread of drug-resistant malaria parasites. Their analysis highlights the importance of carefully choosing which drugs to use for IPTi, and indicates which conditions are most likely to encourage the spread of drug resistance.

Drug use patternshow quickly the body removes each drug, how well an individual's immune response deals with malaria parasites, and how often each person gets bitten by an infected mosquito (the transmission intensity)all affect the spread of drug-resistant parasites. Prudhomme O'Meara and colleagues built these factors into a composite model that incorporates a human and a parasite population model. They then used their model to predict the potential for drug-resistant parasites to spread in low- and high-transmission settings, and to predict how the use of IPT in adults and infants, the time taken for drug elimination, and the treatment of infections (instead of asymptomatic individuals alone) might affect the spread of drug resistance.

One prediction of their model is that whereas fully resistant parasites (which can survive a full therapeutic dose of an antimalarial drug) are more likely to spread under conditions of high transmission, partially resistant parasites (which survive at intermediate drug concentrations) are more likely to spread in low-transmission areas, a result supported by epidemiological observations. The model also predicts that the use of a drug for IPT to which there is no existing resistance in a high-transmission area will accelerate the appearance of partial resistance, followed by an explosion of full resistance. Another analysis indicates that drugs that are rapidly eliminated from the body (e.g., chlorproguanil-dapsone) may be preferable to those that linger (e.g., SP). This latter type of drug maximizes the period of protection from each treatment but also maximizes the time when enough drug is present to allow selection of resistant parasites (the window for selection). Finally, comparing IPTp with IPTi, the model predicts that partially resistant parasites will spread faster when IPT is given to infants (who have little or no immunity to malaria) than when given to adults (who often are immune to some degree).

The researchers stress that their model provides a qualitative, not a quantitative, assessment of how partial and fully resistant malaria parasites will spread in different communities under different drug use strategies. But, they say, the model can be used as a tool to determine the critical questions that need to be addressed before broad implementation of IPT. In particular, they note, their model highlights the importance of carefully selecting the drug to be used in IPTi programs in different settings so that protection is maximized while minimizing the chances of antimalarial drug resistance emerging.

Global warming trend may contribute to malaria's rise

Wed, 22 Mar 2006 06:21:37 PST

( from http://www.rxpgnews.com ) Could global warming be contributing to the resurgence of malaria in the East African Highlands?

A widely-cited study published a few years ago said no, but new research by an international team that includes University of Michigan theoretical ecologist Mercedes Pascual finds that, while other factors such as drug and pesticide resistance, changing land use patterns and human migration also may play roles, climate change cannot be ruled out.

"Our results do not mean that temperature is the only or the main factor driving the increase in malaria, but that it is one of many factors that should be considered," Pascual said. The new study is slated to be published online this week in the Proceedings of the National Academy of Sciences.

After being nearly or completely eradicated in many parts of the world, malaria still affects hundreds of millions of people worldwide and has been on the rise in some highland regions and desert fringes. Because the life cycle of the mosquito that transmits malaria and the microorganism that causes the disease are extremely sensitive to changes in temperature, some scientists have speculated that rising average temperatures may be making conditions more favorable for mosquitoes and pathogen development, leading in turn to the surge in malaria cases.

But a 2002 study found no significant changes in average temperature in the highlands of East Africa, where malaria has become a serious public health problem, prompting its authors to dismiss the malaria-climate link. Not all scientists were convinced, however, and the topic has been hotly debated over the past four years.

Pascual revisited the question, using updated temperature data and improved analysis techniques. The result?

"I did find evidence for an increase in temperature, which the authors of the previous paper said was not there," Pascual said. The increase was small---half a degree over the period from 1950 to 2002---but using a mathematical model, Pascual and coworkers showed that even such slight warming could have biological consequences.

"We showed that a small increase in temperature can lead to a much larger increase in the abundance of mosquitoes," she said. "And because mosquito abundance is generally quite low in these highland regions, any increase in abundance can be an important factor in transmission of the disease."

In the current study, the researchers looked only at the link between temperature and mosquito abundance, not at malaria statistics. In future work, Pascual plans to incorporate malaria data and to explore the interaction of various factors that may affect the spread of malaria.

"I think it's reasonable to assume that these factors are not independent," Pascual said. "It's important to understand how they interact and also to see if we can determine their relative importance. This is a very polarized field, in terms of supporting or not supporting the role of climate versus other factors. We don't want to contribute to the polarization, which I think is very unproductive in terms of the science. I hope we can move from this sort of debate into a more constructive one about interactions and relative roles of all the factors that may be contributing to the resurgence of malaria."

Surprising genetic differences found in southern house mosquito

Sun, 26 Feb 2006 17:22:37 PST

( from http://www.rxpgnews.com ) The southern house mosquito, found everywhere in the tropics and subtropics, is actually composed of genetically different strains, according to a team of researchers led by a scientist from The Academy of Natural Sciences.

This research helps medical entomologists and doctors understand why certain infectious diseases occur in parts of the world but not in others depending on the presence of the disease-transmitting mosquito strains.

In a paper published in the February issue of the American Journal of Tropical Medicine and Hygiene, Dr. Dina Fonseca and her team identified different strains of the southern house mosquito (Culex quinquefasciatus). Until now, researchers were unaware that this one species of mosquito could have consistent variations in its genetic makeup and that the geographical distribution of the mosquito variants explained the occurrence of serious diseases. The diseases include elephantiasis (a disfiguring disease), West Nile virus and other encephalitides, avian malaria and poxvirus. "The surprising thing is that there is actually structure in this mosquito. Researchers had thought that all populations of this mosquito were the same," explained Fonseca, who was the first to examine the genetic makeup of this important disease transmitter.

Frog secretion holds promise as mosquito repellent

Sat, 25 Feb 2006 09:54:37 PST

( from http://www.rxpgnews.com ) The secretions of a bottle-green Australian frog could be used in future mosquito repellents as it is effective at warding off the insects, say scientists.

Researchers at the University of Adelaide gave mice the secretions of the dumpy tree frog and found them remaining bite-free for around 50 minutes compared to 12 minutes for an untreated group, the BBC's online edition reported.

However mice given Deet, the chemical that is used in commercial mosquito repellents, were protected for up to two hours, the study published in the Biology Letters journal said.

The researchers said the frog secretions should not yet be considered as an alternative to Deet, which was originally formulated for the US army after the Second World War.

They said such repellents (based on secretions of the frog) would only have a limited effect in fighting malaria, which is spread by mosquitoes and is responsible for one million deaths a year.

But they said: "The discovery highlights the potential of the unsung properties of amphibian skin."

The research team also found two other Australian species - the desert tree frog and Mjoberg's Toadlet - released mosquito repellent odour from their skin, although their secretions were not tested on mice.

Researchers chose to investigate the frogs because previous research had uncovered that their secretions could act as powerful painkillers and hallucinogens.

New tool can predict malaria epidemics up to five months in advance

Wed, 08 Feb 2006 11:20:37 PST

( from http://www.rxpgnews.com ) A new tool to predict epidemics of malaria up to five months in advance has been developed by a scientist at the University of Liverpool.

The model uses predictions of climate variability to indicate the level of risk of an epidemic up to five months in advance of the peak malaria season the earliest point at which predictions have ever been made. The model will assist doctors and health care providers in preventing and controlling the disease.

Malaria is one of the world's deadliest diseases, killing more than one million people every year, as well as infecting a further 500 million worldwide. The mosquito-borne illness is endemic in several regions globally, but is most acute in Africa, home to an estimated 90 per cent of all cases.

Dr Andy Morse from the Department of Geography and colleagues from the European Centre for Medium Range Weather Forecasting; Columbia University, New York and the Ministry of Health in Botswana, based their early-warning model on population vulnerability, rainfall and health surveillance data and then used forthcoming season forecasts for rainfall to predict unusual changes in the seasonal pattern of disease in Botswana. The team based their study on Botswana as its climate makes it susceptible to malaria epidemics.

Dr Morse said: "The risk of an epidemic in tropical countries such as Botswana increases dramatically shortly after a season of good rainfall when the heat and humidity allow mosquito populations to thrive. By using a number of climate models, we were able to compose weather predictions for such countries, which could then be used to calculate the severity of an epidemic, months before its occurrence."

The team created a prediction system using seven, state-of-the-art, global climate models which produce weather forecasts up to six months in advance. The system allows researchers to assess the probable effect of weather conditions on a malaria epidemic.

