MicrobiologyBytes

Of the four species of Plasmodium (protozoan parasites) that can cause malaria in humans, Plasmodium falciparum is the most dangerous, being responsible for over 1 million deaths each year. It is transmitted when an infected human is bitten by an Anopheles mosquito that goes on to bite another person. The Plasmodium life cycle is complex; the asexually replicating forms which cause disease symptoms are quite distinct from the sexual forms, which mediate transmission between individuals via the bite of a mosquito. In the human, the parasite invades red blood cells, divides clonally, and causes the symptoms of disease. Sexual forms of the parasite also develop in the bloodstream, but only when they are taken up by the mosquito can the second phase of the life cycle proceed. Within the mosquito stomach a conversion occurs: the sexual forms change from crescent-shaped to round before fertilization can occur. This transition is referred to as “rounding up” and the signalling system underlying it, which reacts to the change in host (human to mosquito), has previously been poorly characterized.

After a period of growth in the human host, these sexual forms (gametocytes) lie dormant until taken up by a mosquito. The change in environment from human to mosquito triggers differentiation into mature gametes. In a newly published study, scientists have identified a protein kinase from the parasite that is instrumental in mediating this essential differentiation step. They also gained insight into how this protein kinase might interact with calcium to coordinate these events. By using genetically modified malaria parasites in combination with specific inhibitors of the protein kinase, they showed the feasibility of blocking development of the sexual stage of the parasite’s life cycle. Development of a drug that targets this parasite stage, for use in combination with a curative drug, would be an important tool for controlling the spread of drug resistance.

New work has identified one of the molecules required for the activation of the sexual cycle within the mosquito: PKG. The new paper identifies a protein crucial for the reproductive stages of the pathogen’s lifecycle, called cGMP-dependent protein kinase, or PKG. PKG is an enzyme produced by the malaria parasite. The authors have shown that it is essential for induction of “rounding up”. Normal pathogens are unable to respond to the change in host if PKG is experimentally blocked with an inhibitor; thus, PKG is necessary for the pathogen to become sexually mature. Further, the authors genetically modified the parasite so that PKG was insensitive to the inhibitor, and in these mutants, “rounding up” could proceed normally in the presence of the inhibitor. It is, therefore, PKG specifically (rather than another enzyme) that is the target of the inhibitor. This work suggests a new potential target for anti-malarial drugs. The findings may have important implications for fighting the spread of drug resistance and malaria control, for if you could block PKG activity in the pathogen, which the authors have done using a specific inhibitor, then you have a means of controlling transmission of malaria between individuals.

Gametogenesis in malaria parasites is mediated by the cGMP-dependent protein kinase. 2008 PLoS Biol 6(6): e139

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Malaria is a vector-borne infectious disease caused by protozoan parasites of the genus Plasmodium. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, it infects approximately 515 million people and kills between one and three million people, the majority young children in Sub-Saharan Africa.

Malaria is thought to have infected humans for over 50,000 years, and may have been a human pathogen for the entire history of our species. Close relatives of the human malaria parasite are common in chimpanzees. References to the unique recurring fever of malaria are found throughout recorded history, the earliest from China in 2700 BC. The term malaria originates from the Medieval Italian: mala aria meaning “bad air”, and the disease was also formerly called ague or marsh fever due to its association with swamps, the home of the mosquitos which transmit the parasite.

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In 1880, a French doctor Charles Laveran was the first to observe parasites inside the red blood cells of people suffering from malaria. This was the the first time that protozoan was identified as causing a disease. In 1908, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Cuba, first suggested that mosquitoes were transmitting the disease to and from humans. However, Sir Ronald Ross, working in India, finally proved that malaria is transmitted by mosquitoes in 1898. He did this by showing that certain mosquito species transmit malaria to birds and by isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds:

For the last two years I have been endeavouring to cultivate the parasite of malaria in the mosquito. The method adopted has been to feed mosquitos, bred in bottles from the larva, on patients having crescents in the blood, and then to examine their tissues for parasites similar to the haemamoeba in man. The study is a difficult one, as there is no a priori indication of what the derived parasite will be like precisely, nor in what particular species of insect the experiment will be successful, while the investigation requires a thorough knowledge of the minute anatomy of the mosquito. Hitherto the species employed have been mostly brindled and grey varieties of the insect; but though I have been able to find no fewer than six new parasite of the mosquito, namely a nematode, a fungus, a gregarine, a sarcosporidium, a coccidium, and certain swarm spores in the stomach, besides one or two doubtfully parasitic forms, I have not yet succeeded in tracing any parasite to the ingestion of malarial blood, nor in observing special protozoa in the evacuations due to such digestion.

Apart from combating malaria, what else do Ross’s experiments teach us?

How about the value of persistence? Ross records that before the reported successful experiment, work in the preceding two years involving the examination of approximately a thousand mosquitoes had failed to reveal any parasites. It also shows the benefit of sharing data before publication so as to put forward possibly conflicting interpretations of the results. Today, many a journal editor may have rejected such a speculative, uncontrolled and unreplicated study as Ross’s original paper. And if they had, we might still be waiting to discover the infectious agent responsible for malaria.

Malaria, mosquitoes and the legacy of Ronald Ross.
Bull World Health Organ. 2007 85: 894-896

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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.

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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.

Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting. PNAS 2007 104: 17471-17476

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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.

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?

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Emily Oster, a University of Chicago economist, looks at the statistics on AIDS in Africa and comes up with the conclusion: Everything we know about AIDS in sub-Saharan Africa is wrong. We look for root causes such as poverty and poor health care, but we also need to factor in, say, the price of coffee, and the routes of long-haul truckers. In short, there is a lot we don’t know; and our assumptions about what we do know may keep us from finding the best way to stop the disease. Watch the video:

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

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New figures from the Health Protection Agency show that there were 1758 cases of malaria reported in UK travellers in 2006. Eight of these cases were fatal. 386 of the cases were due to the potentially fatal Plasmodium falciparum which is a major international health risk and which kills more than a million people a year in Africa. 219 were due to Plasmodium vivax which causes a debilitating disease, but is rarely fatal. Where the reason for travel is known, 57% of the malaria cases reported in the UK were in people visiting friends and relatives in the tropics. According to Professor Peter Chiodini, a malaria expert at the HPA:

It is a common misconception that people who were born in places where malaria is rife and who now live in the UK, have immunity to malaria. This is not the case because they very quickly lose the partial immunity they might have acquired whilst they lived there, and people who have never lived in these countries have no immunity. It is particularly important that people are aware that they are at risk if they do not follow advice on malaria prevention.