Malaria parasites must invade the erythrocytes of the host to be able to grow and multiply. Having depleted the host cell of its nutrients, the parasites break out to invade new erythrocytes. Researchers have discovered that a new organelle, the exoneme, which contains a protease SUB1, helps the parasite to escape from old erythrocytes and invade new ones. By scanning thousands of compounds, the researchers also found a plant-derived molecule that was able to block the SUB1 enzyme preventing the merozoites from escaping.
Subcellular Discharge of a Serine Protease Mediates Release of Invasive Malaria Parasites from Host Erythrocytes
Cell 2007 131: 1072-1083
The most virulent form of malaria is caused by waves of replication of blood stages of the protozoan pathogen Plasmodium falciparum. The parasite divides within an intraerythrocytic parasitophorous vacuole until rupture of the vacuole and host-cell membranes releases merozoites that invade fresh erythrocytes to repeat the cycle. Despite the importance of merozoite egress for disease progression, none of the molecular factors involved are known. Just prior to egress, an essential serine protease called PfSUB1 is discharged from previously unrecognized parasite organelles (termed exonemes) into the parasitophorous vacuole space. There, PfSUB1 mediates the proteolytic maturation of at least two essential members of another enzyme family called SERA. Pharmacological blockade of PfSUB1 inhibits egress and ablates the invasive capacity of released merozoites. Our findings reveal the presence in the malarial parasitophorous vacuole of a regulated, PfSUB1-mediated proteolytic processing event required for release of viable parasites from the host erythrocyte.
A quarter of the world population is infected with Toxoplasma gondii, a long-lived and common brain parasite. The normal host for this organism is the domestic cat, so maybe its not so surprising that human infections are also common. New research points to the potential impact of this normally slient pathogen:
Abstract: Chronic Toxoplasma gondii infection is known to trigger potentially adverse immunoregulatory changes, but the long-term implication for heart transplant recipients has not been assessed previously. We evaluated the risk of mortality, development of cardiac allograft vasculopathy (CAV), and acute cellular rejection among T. gondii-seropositive heart transplant (HTx) recipients and the 4 donor/recipient seropairing groups. Frozen pre-HTx serum samples of 288 recipients and 246 donors were evaluated for T. gondii serostatus. Patients had undergone prospective serotesting using alternative assays, and results determined by the 2 methods were compared. Overall, 211 recipients (73%) were seronegative and 77 (27%) were seropositive. In total, 82 recipients died, 76 developed CAV, and 82 had 1 or more episode of treated cellular rejection. Recipient seropositivity was associated with a significantly higher risk of mortality and CAV. Seropositivity did not influence the number of rejection episodes, and donor/recipient seropairing was not a risk factor for any end point.
Malaria has been a major selective force on the human population, and several erythrocyte polymorphisms have evolved that confer resistance to severe malaria. Plasmodium falciparum rosetting, a parasite virulence phenotype associated with severe malaria, is reduced in blood group O erythrocytes compared with groups A, B, and AB, but the contribution of the ABO blood group system to protection against severe malaria has received little attention. We hypothesized that blood group O may confer resistance to severe falciparum malaria through the mechanism of reduced rosetting. In a matched case-control study of 567 Malian children, we found that group O was present in only 21% of severe malaria cases compared with 44-45% of uncomplicated malaria controls and healthy controls. Group O was associated with a 66% reduction in the odds of developing severe malaria compared with the non-O blood groups. In the same sample set, P. falciparum rosetting was reduced in parasite isolates from group O children compared with isolates from the non-O blood groups. Statistical analysis indicated a significant interaction between host ABO blood group and parasite rosette frequency that supports the hypothesis that the protective effect of group O operates through the mechanism of reduced P. falciparum rosetting. This work provides insights into malaria pathogenesis and suggests that the selective pressure imposed by malaria may contribute to the variable global distribution of ABO blood groups in the human population.
African trypanosomes cause sleeping sickness, a fatal disease of humans and livestock in Africa. During their life cycle, these protozoan parasites cycle between the bloodstream of mammals and tsetse flies. Their two main developmental stages are the bloodstream form and the procyclic form in the tsetse fly. Bloodstream trypanosomes thwart their host’s immune response by periodically switching their major surface protein, the variant surface glycoprotein (VSG). When bloodstream trypanosomes are ingested by a tsetse fly, they must quickly shed the VSG and replace it with an unrelated invariant protein more suited to their survival as procyclic organisms in the fly midgut. This paper examines the mechanisms used by trypanosomes to remove the VSG during their differentiation from bloodstream to procyclic form in culture. Scientists deleted the genes for one of the trypanosome’s protease enzymes from the trypanosome genome and found that bloodstream trypanosomes could still differentiate to the procyclic form, but VSG removal was diminished. Deleting the genes for a phospholipase enzyme had a similar effect - they could still differentiate but VSG removal was impaired. When the genes for both the protease and the phospholipase were deleted, bloodstream trypanosomes could not differentiate to the procyclic form, they retained about 60% of the VSG on their surface, and they died in the differentiation medium. These results highlight the synergistic roles of these two enzymes in the differentiation process.
