MicrobiologyBytes

Plasmodium falciparum is a blood parasite that lives for the most part inside red cells. It is responsible for the death of 1-2 million people through malaria every year. The mechanisms by which the parasite invades red cells are complex and not completely understood. For many years it has been known that proteins called glycophorins are used by the parasite to gain entry into the red cell. However, the existence of another protein that allows entry independent of glycophorins has been suspected for nearly as long. The identity of the alternative protein has been a difficult mystery to solve.

Researchers have now identified an alternative protein used by P. falciparum to invade red blood cells. The results may aid the development of a future vaccine for malaria. The researchers identified complement receptor 1 as the protein that enables P. falciparum to invade red blood cells. Proteins called glycophorins are used by the parasite to gain entry into the red cell. However, because infection can take place without glycophorins, researchers suspected that another protein is also involved. Complement receptor 1 (CR1), also known to help protect red cells from attack by the immune system, has been suspected of having other roles in the development of malaria complications. The team was able to demonstrate that this protein is important in the invasion of red cells by using several laboratory strains of malaria as well as strains obtained from Kenya.

P. falciparum may use the CR1 protein instead of glycophorins if the parasite encounters a variant that lacks the glycophorin receptor; if the immune system mounts a response against parasite proteins involved in the dominant pathway due to a previous infection; or if the host were treated with a vaccine that blocks the glycophorin pathway. The recognition of the additional role of complement receptor 1 in red cell invasion will allow the definitive identification of malaria proteins that interact with it and that could be used in a future vaccine cocktail to block red cell invasion.

Complement Receptor 1 Is a Sialic Acid-Independent Erythrocyte Receptor of Plasmodium falciparum. 2010 PLoS Pathog 6(6): e1000968. doi:10.1371/journal.ppat.1000968
Plasmodium falciparum is a highly lethal malaria parasite of humans. A major portion of its life cycle is dedicated to invading and multiplying inside erythrocytes. The molecular mechanisms of erythrocyte invasion are incompletely understood. P. falciparum depends heavily on sialic acid present on glycophorins to invade erythrocytes. However, a significant proportion of laboratory and field isolates are also able to invade erythrocytes in a sialic acid-independent manner. The identity of the erythrocyte sialic acid-independent receptor has been a mystery for decades. We report here that the complement receptor 1 (CR1) is a sialic acid-independent receptor for the invasion of erythrocytes by P. falciparum. We show that soluble CR1 (sCR1) as well as polyclonal and monoclonal antibodies against CR1 inhibit sialic acid-independent invasion in a variety of laboratory strains and wild isolates, and that merozoites interact directly with CR1 on the erythrocyte surface and with sCR1- coated microspheres. Also, the invasion of neuraminidase-treated erythrocytes correlates with the level of CR1 expression. Finally, both sialic acid-independent and dependent strains invade CR1 transgenic mouse erythrocytes preferentially over wild-type erythrocytes but invasion by the latter is more sensitive to neuraminidase. These results suggest that both sialic acid-dependent and independent strains interact with CR1 in the normal red cell during the invasion process. However, only sialic acid-independent strains can do so without the presence of glycophorin sialic acid. Our results close a longstanding and important gap in the understanding of the mechanism of erythrocyte invasion by P. falciparum that will eventually make possible the development of an effective blood stage vaccine.

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Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, researchers have used a chemical genetic approach to assay 309,474 chemicals. Many chemicals in the library of compounds tested showed potent in vitro activity against drug-resistant P. falciparum strains. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a mouse model. These findings provide the scientific community with new starting points for malaria drug discovery.

Chemical genetics of Plasmodium falciparum. Nature 465, 311–315 (2010) doi:10.1038/nature09099

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Malaria and alcohol consumption both represent major public health problems. Alcohol consumption is rising in developing countries and, as efforts to manage malaria are expanded, understanding the links between malaria and alcohol consumption becomes crucial. Our aim was to ascertain the effect of beer consumption on human attractiveness to malaria mosquitoes in semi field conditions in Burkina Faso. We used a Y tube-olfactometer designed to take advantage of the whole body odour (breath and skin emanations) as a stimulus to gauge human attractiveness to Anopheles gambiae (the primary African malaria vector) before and after volunteers consumed either beer (n = 25 volunteers and a total of 2500 mosquitoes tested) or water (n = 18 volunteers and a total of 1800 mosquitoes). Water consumption had no effect on human attractiveness to An. gambiae mosquitoes, but beer consumption increased volunteer attractiveness. Body odours of volunteers who consumed beer increased mosquito activation (proportion of mosquitoes engaging in take-off and up-wind flight) and orientation (proportion of mosquitoes flying towards volunteers’ odours). The level of exhaled carbon dioxide and body temperature had no effect on human attractiveness to mosquitoes. Despite individual volunteer variation, beer consumption consistently increased attractiveness to mosquitoes. These results suggest that beer consumption is a risk factor for malaria and needs to be integrated into public health policies for the design of control measures.

Beer Consumption Increases Human Attractiveness to Malaria Mosquitoes. PLoS ONE 5(3): e9546. doi:10.1371/journal.pone.0009546

The malaria parasite life cycle constitutes one of the most complicated and fascinating life cycles of any organism and thus poses intriguing areas of study for cell biology, molecular biology, and immunology alike. Malaria as a disease is devastating developing countries, especially those in sub-Saharan Africa, causing approximately one million deaths each year, which are mainly attributable to a single parasite species, Plasmodium falciparum. The intricacy of malaria parasite biology has vexed vaccinologists and immunologists for nearly a century and is a major impediment to the development of a fully protective vaccine. A major part of the complexity associated with the malaria parasite life cycle is due to the parasite’s ability to change its cellular and molecular makeup, which is controlled by a genome with more than 5000 recognized genes, and develop in intracellular and extracellular niches in the mammalian host and the mosquito vector.

Plasmodium sporozoites are the product of a complex developmental process in the mosquito vector and are destined to infect the mammalian liver. Attention has been drawn to the mosquito stages and pre-erythrocytic stages owing to recognition that these are bottlenecks in the parasite life cycle and that intervention at these stages can block transmission and prevent infection. Parasite progression in the Anopheles mosquito, sporozoite transmission to the mammalian host by mosquito bite, and subsequent infection of the liver are characterized by extensive migration of invasive stages, cell invasion, and developmental changes. Preparation for the liver phase in the mammalian host begins in the mosquito with an extensive reprogramming of the sporozoite to support efficient infection and survival. This review discusses what is known about the molecular and cellular basis of the developmental progression of parasites and their interactions with host tissues in the mosquito and during the early phase of mammalian infection.

Malaria parasite development in the mosquito and infection of the mammalian host. Ann Rev Microbiol. 2009 63: 195-221

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Anopheles gambiae mosquitoes are the principal vectors of human malaria, a disease with devastating consequences for public health and the economic development of disease-endemic countries. The creation of new tools to control vector populations is a focal point of intensive efforts to eradicate the burden of malaria. As mosquitoes generally copulate only once during their lives, interfering with the mating process is a promising avenue for research into vector control. Unfortunately, very little is known about the molecular or physiological basis of mating and insemination in malaria vectors. Of particular concern is our lack of knowledge about factors and pathways ensuring male reproductive success, such as those that result in sperm storage, oviposition, and the inhibition of remating in females. Improving our understanding of mating biology might not only inform currently proposed strategies for vector control, but could potentially allow the development of entirely novel tools for combating malaria.

Stopping male mosquitoes from sealing their sperm inside females with a ‘mating plug’ could prevent mosquitoes from reproducing, and offer a potential new way to combat malaria. The new study focuses on An. gambiae, the species of mosquito primarily responsible for the transmission of malaria in Africa. These mosquitoes mate only once in their lives, which means that disrupting the reproductive process offers a good way of dramatically reducing their populations. When these mosquitos mate, the male transfers sperm to the female and then afterwards transfers a coagulating mass of proteins and seminal fluids known as a mating plug. This plug is not found in any other species of mosquito and until now, very little was known about the role it plays in An. gambiae reproduction. The authors show that the mating plug is essential for ensuring that sperm is correctly retained in the female’s sperm storage organ, from where she can fertilise eggs over the course of her lifetime. Without the mating plug, sperm is not stored correctly, and fertilisation cannot occur.