Lymph nodes found to host malarial parasites

Mon, 23 Jan 2006 16:03:37 PST

( from http://www.rxpgnews.com ) Malarial parasites develop not only in the liver - as believed until now - but also in lymph nodes, says a new study.

When a mosquito infected with plasmodium bites a mammal, the immature parasites travel to the animal's liver, which until now scientists thought was the only place where they could develop.

But researchers led by Robert Ménard of Pasteur Institute in Paris found that the parasites developing in an unexpected place: the lymph nodes, according to a report published on the website of the Howard Hughes Medical Institute (HHMI).

The researchers infected mosquitoes with fluorescent-tagged plasmodium parasites and then allowed the mosquitoes to bite a mouse. From each mosquito bite, they found an average of 20 fluorescent parasites embedded in the animal's skin.

They found that the parasites moved through the skin in a random, circuitous path at a speed that is amongst the fastest recorded for any migrating cell. After leaving the skin, the parasites frequently invaded blood vessels. However, many of the parasites also invaded lymphatic vessels, they found.

About 25 percent of the parasites injected by the mosquito bites were drained by lymphatic vessels and ended up in lymph nodes close to the site of the bite. Their journey seemed to stop there.

Within about four hours of the mosquito bite, many of the lymph node parasites appeared degraded. They were also seen interacting with key mammalian immune cells, suggesting that the immune cells were destroying them.

A small number of the parasites in the lymph nodes, however, escaped degradation and began to develop into forms usually found only in the liver.

Up to now, researchers believed that although both blood and lymphatic vessels take up plasmodium parasites, they all end up in the liver, Ménard said. "Nobody had proposed that they actually might stop" in the lymph nodes and develop there, he observed.

Understanding the intricacies of the mammalian immune response to plasmodium infection might help scientists create better vaccines, including vaccines that target parasites before they develop in the liver, Ménard said.

Parasite development in lymph nodes could even be one reason why there is so much tolerance to these parasites, he suggested.

Malaria Parasites Can Develop in Lymph Nodes

Mon, 23 Jan 2006 01:51:37 PST

( from http://www.rxpgnews.com ) In the first quantitative, real-time imaging study of the travels of the malaria parasite Plasmodium through mammalian tissue, researchers at the Pasteur Institute in Paris found the parasites developing in an unexpected place: the lymph nodes.

The parasites' presence in the lymph nodes almost certainly has implications for the mammalian immune response, said Robert Ménard, a Howard Hughes Medical Institute (HHMI) international research scholar who led the study.

When a mosquito infected with Plasmodium bites a mammal, the immature parasites travel to the animal's liver, which, until now, scientists thought was the only place they could develop, Ménard said. Once they have fully developed, the parasites burst out of the liver cells and infect red blood cells, beginning the onset of malaria.

Although researchers understand this life cycle, no one has measured directly how many parasites a mosquito bite transmits or where else in a mammal's body they travel, said Ménard. To find out, he and his colleagues infected mosquitoes with fluorescently tagged Plasmodium parasites, and then allowed the mosquitoes to bite a mouse. From each mosquito bite, they found an average of 20 fluorescent parasites embedded in the animal's skin. Ménard found that the parasites moved through the skin in a random, circuitous path at a speed that is amongst the fastest recorded for any migrating cell.

After leaving the skin, the parasites frequently invaded blood vessels. About 25 percent of the parasites injected by the mosquito bites were drained by lymphatic vessels and ended up in lymph nodes close to the site of the bite. Their journey seemed to stop there, as the malaria parasites almost never appeared in lymph nodes farther away.

Within about four hours of the mosquito bite, many of the lymph-node parasites appeared degraded. They were also seen interacting with key mammalian immune cells, suggesting that the immune cells were destroying them.

A small number of the parasites in the lymph nodes, however, escaped degradation and began to develop into forms usually found only in the liver. Up to now, researchers believed that, although both blood and lymphatic vessels take up Plasmodium parasites, they all end up in the liver, Ménard said. By 52 hours after the mosquito bites, no parasites remained in the lymph nodes, which suggests that they can't develop completely there, Ménard said. Only fully developed parasites can infect red blood cells and cause malaria, so the lymph-node parasites probably don't contribute to the appearance of malaria symptoms, he added. But even partially developed or destroyed parasites could significantly affect how the immune system responds to infection, he noted.

Another unexpected finding adds even more complexity to the mammalian immune response to the malaria parasite. This second influx of parasites could prompt a somewhat different immune response in the host, and those parasites might have different fates. Parasites developing in the lymph nodes could have two opposite effects on the body's immune response, he explained. They might alert the body that an invader is present and activate a protective immune response. Understanding the intricacies of the mammalian immune response to Plasmodium infection might help scientists create better vaccines, including vaccines that target parasites before they develop in the liver, Ménard said. Parasite development in lymph nodes could even be one reason there is so much tolerance to these parasites, he suggested.

How Plasmodium falciparum sneaks past the human immune system

Thu, 29 Dec 2005 16:22:38 PST

( from http://www.rxpgnews.com ) The world's deadliest malaria parasite, Plasmodium falciparum, sneaks past the human immune system with the help of a wardrobe of invisibility cloaks. If a person's immune cells learn to recognize one of the parasite's many camouflage proteins, the surviving invaders can swap disguises and slip away again to cause more damage. Malaria kills an estimated 2.7 million people annually worldwide, 75 percent of them children in Africa.

Howard Hughes Medical Institute (HHMI) international research scholars in Australia have determined how P. falciparum can turn on one cloaking gene and keep dozens of others silent until each is needed in turn. Their findings, published in the December 28, 2005, issue of Nature, reveal the mechanism of action of the genetic machinery thought to be the key to the parasite's survival.

A DNA sequence near the start of a cloaking gene, known as the gene's promoter, not only turns up production of its protein, but also keeps all other cloaking genes under wraps, according to Alan Cowman and Brendan Crabb, HHMI international research scholars at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, and their co-authors. "The promoter is all you need for activation and silencing," Cowman said. "It's the main site of action where everything is happening."

Malaria parasites enter human blood from infected mosquitoes. The organisms invade and promptly remodel red blood cells. They decorate the surface of the cells they occupy with a protein called PfEMP1, made by the var gene family.

Using this versatile surface protein, the parasite evades the host's immune system using two basic strategies. First, the protein sticks infected red blood cells to the blood vessel lining, removing the infected cells from circulation, where they would probably be destroyed.

But the protein cannot protect the parasite from patrolling immune cells, which eventually detect the invader and recruit troops to fight it. So, during a malaria infection, a small percentage of each generation of parasites switches to a different version of PfEMP1 that the body has never seen before. In its new disguise, P. falciparum can invade more red blood cells and cause another wave of fever, headaches, nausea, and chills.

"It's like a leopard being able to change its spots," Cowman said. "New forms come up, and the immune system beats them down again. Because of this a lot of people think you need five years of constant exposure to malaria in its different disguises to gain immunity."

Many children do not survive malaria long enough to develop immunity. And without continuous exposure, hard-won immunity may disappear. For example, adults in Papua New Guinea who move to work in the mining industry, which is in mountainous regions that are mosquito-free, lose their immunity within a short time, he said.

The diverse genetic sequences of the 60 var cloaking genes all code for remarkably similar protein structures, the malaria researcher added. The genes are generally found at the ends of P. falciparum's 14 chromosomes, although some of them cluster in internal regions.

In April 2005, Cowman, Crabb, and colleagues showed that var genes are regulated by the chromosome packaging, which unwraps one gene to be expressed at a time and literally packs away the inactive genes. In chromosomes, DNA can be encased so securely by some proteins that other proteins cannot access the nucleic acid for transcription, a process known as epigenetic silencing.

In their new paper, the researchers show that the activation of a var gene promoter is all it takes to trigger both the production that gene's protein and the epigenetic silencing of the 59 other var genes. As in a previous study, they found that the physical location of the promoter within the nucleus seems to make a difference. The genetic activity occurred at the edge of the nucleus, with the activated promoter surrounded by chromosome ends containing silenced var genes.

To do this research, the scientists had to master the difficult technique of cloning large DNA sequences with a var promoter attached to various genes, inserting them into plasmid vectors, and introducing them into red blood cells infected by malaria parasites.

In one experiment, they set up a system where var gene expression could be studied using drug selection rather than the immune pressure that is normally needed to select variants in the field. Using this system they found that the information required for switching var genes on and off was contained within a promoter and that when active this could silence all of the var genes in the parasite.

"This is the first time anyone has actually been able to infiltrate an antigenic variation program," Cowman said. "We forced the cell to switch our gene on and others off." Their system can be used to study blood samples from people in the field to determine how they gain immunity over time.

Kirk Deitsch's lab at Cornell University found that a piece of shared DNA--discarded in the process of translating the protein from its genetic instructions--was a key regulator of var gene silencing and activation. The HHMI researchers confirmed that this gene segment caused tighter packaging for the silenced genes, but they also showed that it wasn't vital.

The researchers are continuing to disassemble the var gene machinery, piece by piece. They want to identify the proteins that unpack and activate the promoter region and learn more about the other proteins in the nuclear compartment that make it the prime spot for var gene activation. Eventually, they think their work may lead to new types of therapies that interfere with the parasite's immune evasion strategies.

Evaluating Host Genetic Factors For Malaria Risk

Tue, 08 Nov 2005 17:47:38 PST

( from http://www.rxpgnews.com ) Malaria parasites invade human red blood cells, and it had already been recognized in the 1940s that diseases of red blood cells such as thalassemia and sickle-cell anemia, which are the most common group of genetic disorders in humans, are mainly found in populations exposed to malaria and their descendants. It seems that much of the genetic variation that affects the phenotype of red blood cells appears to have evolved due to natural selection by malaria. Susceptibility to malaria is also thought to be determined by genetic variation in the human immune system. We know less about the specific immune system genes involved, but this is an important area of research because researchers hope that understanding the molecular basis of natural immunity will speed up the development of an efficient malaria vaccine.

Rather than focusing on the identification of specific genes and gene variants, Margaret J. Mackinnon and colleagues are interested in the relative contributions of host genetics and other factors to the risk of malaria. To estimate the overall contribution of genetic factors to the difference in disease incidence between individuals within a population, one needs three types of data: (1) disease incidence for individuals over a certain period of time (to be able to determine an individual's risk), (2) information on genetic relatedness of the individuals in the population, and (3) a setup in which individuals with different levels of relatedness share the same environment and/or where related individuals live in different environments. (The third condition is essential to distinguish between genetic and environmental effects.)

Mackinnon and colleagues studied two populations of children from a malaria-endemic area in Kenya for which they could obtain the necessary data. In one case, they determined incidence of mild clinical malaria in 640 children over a period of five years. Genetic relatedness between the children was determined by verbal interviews with their mothers. A typical household (i.e., shared environment) consisted of a group of three to six adjacent houses. Within each household, the children formed several full-sibling, half-sibling, and first-cousin groups. The second study monitored severe malaria that led to hospitalization and nonmalaria hospitalizations in 2,900 children, also over a five-year period. This analysis concentrated on full-siblings.

Using a standard statistical genetics method of relating similarity in phenotype to similarity in genotype, they found that host genetic factors accounted for approximately one-quarter to one-third of the total variation in susceptibility in the populations to malaria. Of this percentage, only a small proportion could be attributed to the best known malaria resistance genes. This is consistent with other studies that suggest that malaria susceptibility is under the control of many different genes, with each individual gene having a relatively small epidemiological effect.

When assessing the contribution of household factors, the researchers found that for mild clinical malaria, those factors accounted for slightly more than a quarter of the total variation. For hospitalized malaria, they contributed about 15%, and for hospitalizations with fever that turned out not to be malaria, they contributed approximately 35%. Overall, children living in the 10% of households with the highest malaria incidence had approximately twice as many infections per year than those living in the 10% of households with the lowest incidence.

The researchers do not question the long-term benefits of understanding the genetic factors but conclude that âidentifying and tackling the household effects must be the more efficient route to reducing the burden of disease in malaria-endemic areas.â Factors such as suitable conditions for mosquitoes to breed and survive as well as human behavior are likely to play major roles. âWe need to determine what makes the difference between low-risk and high-risk households,â Mackinnon says, âbut whatever it is, it seems likely to be an easy target using tools such as education and the low-cost, low-tech devices that we already have at hand such as bed nets, residual indoor spraying, and cleaning up backyards for mosquito breeding sites.â

Genes determine mosquitoes feeding habits

Thu, 20 Oct 2005 22:59:38 PST

( from http://www.rxpgnews.com ) Entomologists have isolated three key genes that determine when female mosquitoes feed on blood and when they decide to switch to an all-sugar diet to fatten up for the winter.
David Denlinger, professor of entomology at Ohio State University, hopes this discovery will lead scientists to other genes that help the mosquitoes survive cold weather in particular, those genes related to how insects handle the West Nile Virus when they enter a kind of hibernation.

Denlinger and Rebecca Robich, a former doctoral student at Ohio State and now a research fellow at the Harvard School of Public Health, published their findings in the online edition of the Proceedings of the National Academy of Sciences.

Only female mosquitoes draw blood, and only females survive the winter. Proteins in the blood they suck from humans and other animals enable the mosquitoes to produce eggs, and the sugars which they eat in the form of rotting fruit or nectar let them double their weight in fat so they can survive without food until the next spring.

As the days begin to get shorter, two genes that code for digesting blood switch off, and a different gene for digesting sugar and retaining fat switches on.

Normally mosquitoes are out taking blood from you and me, but when they're programmed to begin this hibernation phase we call diapause, the blood response shuts down. They can't tolerate a blood meal at that time. They switch completely to sugar, so that's a pretty dramatic metabolic shift, Denlinger said. Denlinger and Robich compared the genes expressed in the normal females to the ones that had entered diapause. After only a few days in short-light conditions, the mosquitoes that had entered diapause stopped expressing two genes for blood digestion, and started expressing one for sugar digestion and fat retention.

We are just beginning to understand the genes that regulate diapause, Denlinger said. The genes for these digestive enzymes provide a kind of marker, so you can detect whether an insect is in diapause, but I think other genes are the ones that cause diapause to begin.

Understanding these genes is important, he said, because scientists suspect that mosquitoes have some genetic trick for controlling the West Nile Virus when they enter diapause.

There are suggestions that the virus survives through the winter, inside the bodies of these females, he said. When the mosquito goes dormant, we think something in its body causes the virus to go dormant, too. The virus stops replicating, then starts replicating again in the spring when the mosquito leaves dormancy.

Whether scientists could use this information to manipulate mosquito populations to control the spread of West Nile will take years to find out, he added.

Drug Combo Against AIDS-Related Infections Also Prevents Malaria

Wed, 19 Oct 2005 20:54:38 PST

( from http://www.rxpgnews.com ) A drug combination used to prevent pneumonia and opportunistic bacterial infection in persons with HIV/AIDS has unexpectedly been found to be highly effective at preventing malaria, according to a study published in the November 15 issue of The Journal of Infectious Diseases, now available online.

The combination, trimethoprim-sulfamethoxazole (TS), is known to reduce morbidity and mortality from certain opportunistic infections in HIV-infected individuals, and is widely recommended for individuals with advanced disease, both in developed and developing countries. In addition, TS shares many properties--including resistance patterns--with a leading anti-malarial therapy, sulfadoxine-pyrimethamine (SP), causing concern that widespread use of TS prophylaxis might increase the number of malarial parasite strains resistant to SP treatment, thereby increasing the risk that SP treatment may fail in HIV-infected individuals who contract malaria.

These concerns prompted Christopher V. Plowe, MD, MPH, and colleagues at the University of Maryland School of Medicine and the Malaria Research and Training Center at the University of Bamako to conduct a study to determine whether TS prophylaxis impairs SP efficacy for treating malaria. The investigators studied 160 children (aged 5-15 years) given TS prophylaxis and 80 children in a control group receiving no preventive treatment in Mali, where malaria is endemic and rates of HIV infection in children are low. Plowe and colleagues were expecting to compare the success of SP treatment on malarial episodes in both groups. What they encountered, however, was just a single clinical episode of malaria in the TS group, and the infected individual had an adequate clinical and parasitological response to SP. In the control group, there were 72 episodes of malaria and three instances of SP failure.

Lack of malarial episodes in the TS group precluded meaningful comparison of SP efficacy in the TS and control groups, but, importantly, TS was shown to be a highly effective prophylactic agent against malaria in this population, reducing the incidence by 99.5%.

In addition to being protected against malaria, children in the TS group also experienced fewer gastrointestinal illnesses and had slightly higher hemoglobin levels than those in the control group. The authors pointed out that such benefits did not mean that routine TS prophylaxis should be used in healthy children but that they did mitigate concerns about TS use in HIV-exposed children whose HIV status is not yet known.

Although the authors cautioned that studies of SP efficacy in persons taking TS prophylaxis are still needed and that SP should be used only with caution in those taking TS who contract malaria, based on the results of this study and the clear evidence that TS prevents death in persons living with HIV in a variety of African settings, concerns about spreading SP resistance do not justify further delays in implementing TS prophylaxis.

Mosquito sexing technique promosing in malaria control

Tue, 11 Oct 2005 00:58:38 PST

( from http://www.rxpgnews.com ) Scientists have genetically modified male mosquitoes to express a glowing protein in their gonads, in an advance that allows them to separate the different sexes quickly.

By providing a way to quickly sex mosquitoes, the advance paves the way for pooling large numbers of sterile males which could be used to control the mosquito population.

Research published online today in Nature Biotechnology, shows how a team from Imperial College London have altered male mosquitoes to express a green fluorescent protein in their gonads. Coupled with a high speed sorting technique, scientists will be able to identify and separate the different mosquito sexes much more easily than by manually sorting.

Professor Andrea Crisanti, senior author of the paper, from Imperial College London, said: "This advance could have enormous implications for controlling mosquito populations. Now that we can identify males and females at an early stage, it will be possible to release sterile males into the population without the risk of releasing additional females. The release of sterile males has proven effective in controlling several insect pests when methods for sorting sex are available.

"Female mosquitoes are responsible for spreading malaria, and also for damage to crops, but they are only able to breed once before dying. By forcing females to breed with sterile males, we can stop them creating additional mosquitoes and at the same time, reduce the population."

The team used the mosquito Anopheles stephensi, the mosquito responsible for much of the malaria in Asia. They engineered the mosquito larvae to express an enhanced green fluorescent protein (EGFP). The modified larvae were mixed with normal larvae, and the researchers were able to identify the modified male mosquitoes by their fluorescent gonads.

When the genetically modified mosquitoes were mixed with normal male and female mosquitoes, they found the females were as likely to breed with the modified mosquitoes as they were with the normal ones.

This work builds on earlier work by the Imperial team published in 2000, demonstrating for the first time the insertion of a foreign gene into the mosquito genome. This raised the possibility that genetic manipulation could be used as a control method in mosquito populations.

Professor Crisanti adds: "Although there have been a number of control programmes to eradicate malaria, none of these have been entirely successful, and many have also had side effects, such as environmental damage through insecticides. This advance could one day make a major impact on the burden of ill health caused by malaria, and is another step towards how genetic modification can be used safely to deal with global problems."

Intermittent Prophylaxis Prevents Malaria in Infants

Thu, 06 Oct 2005 15:30:38 PST

( from http://www.rxpgnews.com ) Giving infants preventive treatment for malaria can reduce malaria and anaemia even in seasonal, high transmission areas such as Ghana, finds a study in recent BMJ.

But concern exists about a possible rebound when treatment is stopped, warn the authors.

The study followed over 2,400 infants in Ghana who were given a preventive treatment for malaria or a placebo (dummy pill) when they received routine vaccinations and at 12 months of age.

Preventive treatment reduced malaria by 25% and anaemia by 35% up to age 15 months. However, malaria levels increased 20% when treatment was stopped in the second year of life.

The protective effect was also substantially lower than that reported from previous studies in Tanzania.

Because these findings run counter to earlier studies, the authors suggest that more data are needed to decide on the appropriate dose schedule for preventive drugs in areas with high seasonal transmission and its interaction with insecticide treated bed nets.

However, intermittent preventive treatment in infants, linked to the expanded programme of immunisation schedule, has the potential to reduce the burden of malaria even in areas with high seasonal transmission, they conclude.

Tracking how the malaria pathogen destroys the host cells

Fri, 23 Sep 2005 15:12:38 PST

( from http://www.rxpgnews.com ) By specially tagging the outer and inner membranes of red blood cells infected with the malaria parasite and tracking the cellular changes that precede the cell bursting event that disperses parasites to other blood cells, a group of researchers has deepened our understanding of how the malaria pathogen destroys the cells in which it resides. The work is reported in Current Biology by Joshua Zimmerberg and colleagues at the U.S. National Institutes of Health.

Malaria devastates humanity: Approximately every 10 seconds, another child dies as a result of a malarial infection. Globally, it is the third biggest killer, and it mostly kills children. The emergence of all-drug-resistant strains of Plasmodium falciparum, the parasite responsible for most human malarial disease, is a frightening new reality that mandates aggressive research to develop new vaccines and drugs, particularly to uncover new targets for therapeutic agents. A major area of current ignorance is the mechanism by which parasites are released from the infected red blood cells within which they multiply.

To learn more about this release process, in their new work the researchers used high-quality microscopy and a "Nan crystal" fluorescent tag that allowed them to follow the behavior of membranes of infected cells during an extended period of time. The authors discovered that many minutes before release, infected cells look irregular, resembling a fried egg, with the parasites bunched together in the center. They found that just prior to release, cells round up and become very symmetric, resembling a flower, with the parasites (present beneath the cell-membrane surface) appearing like the petals.

The researchers showed that at the seemingly explosive event of release itself, cellular membranes fold upon themselves and bubble into small vesicles, allowing the newly born parasites (in this stage they are called merozoites) to infect neighboring red blood cells. Further experiments involving labeled membrane components showed that there is no membrane fusion during release, but that instead it is likely that a build-up of pressure occurs inside the cell, causing cell-membrane rupture and subsequent merozoite release. This idea was substantiated by experiments showing that shrinking cells to prevent their bursting stopped the release stage and thus stopped the infection from further development.

Clues to the Evolution of the Malarial Chromosome

Tue, 13 Sep 2005 15:59:38 PST

( from http://www.rxpgnews.com ) Understanding the recombination patterns across a chromosomedetermining the positions and frequency of genetic exchanges between homologous chromosomesis crucial for understanding and tracking inheritance of traits. Mapping genes that affect parasites' traits, such as responses to various antimalarial agents, is possible because, during meiosis, homologous chromosomes line up and may exchange segments. Genesor any polymorphic bits of DNAthat are close together tend to remain linked during this process, while those far apart tend to become separated. Identifying and following polymorphic markers through multiple generations is a key technique for genetic mapping.

For Plasmodium falciparum, the microbe that causes malaria, chromosomal mapping is necessary for understanding the evolution of the parasite and development of drug resistance, but multiple factors make this a complex task. In this issue, Jianbing Mu and colleagues use single nucleotide polymorphisms (SNPs) to evaluate some of these factors, and set the stage for further mapping of this important parasite's genome.

The authors began by locating 183 SNPs spaced across Chromosome 3 in 99 P. falciparum populations from throughout the world. Not all SNPs were found in all populations, indicating a more recent evolutionary origin for some SNPs; these differences were then used to track evolution and migration in parasites. Statistical analysis of the SNPs allowed the populations to be parsed into five groups, largely corresponding to continents. More refined analysis of the SNPs revealed possible migratory history, including a recent migration of an African variety to coastal South America.

Mu and colleagues also showed for the first time that the historical rate of recombination varies widelyover 20-foldamong different populations. A large part of the variation is due to a combination of the frequency of infections with multiple parasite strains (because sexual recombination occurs only within an infected mosquito) and the degree of inbreeding within a parasite population. Inbreeding tends to lower the extent of detectable recombination events, while multiple infections by different strains increase it.

Despite the wide differences in recombination rates, all populations had a similar clustering of recombination hot spots at the middle and ends of the chromosome. Recombination is most likely to occur at these spots, and the similar localization reflects either the common evolutionary history of all the populations or localization of crossover events to particular genomic regions.

The authors compared their results from population structure analysis with those using SNPs from genes that might be influenced by drug pressure. Their results showed that misleading inferences about the parasite population structures could be derived using information from genes that are potentially under drug selection.

These results are important because they provide information on the multiple complex factors that must be considered in understanding the genomic structure of P. falciparum, which is critical for identifying genes that contribute to phenotypes such as drug resistance and virulence. Reseachers conducting future mapping studies will be able to draw on the important findings and caveats revealed by this work to refine their own methods and interpret their results.

How Plasmodium breaks in to blood cells

Tue, 30 Aug 2005 01:16:38 PST

( from http://www.rxpgnews.com ) Plasmodium falciparum, the most lethal malaria parasite, is a housebreaking villain of the red blood cell world. Like a burglar searching for a way in to his targeted premises, the parasite explores a variety of potential entry points to invade the red blood cells of its human victims. When a weak point is found, the intrusion proceeds.

Scientists have known about the parasite's housebreaking habit for a decade, but just how it breaks in to blood cells has been unknown.

Now, an international team of scientists, led by WEHI's Professor Alan Cowman, has discovered the gene - known as PfRh4 - that the parasite uses as a tool to switch between potential invasion points. More specifically, the gene provides the parasite with the ability to switch from receptors on red blood cells that contain sialic acid to those that do not.

In effect, if the gene finds all the doors locked, then it will try all the windows until it finds one it can force open.

The team who performed the research work consisted of Janine Stubbs, Ken Simpson, Tony Triglia, David Plouffe, Christopher J. Tonkin, Manoj T. Duraisingh, Alexander G. Maier and Elizabeth Winzeler. Professor Cowman and his team at WEHI worked with researchers from the Scripps Research Institute (TSRI) in La Jolla, California and the Genomics Institute of the Novartis Research Foundation in San Diego, California.

This discovery made by the group will have a profound impact upon the design of new anti-malarial vaccines, since the inactivation of this single protein could block multiple entry points currently open to the parasite.

Artesunate shown to be more effective than Quinine in severe malaria

Sat, 27 Aug 2005 03:40:38 PST

( from http://www.rxpgnews.com ) A drug derived from an ancient Chinese herb has been shown to reduce the risk of death from severe malaria by a third, potentially saving hundreds of thousands of lives in nations on our doorstep.

A trial in malaria patients from four countries has shown a clear benefit over standard treatment with quinine, says Professor Nicholas Anstey of the Menzies School of Health Research in Darwin, Australia, which participated in the trial in partnership with the Indonesian Ministry of Health.

The regional collaboration between the Indonesian Ministry of Health and Darwin's Menzies School of Health Research has a joint research facility in Timika in Papua province, eastern Indonesia. Hospitals in Bangladesh, Myanmar (Burma), and India also participated in the study, which was coordinated by the Wellcome Trust Unit in Bangkok, Thailand.

The results of the trial are reported in the latest edition of the international medical journal, Lancet, which is published today.

Quinine has been the standard drug for the treatment of severe malaria in most countries, Professor Anstey said. This new trial clearly shows that artesunate, derived from sweet wormwood, or Artemisia annua, has fewer side effects and is more effective than quinine in preventing death in adults with severe malaria.

In total, 1461 patients with severe malaria were treated with either quinine or artesunate. Of these, 20% were enrolled at the Indonesian Ministry of Health/Menzies field site in Papua province.

There were a third fewer deaths among those receiving artesunate: 15% of seriously ill patients died compared to 22% of those treated with quinine.

"Falciparum malaria, the most severe form of the infection, is a major cause of death in our region. At least 120 million cases of falciparum malaria occur in South East Asia each year," Professor Anstey said.

"The reduction in mortality from severe malaria associated with artesunate therapy is excellent news for the poorest communities of the region," he said. "This is the first time that any drug has been demonstrated to be better than quinine at saving lives since the latter was first introduced into Europe nearly 400 years ago."

As a result of this study the Indonesian Ministry of Health has already decided to change national drug policy for treatment of severe malaria from quinine to artesunate.

"The major aim of our collaborative studies in Papua with the Indonesian Ministry of Health is to improve the treatment of malaria and to provide information to policy makers," Professor Anstey said. "We were pleased that the participation of the Indonesian Ministry of Health/Menzies field site in this multi-centre study has contributed to national policy change."

Professor Anstey said a key feature of the trial was the collaboration of dozens of investigators in the four Asian countries, coordinated by Dr Arjen Dondorp and Professor Nick White at the Wellcome Trust Unit at Mahidol University in Bangkok.

The Principal investigator from the Indonesian Ministry of Health was Dr Emiliana Tjitra. The Indonesian Ministry of Health and Menzies School of Health Research contributed a joint team of 13 staff at their research site in Papua Province.

The trials, conducted between June 2003 and May 2005, were funded by a grant from the Wellcome Trust and coordinated as part of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme funded by the Wellcome Trust of Great Britain.

PfRh4 gene expands malaria's invasion options

Fri, 26 Aug 2005 09:20:38 PST

( from http://www.rxpgnews.com ) The malaria parasite Plasmodium falciparum uses different pathways to invade red blood cells, evading the body's immune system and complicating efforts to create effective vaccines against the disease. A research team led by Australia's Alan F. Cowman, an international research scholar with the Howard Hughes Medical Institute, has identified a gene that the parasite uses to switch back and forth between invasion pathways.

Researchers from the Scripps Research Institute in La Jolla, California, and the Genomics Institute of the Novartis Research Foundation in San Diego contributed to the work, which was published in the August 26, 2005, issue of Science.

P. falciparum causes the most lethal form of malaria, which results in one million deaths a year worldwide.

Some P. falciparum strains invade red blood cells via protein receptors on the surface that contain a sugar known as sialic acid. If scientists treat blood cells with an enzyme to remove sialic acid, the parasite can no longer invade. Other strains including one called W2mef can invade using the sialic acid receptors, but also have the ability to switch to other pathways if necessary.

"It's a bit like someone trying to get into a house with different doors," says. Cowman of The Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, and the study's senior author. "When you remove sialic acid, you block half the doors. W2mef normally goes in through the receptors with sialic acid, but it can switch so it has two methods of entry."

To investigate how the parasite manages to switch to an alternative mode of blood cell invasion, Cowman and colleagues produced lines of the W2mef parasite that used sialic acid for invasion, and lines that could invade without it. Then they compared the differences in gene activity between the two types and identified two genes that warranted further study.

The team found only two genes whose activity differed between parasites that used sialic acid and those that did not. The first of these was a gene known as P. falciparum reticulocyte-binding like homolog 4 (PfRh4) that's similar to other genes known to play a role in the invasion of red blood cells by P. falciparum and related parasites. The second gene, EBA165, did not appear to produce a functional protein, and the scientists suspect it had been activated only because it was physically adjacent to PfRh4. Using a second, more quantitative approach, the team found that the two genes were 60- to-80 times more active in the sialic acid-independent parasites than in those that needed the sugar for cell entry.

These results suggested that activation of the PfRh4 gene was required for the parasite to make the switch to sialic acid-independent invasion. Indeed, the team was able to find PfRh4 protein in sialic acid-independent parasites, but not in the sialic acid-dependent lines. And when the group constructed parasites in which the PfRh4 gene was disrupted, they found that those parasites would not grow in the absence of sialic acid, although they grew normally on cells with the sugar further suggesting that activation of the PfRh4 gene is required for switching from sialic acid-dependent to independent invasion.

"Activation of PfRh4 represents a previously unknown mechanism to switch invasion pathways and provides P. falciparum with exquisite adaptability in the face of receptor changes and immune system responses," the team concluded.

The results have important implications for the design of anti-malaria vaccines. The molecule on the parasite that binds to sialic acid receptors on host cells is considered a target in anti-malaria medications, but Cowman notes that if only that gene is blocked, some parasites can still use PfRh4 to switch to other means of entry. "If both genes are disrupted, it blocks both ways of getting in," he says.

Measuring Hidden Parasites in Falciparum Malaria

Wed, 24 Aug 2005 23:22:38 PST

( from http://www.rxpgnews.com ) Approximately 40% of the worlds population, mostly living in the worlds poorest countries, is at risk of malaria. In the tropical and subtropical regions of the world, malaria causes 300 million acute illnesses and at least 1 million deaths annually. Ninety percent of these deaths occur in Africa, south of the Sahara, mostly among young children.

To assess disease severity, peripheral blood parasitemia is measured, but this is only a weak predictor of mortality in falciparum malaria. In addition, a microscopist is only able to count the less pathogenic circulating stages of the parasite, whereas the more pathogenic parasitized erythrocytes, sequestered in the capillaries and containing mature parasites, are not seen and therefore not counted. However, sequestered Plasmodium falciparum parasites secrete Histidine-rich protein 2 (PfHRP2), which is liberated into the plasma at schizont rupture.

In this months PLoS Medicine, Arjen Dondorp and colleagues suggest that the plasma concentration of this protein might provide a better estimate for the patients total parasite biomass and therefore be a more accurate prognostic indicator than circulating parasite load. There is evidence to support this hypothesis. A recent study by the same team measured PfHRP2 in P. falciparum cultures, and showed that approximately 89% of PfHRP2 is liberated at schizont rupture and that the variation in the amount released is limited.

In the current study the researchers measured plasma PfHRP2 concentrations in 337 patients with varying severity of falciparum malaria and, using a simple mathematical model, estimated the total body parasite biomass. This value was compared with measures of disease severity and outcome. The developmental stage distribution of circulating parasites, which also provides information on the sequestered parasites, was also evaluated in relation to plasma PfHRP2 levels in these patients.

The researchers found that the estimated geometric mean parasite burden was more than six times higher in patients with severe malaria than in patients hospitalized without signs of severe disease, and was highest in patients who died. Statistical analysis revealed that the estimated total parasite biomass was clearly associated with disease severity and outcome. By contrast, peripheral blood parasitemia and the number of circulating parasites were not associated with disease outcome, nor with other measures of severity such as admission plasma lactate concentrations.

The finding that sequestered parasite biomass is associated with disease severity fits with current thinking that sequestration of erythrocytes containing the mature forms of the parasite is the central pathological process in falciparum malaria.

However, the team noted there were several factors that might contribute to inaccuracies in the model. For example, the amount of PfHRP2 secreted per parasite varies between different parasite strains. Also, in high transmission areas, where partial immunity against the disease develops, clearance of PfHRP2 might be increased in the presence of antibodies against the protein; in these areassuch as countries in sub-Saharan Africathe model would thus underestimate the parasite burden and might need to be adapted further for use.

Despite these issues, estimates of plasma PfHRP2 concentrations may be useful as a research tool to stratify patients parasite loads, say the authors. They conclude that quantitative measurements of plasma PfHRP2 in patients with falciparum malaria could be used to estimate the total parasite biomass, a parameter pivotal in the pathophysiology of the disease, and that this total parasite biomass is associated with clinical measures of the severity of the disease.

LMP-420 reduces endothelial cell activation in cerebral malaria

Tue, 23 Aug 2005 20:10:38 PST

( from http://www.rxpgnews.com ) In a paper published online in PLoS Medicine researchers from Marseille describe the effects of a new compound that may be a future treatment for patients with cerebral malaria. The compound¡XLMP-420¡Xinhibits two of the molecules produced in the brain when affected by cerebral malaria.

Cerebral malaria is a complication that can occur in malaria caused by the parasite Plasmodium falciparum. In cerebral malaria, the parasites infect the red blood cells that accumulate within the very small capillaries that flow through the tissues of the brain. Even when treated, cerebral malaria has a fatality rate of 15% or more.

Using an in vitro model of cerebral malaria, the researchers, led by George Grau, found that LMP-420 potently reduced the activation of endothelial cells (cells that line the small blood vessels), how well malaria-infected red blood cells stuck to these endothelial cells, and the release of micro particles from the same cells¡Xthree major features of cerebral malaria.

The authors caution that the experimental in vitro results do not necessarily predict potential efficacy in either animal models or humans, especially since in their model the LMP-420 had to be given before the disease process was established. Nevertheless, this avenue of research is a promising one to explore further.

Fansidar could have a new lease on life as a protective malaria drug

Fri, 19 Aug 2005 13:38:38 PST

( from http://www.rxpgnews.com ) A dramatic reduction in the impact of malaria is in prospect with a clinical drug trial to begin in Papua New Guinea early next year. Success in the trial would open the way to relief in the 10% of humanity infected with this debilitating and often fatal disease over 500,000,000 people.

The Walter and Eliza Hall Institute of Medical Research is collaborating with the Papua New Guinea Institute of Medical Research (PNGIMR) and the University of Melbourne to confirm significant health benefits in the new application of an old malaria drug at just 12 cents a dose. The project is supported by a AUD$3.7 million grant to PNGIMR from the Bill and Melinda Gates Foundation.

Fansidar is a 20-year-old malaria drug. As with many other such curative drugs, its effectiveness has declined over time with increased resistance by the malaria parasite. But initial clinical evidence suggests that Fansidar could have a new lease on life as a protective drug that strengthens a person's own immune system against malaria.

Early field experiments were conducted in the African country of Tanzania in the late 1990s. These suggested that giving just one Fansidar tablet to an apparently healthy child during their routine infant immunization visits dramatically reduced the impact of any subsequent malaria infection. Used in this way, Fansidar does not prevent malaria but seems to produce a massive 50% reduction in death, debilitation and complications of malaria, such as severe anaemia and raging fevers.

Joint project leader, Dr Louis Schofield from WEHI, says, "There seems to be a totally unexpected residual immunological effect when children are given this tablet as a preventative rather than as a post-infection treatment for malaria. While the drug itself dissipates in the bloodstream over a few days, it appears to enable the immune system to re-energize and more successfully combat any subsequent malarial infection. We suspect that many toddlers who seem reasonably healthy might actually have low level malarial infections that are eliminated by Fansidar, allowing the immune system to develop to its full potential."

WEHI's Dr James Beeson adds, "Most of the 2 million or so annual deaths from malaria and much of the severe illness involves children under five years of age. Pregnant women are also highly susceptible to the effects of malaria, but the good news is that they too appear to have much greater immune protection conferred by the preventative or 'presumptive' use of Fansidar. This looks like a case of teaching an old drug new tricks or perhaps the old drug teaching us that it can perform tricks that we never suspected it could."

The four-year trial is being conducted in PNG for a number of reasons. First, PNG is a relatively confined area with a high concentration of all four types of global malaria unlike Africa, where one type predominates. Second, outstanding field researchers with clinical trial capability from the PNGIMR can collaborate with world leading Australian experts in malaria from WEHI and the University of Melbourne. Third, the organizational and public health infrastructure already exists to dispense the tablets in a controlled way, since PNG's children routinely attend clinics to be vaccinated against a range of other diseases.

To Mosquitoes, People with Malaria Smell Like Dinner

Wed, 10 Aug 2005 21:13:38 PST

( from http://www.rxpgnews.com ) Malaria is a misnomer. People used to believe that poisoned or bad air, the translation of the Italian phrase mal aria, caused disease. In the 19th century, when parasitologists figured out that single-celled parasites cause malaria, they didnt bother to change the diseases name. Experimenters proved that these parasites need a host organism to surviveso they cant be transmitted through airand that the hosts, mosquitoes, carry the parasite to humans.

Researchers were optimistic that if they could find a diseases cause, they could also find the cure. Kill the mosquitoes and eradicate malaria. And with the advent of DDT and less environmentally harmful insecticides, potent anti-malarial drugs, and international funding in the late 20th century, eradication of malaria seemed imminent.

But that expectation underestimated the flexibility of living creatures. Mosquitoes acquired resistance to insecticides while the parasites acquired resistance to anti-malarial drugs. Worse, the aggressive eradication campaign skipped over vast regions of the globe, especially sub-Saharan Africa.

Malaria remains a devastating problem in Africa for several reasons. Environmental conditions provide an amenable atmosphere for both Plasmodium falciparum, the most dangerous form of the parasite, and the Anopheles gambiae mosquito, the most effective vector. Also, many countries in sub-Saharan Africa lack the infrastructure to protect their citizens from malaria. Given the overwhelming scope of malarial infection in Africa, new understanding of the disease will help epidemiologists devise targeted anti-malarial strategies.

A new study conducted in Western Kenya by Jacob Koella and colleagues analyzed mosquito behavior to discover how it facilitates the transmission of malaria. The research determined that mosquitoes are more attracted to people infected with transmittable malaria than to either people infected with non-transmittable forms of the disease or uninfected people. To measure the attraction of the mosquitoes, the researchers set up a chamber of infected mosquitoes surrounded by tents containing the study participants. A device called an olfactometer wafted the odors of each participant toward the mosquitoes. Researchers measured which smell most attracted the hungry bugs.

This question had long stalled scientists because of contradictory and indirect evidence. Sweat, breath odor, and high body temperature all increase mosquitoes blood lust, and no previous study had isolated the variable of malarial infection.

To control for the natural variation in how attractive mosquitoes found each participant, Koella et al. compared the number of mosquitoes that were attracted to infected people to the number of mosquitoes that were attracted to those same people after they were no longer infected. The researchers found that in general, an individual attracted more mosquitoes when infected with transmittable malaria. This demonstrates that malaria, in addition to causing fever, vomiting, headache, and sometimes death, causes more mosquito bites. The biting mosquitoes will then pick up the parasite and spread it to other people.

As another control, the researchers compared infection with a non-transmittable form of the parasite to infection with the transmittable form and to no infection. A mosquito can pick up the malaria parasite only when in its sexually reproductive stage. The transmittable parasite, known as a gametocyte, multiplies in the mosquitos belly before traveling to the mosquitos salivary glands and, eventually, to the blood of the next human victim. But the malaria parasite has a complicated life cycle that also includes non-transmittable asexual stages. Koella and colleagues found that these parasitic forms, unlike the sexually reproductive form, did not make humans more attractive to mosquitoes.

Previous to the recent study, malaria researchers had proved that mosquito biting rates greatly influence the spread of malaria. Koella and colleagues showed that the parasite itself increases these biting rates when it is ready for a new host.

Controlling the spread of malaria by "perfumes"

Fri, 01 Jul 2005 13:00:38 PST

( from http://www.rxpgnews.com ) A five-year, $8.5-million dollar research project, designed to substantially reduce the spread of malaria by redirecting mosquitoes with odor cues, is being undertaken by an international team of scientists including John Carlson, the Eugene Higgins Professor of Molecular, Cellular, and Developmental Biology at Yale University.

The project is one of the 43 "groundbreaking" research projects to improve health in developing countries that have been offered a total of $436 million in support from a Grant from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative. Carlson, will work on a project with scientists at Vanderbilt University, which will administer the award, Wageningen University in the Netherlands, Ifakara Health Research and Development Centre in Tanzania and the Medical Research Council Laboratories in Gambia (Africa).

Hundreds of millions of people are infected with malaria -- and hundreds of thousands die -- annually. Female malaria mosquitoes "smell" with specialized receptors in their antennae and are drawn to particular human odors that say "dinner." After biting, while the mosquito feeds on blood that is needed for its egg production, parasites from the mosquito enter and infect the human. When an infected person is bitten again, the parasite can be transmitted to an uninfected mosquito and spread further.

The specific aim of the project is to reduce the population of malaria transmitting mosquitoes by identifying effective "perfumes" that act as attractants to traps or as mosquito repellents. Scientists at Yale and Vanderbilt will identify odors that act on mosquito receptors and create the "perfumes," and the Dutch researchers will study the mosquito behaviours that the odors elicit. Odorant blends giving the strongest reaction (attracting, repelling or causing confusion) will then be tested in a simulated natural situation in Ifakara, Tanzania. And finally, the ideal blend of odors will be sent to African villages in Gambia and Tanzania for full-scale, practical tests in different geographical extremes and mosquito populations.

The eventual products will keep malarial mosquitoes from infecting humans and will be inexpensive, safe for humans, livestock and crops, and easy to use in rural locations. It is hoped that they may also be used against other pathogenic mosquitoes, such as Aedes aegypti, which spreads dengue fever , and Culex pipiens, carrier of the West-Nile virus.

The search for compounds affecting mosquito olfaction will initially be carried out in a system, developed in Carlson's laboratory, in which the mosquito receptors are made in the antenna of genetically engineered fruit flies, Drosophila, that can be studied much more easily than the mosquito itself. In research published last year in Nature, Carlson and graduate student Elissa Hallem used the system to show that one particular mosquito odor receptor responds strongly to a component of human sweat. Such receptors will now be tested with a large collection of other compounds to identify molecules useful as attractants or repellents.

The project is based largely on earlier work carried out by the Carlson laboratory that identified the first insect odor receptors, using a novel computer algorithm, as well as the first insect taste receptors. Last year, in a study published in the journal Cell, Hallem and Carlson established a comprehensive receptor-to-neuron map of the fly's antenna.

In two studies published earlier this year in Neuron, the laboratory reported major work on the mechanism of olfaction. The first showed that two functional odor receptors can be co-expressed in one neuron, a breach of one of the most central tenets in the field of olfaction. The second identified the molecular basis of odor coding in the insect's larval stage. Much of the research was done by graduate students in Carlson's laboratory, five of whom have won awards for their Ph.D. theses in the past six years.

Immune system might be involved in Sickle cell protection against malaria

Tue, 31 May 2005 19:01:38 PST

( from http://www.rxpgnews.com ) In this month's issue of the freely available online journal PLoS Medicine, Dr. Thomas N. Williams and colleagues from Kilifi, Kenya, show that the protection against malaria given by carrying the gene for sickle cell haemoglobin may involve the immune system. Studying a group of children and adults in the Kilifi District of coastal Kenya, they found that this protection increased during childhood up to age 10, and then declined.

It is estimated that cases of malaria causes approximately a million deaths yearly, the overwhelming number of which are young children in sub-Saharan Africa. It has been known for many years that in those areas most afflicted by malaria the gene for sickle cell hemoglobin (HbS) occurs very frequently. The protection against malaria occurs in people who are heterozygote (HbAS), i.e., have one normal and one sickle gene, and previous work has suggested that there is an immune component to this protection.

To discover whether the protection provided by HbAS is innate or varies with age, the authors studied age-specific malaria in a sample of children and adults in the Kilifi District of coastal Kenya. Protection against mild malaria increased up to 60% at age 10, decreasing to 30% in older children.

Research into malaria has yet to yield an effective vaccine but this work may provide some insights for such research. The authors suggest mechanisms by which HbAS could affect immunity, for example, accelerated acquisition of antibodies to altered host proteins expressed on the malaria-infected red cell surface.

10 years before malaria vaccine is ready for widespread use

Thu, 28 Apr 2005 18:34:38 PST

( from http://www.rxpgnews.com ) A seminar on malaria in this week's issue of THE LANCET states that it will be at least a decade before a vaccine for the disease will be ready for widespread use and emphasises the need to expand the use of existing control methods.

Brian Greenwood (London School of Hygiene and Tropical Medicine, UK) and colleagues state that prevention and treatment of malaria could be greatly improved with existing methods if increased financial and labour resources were available. Combination therapies based on drugs derived from the plant Artemisia annua (ACTs) have now been adopted by many endemic countries, although cost is likely to be a problem in ensuring their widespread use. ACTs are highly effective, even in areas where there is a high level of resistance to other antimalarial drugs. (See this week's issue Lancet 365; 1467-73, Lancet 365; 1474-1480) Insecticide-treated bed-nets provide a simple but effective means of preventing malaria, especially with the development of longlasting nets in which insecticide is incorporated into net fibres and is not removed during washing.

However, the authors state that new approaches to prevention and treatment are needed including malaria vaccines. One malaria vaccine, RTS, S/AS02 has provided substantial, short-lived protection in volunteers exposed experimentally to bites by infected mosquitoes and in semi-immune adults in The Gambia exposed to natural infection. (See Lancet 2001; 358: 1927-34) In a subsequent trial in Mozambican children, the RTS, S/AS02 vaccine gave 30% protection against the first clinical episode of malaria and 58% protection against severe malaria. (See Lancet 2004; 364: 1411-20) Other promising candidates are undergoing clinical trials.

Professor Greenwood states: "Malaria vaccine research has progressed rapidly over the past few years, helped by the availability more funds and by improved organisation mediated through organisations such as the Malaria Vaccine Initiative. However, it is likely to be at least a decade before an efficacious vaccine is available for widespread use in malaria-endemic countries."

Coartem(R) is the Most Effective Available Treatment for Malaria in African Children

Wed, 27 Apr 2005 09:28:38 PST

( from http://www.rxpgnews.com ) A new study published in The Lancet suggests that the combination of artemether and lumefantrine, available from Novartis (NYSE:NVS) under the brand name Coartem(R) , is the most effective available treatment for malaria in children in areas of Africa where resistance to conventional anti-malarial drugs is high. Developed and produced by Novartis and its Chinese partners, Coartem is currently the only fixed-dose artemisinin-based combination therapy pre-qualified by the World Health Organization (WHO) for procurement by United Nations agencies.

Recently, the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria approved a grant of USD 170 million to seven African nations for the procurement of Coartem over the next two years.

"These new clinical data confirm that Coartem is the current gold standard to treat malaria in areas of high resistance to conventional anti-malarials and is as such a life-saving drug," said Dr. Daniel Vasella, Chairman and CEO of Novartis. "When combined with the most recent financing commitment from the Global Fund, these results underpin our efforts to rapidly ramp up the production of Coartem."

Since 2001, Novartis has supplied more than six million treatments of artemether-lumefantrine on a non-profit basis for distribution to the public sector in malaria-endemic developing countries. Production of Coartem, currently the leading artemisinin-based combination therapy (ACT), has increased from 100,000 treatments in 2002 to a projected 30 million treatments in 2005. The original 2001 agreement between Novartis and the WHO forecast demand for Coartem at just over two million treatments in 2005. Since then, non-binding demand forecasts provided by WHO have continuously increased, including a six-fold jump in the 2005 demand forecast between December 2003 and March 2004. In this three month period, the WHO demand forecast surged from 10 million to 60 million treatments.

Results of new study by the London School of Hygiene and Tropical Medicine In the April 23, 2005 edition of The Lancet, Dr. T. K. Mutabingwa and colleagues at the London School of Hygiene and Tropical Medicine reported on a randomised trial of anti-malarial drug combinations for children (aged 4-59 months) with uncomplicated malaria in Muheza, Tanzania. This area has a high prevalence of resistance to sulfadoxinepyrimethamine and chloroquine. Children were randomly allocated three days of amodiaquine (n=270), amodiaquine+sulfadoxine-pyrimethamine (n=507), amodiaquine+artesunate (n=515), or a three-day six-dose regimen of artemether-lumefantrine (n=519). Drugs were taken orally, at home, unobserved by medical staff. The primary endpoint was parasitological failure by day 14 assessed blind to treatment allocation. Secondary endpoints included day 28 follow-up and gametocyte carriage.

Analysis was by intention to treat. Of 3,158 children screened, 1,811 were randomly assigned treatment and 1,717 (95%) reached the 14-day follow-up. The amodiaquine group was stopped early by the data and safety monitoring board because it reached a pre-determined stopping rule of more than 40% parasitological failure by day 14. By day 14, the parasitological failure rates were 103 of 248 (42%) for amodiaquine, 97 of 476 (20%) for amodiaquine+sulfadoxinepyrimethamine, 54 of 491 (11%) for amodiaquine+artesunate, and seven of 502 (1%) for artemether-lumefantrine. By day 28, the parasitological failure rates were 182 of 239 (76%), 282 of 476 (61%), 193 of 472 (40%), and 103 of 485 (21%), respectively. The difference between individual treatment groups and the next best treatment combination was significant (p less than 0.001) in every case. Recrudescence rates by day 28, after correction by genotyping, were 48.4%, 34.5%, 11.2%, and 2.8%, respectively.

The authors concluded that there are few options for treating malaria where there is a high level of resistance to sulfadoxinepyrimethamine and amodiaquine.

Unprecedented scale-up underway The rapid scale-up underway at Novartis to meet public sector demand for Coartem is unprecedented in commercial drug production for a new chemical entity. The effort will require operation of two large scale manufacturing plants to produce more than 1.9 billion Coartem tablets -- which equates to 120 million treatments -- in 2006.

"We have already significantly increased our investments in Coartem production, including in the cultivation of Artemisia annua and the extraction of artemisinin, which is currently in short supply due to the annual planting cycle," Dr. Vasella added. "We are confident that we will succeed in increasing the available volumes to 30 million treatments by the end of the year and to 120 million treatments in 2006. While we provide Coartem at cost, our efforts would be in vain without the Global Fund's financial aid allowing governments of malaria endemic countries to purchase the drug."

Novartis said its investments are focused on expanding manufacturing infrastructure, increasing and diversifying the supplier base for the production of raw material and transitioning a largely wild crop to commercial plantation cultivation. For the first time, significant volumes of artemisinin will be produced in Africa following the 2005 harvest.

Novartis said its ability to meet 2005 Coartem production goals remains dependent upon the availability of sufficient supplies of the key natural raw material Artemisia annua and the extraction product artemisinin, and, most importantly, the timely receipt of firm Coartem orders from affected countries.

"Firm financing commitments for the purchase of ACTs is perhaps the highest return investment in improving public health that donor organizations can make today," said Professor Bob Snow, a leading scientist in the field of malaria research and public health, from Kenya Medical Research Institute, Nairobi and University of Oxford, UK. "Millions of lives can be saved through swift and decisive action that bridges the gap between enormous public demand and the realities of commercial supply for artemether-lumefantrine and other ACTs."

Novartis communicated its 2006 production goal of 120 million treatments to leading representatives of the WHO, the Global Fund for HIV/AIDS, Tuberculosis and Malaria, African health ministries and other key stakeholders in the battle against malaria at its annual Coartem Advisory Board meeting held last month in Dakar, Senegal.

About Coartem

Coartem is a highly effective and well tolerated anti-malarial that achieves cure rates of up to 95%, even in areas of multi-drug resistance. It is indicated for the treatment of falciparum malaria, the most dangerous form of malaria. Coartem is the only pre-qualified, fixed-dose ACT combining artemether, an artemisinin derivative, and lumefantrine. This fixed-dose combination is of great benefit to patients as it facilitates treatment compliance and supports optimal clinical effectiveness.

Artemisinin is a compound extracted from the sweet wormwood plant and has been used for centuries in traditional Chinese medicine to treat fever. An artemisinin-based combination therapy is a combination of two or more drugs (one of which is an artemisinin derivative) with different modes of action and different targets. Studies have shown that using two or more drugs in combination has the potential to delay the development of resistance in areas of low transmission. Artemisinin-based combination therapies in particular have been found to be highly effective treatments for malaria and their potential to delay resistance in areas of intense transmission is under investigation.

Coartem was co-developed by Novartis in collaboration with Chinese partners who also supply the active ingredients (artemether and lumefantrine). The final Coartem tablets are produced in China by Novartis. Coartem is currently registered in 79 countries worldwide and more than six million patients have benefited from this innovative treatment since its first registration in October 1998. Coartem has been extensively studied in multi-center clinical trials involving more than 3,000 patients.

Reducing Malaria Transmission in Africa

Tue, 26 Apr 2005 22:25:38 PST

( from http://www.rxpgnews.com ) There are 300 million cases of malaria each year worldwide, causing one million deaths. Around 90% of these deaths occur in Africa, mostly in young children. One of the greatest challenges facing Africa in the fight against malaria is drug resistance; resistance to chloroquine (CQ), the cheapest and most widely used antimalarial, is common throughout Africa, and resistance to sulfadoxine-pyrimethamine (SP), the first-developed and least expensive alternative to CQ, is also increasing in eastern and southern Africa.

These trends have forced many countries to change their treatment policies and use more expensive drugs, including drug combinations that will hopefully slow the development of resistance. One avenue of research is to identify combinations that minimize gametocyte emergence in treated cases and prevent selective transmission of parasites resistant to any of the partner drugs.

In this month's PLoS Medicine Colin Sutherland and colleagues tested two leading combination therapies in children with uncomplicated malaria. One regimen was an artemisinin-based combination consisting of artemether and lumefantrine (co-artemether, trade names CoArtem and Riamet). The other was a combination of CQ and SPcurrently under consideration in several African countries, largely due to its low cost. In this randomized, controlled trial, 497 children with acute uncomplicated falciparum malaria were given either a combination of CQ and SP or six doses of co-artemether (91 received CQ/SP and 406 received co-artemether), and their blood was tested for infectivity to mosquitoes seven days after treatment. During follow up at seven, 14, and 28 days the team found that children treated with co-artemether were significantly less likely to carry gametocytes in their blood than children treated with CQ and SP7.9% compared with 48.8%.

Altogether, the six-dose regimen of co-artemether was highly effective at reducing the prevalence and duration of gametocyte carriage. The numbers of gametocytes and the infectiousness to mosquitoes at day 7 were also reduced compared to a combination of CQ and SP, said the authors. Other studies have already shown the potential of co-artemether combination therapy to both cure malaria and reduce gametocyte carriage, acknowledged the authors. However, this study is the first to demonstrate the treatment's potential to markedly reduce the infectiousness of patients to mosquitoes, and has done so in a sub-Saharan African setting with highly seasonal transmission and where asymptomatic infections are common.

Do the results mean co-artemether should be introduced as a first-line treatment for malaria in Africa? The authors are hesitant and suggest there might be compliance issues with the six-dose regimen. The requirement of oily food for adequate absorption might also lead to inadequate drug levels in the blood of many treated individuals.

The authors suggest that co-artemether as a first-line treatment is not likely to reduce overall transmission of Plasmodium falciparum within the community but rather would reduce selective transmission of resistant parasites in treated patients. Hence, co-artemether could have a public health benefit by reducing the impact of drug resistance.