The organochlorine compound DDT (Dichloro-Diphenyl-Trichloroethane) was first synthesized in 1874, but its insecticidal properties were not discovered until 1939 by the Swiss scientist Paul Muller, who was awarded the 1948 Nobel Prize in Physiology and Medicine for his efforts. DDT kills by opening sodium ion channels in insect neurons, causing the neuron to fire spontaneously. This leads to spasms and eventual death. Insects with mutations in their sodium channel gene or with up-regulation of genes expressing cytochrome P450 may become resistant to DDT and similar insecticides.
In the early years of World War II DDT was used with great effect to combat mosquitoes spreading malaria, typhus, and other insect-borne human diseases among both military and civilian populations. After the war, DDT was made available as an agricultural insecticide, and its production and use skyrocketed.
In 1955 the World Health Organization began a program to eradicate malaria worldwide, relying largely on DDT. Though this effort was initially highly successful (reducing mortality rates from 192 per 100,000 to a low of 7 per 100,000), resistance soon emerged in many insect populations as a consequence of the widespread agricultural use of DDT. In the 1960s, the environmental impacts of indiscriminate spraying of DDT became known. As a persistent organic pollutant, DDT accumulated in the food chain and had severe effects on fish, amphibians, birds, and rather less well known impacts on mammals, including humans. DDT can still be found in the fat reserves of polar bears, penguins, and possibly you, thousands of miles away from where it was ever sprayed. In 1987 the US EPA classified DDT as a probable human carcinogen. DDT is also known to be an endocrine disruptor and to cause developmental problems in infants.
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In the 1970s and 1980s, agricultural use of DDT was banned in most developed countries, in 1970 in Scandinavia, 1972 in the USA, but not until 1984 in the UK. The Stockholm Convention which came into effect in 2004 outlawed several persistent organic pollutants, and restricted the use of DDT to the control of insect vectors of human diseases. After these bans, the populations of many severely threatened species, such as the American bald eagle, rebounded.
In September 2006, the World Health Organization announced that DDT will be used as one of the three main tools against malaria, and recommended indoor spraying in epidemic areas and places with high malaria transmission. USAID now funds the use of DDT overseas. DDT sprayed inside a home provides protection from mosquitoes for up to six months. New studies show that despite mosquito resistance to DDT, it also acts as a powerful insect repellent.
Malaria afflicts between 300 million and 500 million people each year. The World Health Organization estimates that around 1 million people die of malaria and malaria-related illness every year, with 90% of these deaths in Africa, mostly in children under the age of five. To put that in perspective, that is equivalent to the death toll of around ten of the nuclear bombs dropped on Hiroshima during World War II. Malaria also weakens the economies of poor countries. People who become infected cannot work or die. Infected children can suffer brain damage. The World Bank estimates that malaria costs Africa more than US$100 billion annually and this cost is growing by 1.3 per cent each year. In 2004, when Uganda publicly contemplated reintroducing DDT to fight malaria, the European Union made threats that the country’s US$32 billion agriculture exports could be at risk if tough new measures were not taken to ensure DDT residues did not find their way into food crops.
As a result of the WHO program, the number of African countries spraying DDT inside houses has exploded. Eritrea, Madagascar, Ethiopia, Swaziland, Senegal, Ghana, Angola, South Africa, Mauritius, Mozambique, Zimbabwe, Namibia, Zambia and Burkina Faso are all using the chemical. Uganda, where more than 100,000 people died from malaria in 2006, began spraying it this year in a pilot project, and Tanzania and Malawi may follow. But Rwanda, Burundi and Kenya (a major producer of pyrethrum, the main alternative to DDT) are so far refusing to adopt the use of the chemical. In 1995, South Africa stopped spraying DDT to control malaria, citing international pressures, but as soon as the ban started, the incidence of malaria rose.
DDT is cheap. Safer pyrethrum-based insecticides are 20 times more costly, often too expensive for developing countries. The price of controlling malaria in Africa has been estimated at US$1 billion per year, but foreign aid targeting the disease has never topped US$200 million.
So my question to you is this: imagine you are the president of the world, but with a limited budget. What would you do?
Parasitic infections continue to bring misery and death to millions of people in developing countries, so it is encouraging that medicine is beginning to catch up with these persistent pests. Recently, by sequencing the entire genome of two particularly troublesome parasites, scientists have come one step closer to understanding how they tick, and figuring out how to stop then in their tracks.