The researchers analysed the composition of the protein-rich mating plug and discovered that it is formed when an enzyme called transglutaminase interacts with other proteins in the male mosquito’s seminal fluid. This interaction causes the seminal fluids to coagulate into a gelatinous solid mass. When the research team removed this enzyme in male mosquitoes in the lab, the fluids failed to coagulate and form the plug. Furthermore, when these males, lacking the key protein and therefore the plug, mated with females, reproduction was not successful. The male mating plug is not a simple barrier to insemination from rival males, as has been previously suggested. Instead, the plug plays an important role in allowing the female to successfully store sperm in the correct way inside her, and as such is vital for successful reproduction. If in the future we can develop an inhibitor that prevents the coagulating enzyme doing its job inside male An. gambiae mosquitoes in such a way that can be deployed easily in the field – for example in the form of a spray as it is done with insecticides – then we could effectively induce sterility in female mosquitoes in the wild. This could provide a new way of limiting the population of this species of mosquito, and could be one more weapon in the arsenal against malaria.

Transglutaminase-Mediated Semen Coagulation Controls Sperm Storage in the Malaria Mosquito. 2009 PLoS Biol 7(12): e1000272. doi:10.1371/journal.pbio.1000272
Insect seminal fluid proteins are powerful modulators of many aspects of female physiology and behaviour including longevity, egg production, sperm storage, and remating. The crucial role of these proteins in reproduction makes them promising targets for developing tools aimed at reducing the population sizes of vectors of disease. In the malaria mosquito Anopheles gambiae, seminal secretions produced by the male accessory glands (MAGs) are transferred to females in the form of a coagulated mass called the mating plug. The potential of seminal fluid proteins as tools for mosquito control demands that we improve our limited understanding of the composition and function of the plug. Here, we show that the plug is a key determinant of An. gambiae reproductive success. We uncover the composition of the plug and demonstrate it is formed through the cross-linking of seminal proteins mediated by a MAG-specific transglutaminase (TGase), a mechanism remarkably similar to mammalian semen coagulation. Interfering with TGase expression in males inhibits plug formation and transfer, and prevents females from storing sperm with obvious consequences for fertility. Moreover, we show that the MAG-specific TGase is restricted to the anopheline lineage, where it functions to promote sperm storage rather than as a mechanical barrier to re-insemination. Taken together, these data represent a major advance in our understanding of the factors shaping Anopheles reproductive biology.

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Short Disney film (The Winged Scourge, 1943):

via Twisted Bacteria, via Microbeworld

Malaria is a major contributor to the global disease burden, and disproportionately affects low-income countries with climates suitable for transmission. Vector control strategies have proven effective in reducing malaria transmission and prevalence, and are a key element of current malaria control initiatives. Indoor residual spraying and insecticide-treated bednets (ITNs) have been and remain the dominant methods of controlling malaria vectors, but problems of public health and insecticide resistance associated with chemical insecticides have increased interest in alternate methods, including novel biological methods. Because the incubation period of the malaria parasite is relatively long in comparison to the average adult mosquito lifespan, biological methods of vector control that have sublethal and lethal effects at different points in the mosquito life cycle may substantially reduce the potential for malaria transmission.

Biopesticides containing a fungus that is pathogenic to mosquitoes may be an effective means of reducing malaria transmission, particularly if used in combination with insecticide-treated ITNs. Results of a new study show that incorporating this novel vector control technique into existing vector management programmes may substantially reduce malaria transmission rates and help manage insecticide resistance. Using data from laboratory and field studies, the model estimates the impact of different vector control interventions on the mosquito life cycle and the average numbers of mosquitoes that survive to transmit malaria.  The results indicate that in order to successfully control malaria transmission, single intervention strategies must be widely used across the community, whether the strategy involves fungal biopesticides or ITNs.  If used in combination, the model shows that the interventions can interact to produce greater-than-expected reductions in malaria transmission rates.

This outcome is achieved because the presence of ITNs can increase mosquito exposure to biopesticide-sprayed surfaces.  Efficient combinations of interventions may allow each to be used at lower levels, and slow the development of resistance in the mosquito population.  The results suggest that combining fungal biopesticides and ITNs may be an efficient and effective strategy for malaria vector control. Malaria is a major contributor to the global disease burden, and disproportionately affects low income countries with climates suitable for transmission.  Mosquito control relies heavily on chemical insecticides, but growing problems of insecticide resistance have led to increased interest in novel methods, including biocontrol.  The Global Strategy for Integrated Vector Management, developed by the World Health Organisation, encourages the use of multiple vector control technologies in combination.  This research has used computer modelling to identify ways in which interventions can be combined to maximise the impact on malaria transmission, given the resources available.

Combining Fungal Biopesticides and Insecticide-Treated Bednets to Enhance Malaria Control. 2009 PLoS Comput Biol 5(10): e1000525 doi:10.1371/journal.pcbi.1000525
In developing strategies to control malaria vectors, there is increased interest in biological methods that do not cause instant vector mortality, but have sublethal and lethal effects at different ages and stages in the mosquito life cycle. These techniques, particularly if integrated with other vector control interventions, may produce substantial reductions in malaria transmission due to the total effect of alterations to multiple life history parameters at relevant points in the life-cycle and transmission-cycle of the vector. To quantify this effect, an analytically tractable gonotrophic cycle model of mosquitomalaria interactions is developed that unites existing continuous and discrete feeding cycle approaches. As a case study, the combined use of fungal biopesticides and insecticide treated bednets (ITNs) is considered. Low values of the equilibrium EIR and human prevalence were obtained when fungal biopesticides and ITNs were combined, even for scenarios where each intervention acting alone had relatively little impact. The effect of the combined interventions on the equilibrium EIR was at least as strong as the multiplicative effect of both interventions. For scenarios representing difficult conditions for malaria control, due to high transmission intensity and widespread insecticide resistance, the effect of the combined interventions on the equilibrium EIR was greater than the multiplicative effect, as a result of synergistic interactions between the interventions. Fungal biopesticide application was found to be most effective when ITN coverage was high, producing significant reductions in equilibrium prevalence for low levels of biopesticide coverage. By incorporating biological mechanisms relevant to vectorial capacity, continuous-time vector population models can increase their applicability to integrated vector management.

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Neglected tropical diseases (NTDs) are the most common conditions affecting the poorest 500 million people living in sub-Saharan Africa (SSA), and together produce a burden of disease that may be equivalent to up to one-half of SSA’s malaria disease burden and more than double that caused by tuberculosis. Approximately 85% of the NTD disease burden results from helminth infections. Hookworm infection occurs in almost half of SSA’s poorest people, including 40–50 million school-aged children and 7 million pregnant women in whom it is a leading cause of anaemia. Schistosomiasis is the second most prevalent NTD after hookworm (192 million cases), accounting for 93% of the world’s number of cases and possibly associated with increased horizontal transmission of HIV/AIDS. Lymphatic filariasis (46–51 million cases) and onchocerciasis (37 million cases) are also widespread in SSA, each disease representing a significant cause of disability and reduction in the region’s agricultural productivity. There is a dearth of information on Africa’s non-helminth NTDs. The protozoan infections, human African trypanosomiasis and visceral leishmaniasis, affect almost 100,000 people, primarily in areas of conflict in SSA where they cause high mortality, and where trachoma is the most prevalent bacterial NTD (30 million cases). However, there are little or no data on some very important protozoan infections, e.g., amebiasis and toxoplasmosis; bacterial infections, e.g. typhoid fever and non-typhoidal salmonellosis, the tick-borne bacterial zoonoses, and non-tuberculosis mycobaterial infections; and arboviral infections. Thus, the overall burden of Africa’s NTDs may be severely underestimated. A full assessment is an important step for disease control priorities, particularly in Nigeria and the Democratic Republic of Congo, where the greatest number of NTDs may occur.

If you want to make a difference, start here.

Neglected Tropical Diseases in Sub-Saharan Africa: Review of Their Prevalence, Distribution, and Disease Burden. 2009 PLoS Negl Trop Dis 3(8): e412. doi:10.1371/journal.pntd.0000412

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