Draft Genome of the Filarial Nematode Parasite Brugia malayi Science 2007 317: 1756-1760
Parasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the 90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict 11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during 350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design.
Genomic minimalism in the early diverging, intestinal parasite, Giardia lamblia Science 2007 317: 1921-1926
The genome of the eukaryotic protist Giardia lamblia, an important human intestinal parasite, is compact in structure and content, contains few introns or mitochondrial relics, and has simplified machinery for DNA replication, transcription, RNA processing, and most metabolic pathways. Protein kinases comprise the single largest protein class and reflect Giardia’s requirement for a complex signal transduction network for coordinating differentiation. Lateral gene transfer from bacterial and archaeal donors has shaped Giardia’s genome, and previously unknown gene families, for example, cysteine-rich structural proteins, have been discovered. Unexpectedly, the genome shows little evidence of heterozygosity, supporting recent speculations that this organism is sexual. This genome sequence will not only be valuable for investigating the evolution of eukaryotes, but will also be applied to the search for new therapeutics for this parasite.
Apicomplexans are the pathogens responsible for malaria, toxoplasmosis, and crytposporidiosis in humans, and a wide range of livestock diseases. These unicellular eukaryotes are stealthy invaders, sheltering from the immune response in the cells of their hosts, while at the same time tapping into these cells as source of nutrients. The complexity and beauty of the structures formed during their intracellular development have made apicomplexans the darling of electron microscopists. Dramatic technological progress over the last decade has transformed apicomplexans into respectable genetic model organisms. Extensive genomic resources are now available for many apicomplexan species. At the same time, parasite transfection has enabled researchers to test the function of specific genes through reverse and forward genetic approaches with increasing sophistication. Transfection also introduced the use of fluorescent reporters, opening the field to dynamic real time microscopic observation. Parasite cell biologists have used these tools to take a fresh look at a classic problem: how do apicomplexans build the perfect invasion machine, the zoite, and how is this process fine-tuned to fit the specific niche of each pathogen in this ancient and very diverse group? Building the Perfect Parasite: Cell Division in Apicomplexa
PLoS Pathogens 3, 6, e78
River blindness (onchocerciasis) is caused by the filarial nematode Onchocerca volvulus, a parasite transmitted by Similium blackflies which breed alongside fast-flowing tropical rivers and streams. Around 37 million people worldwide are suspected to be infected with the parasite. Ivermectin (derived from the bacterium Streptomyces avermitilis), in the form of a single annual dose, is the drug that has been widely used for river blindness since 1987. Although invermectin does not kill substantial numbers of adult O. volvulus at standard doses, it prevents them releasing microfilariae and keeps skin counts of microfilariae low, preventing symptoms of the disease and transmission to others.
Researchers studied studied 2,501 people in 20 communities in Ghana, West Africa. Of these, 19 had received between 6-18 annual doses of ivermectin, while one community had never been given ivermectin. Although ivermectin remains a potent microfilaricide, the results suggest that resistant adult parasite populations which are not responding as expected to ivermectin are emerging. A high rate of repopulation of skin with microfilariae will allow parasite transmission, possibly with ivermectin-resistant O. volvulus which could eventually lead to a return of river blindness. Any parasite control program which relies on a single antimicrobial agent is always at risk of derailment - the time has come for viable alternatives to invermectin to be developed and introduced.
The U.S. Centers for Disease Control (CDC), collaborating with the Food and Drug Administration and other partners, has identified an outbreak of a serious but rare eye infection called Acanthamoeba keratitis. This infection is caused by a free-living amoeba (Acanthamoeba) a microscopic organism found everywhere in nature. Infections can result in permanent visual impairment or blindness.
CDC has received reports of 138 cases of culture-confirmed Acanthamoeba keratitis in 35 states and Puerto Rico, with complete patient data available for 46 case-patients. Thirty-nine of the 46 case-patients wore soft contact lenses. Preliminary information obtained by CDC from patient interviews indicates that, among soft contact lens users who reported the use of any type of solution, 58% reported having used a particular contact lens solution in the month prior to symptom onset. Out of the 37 case-patients for whom clinical data was available, 24% failed medical therapy and required or are expected to undergo corneal transplantation.
Experts say that contact lens users should avoid “risky behaviors” such as swimming in lakes and rivers while wearing contact lenses. And even washing the face in tap water can be a cause of infection. People are also advised to change their lens solution every day, not merely top up the solution sitting in the lens cases.
Elephantiasis is a parasitic disease known to the medical profession as lymphatic filariasis. The common name refers to the thickening of the skin and underlying tissues which occurs, especially in the legs and genitals:
A quarter of the world population is infected with Toxoplasma gondii, a long-lived and common brain parasite. The normal host for this organism is the domestic cat, so maybe its not so surprising that human infections are also common. New research points to the potential impact of this normally slient pathogen:
