Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large‐scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.     

A genetic model of the effects of insecticide-treated bed nets on the evolution of insecticide-resistance

Background and objectives: The evolution of insecticide-resistance in malaria vectors is emerging as a serious challenge for the control of malaria. Modelling the spread of insecticide-resistance is an essential tool to understand the evolutionary pressures and dynamics caused by the application of insecticides.Methodology: We developed a population-genetic model of the spread of insecticide-resistance in a population of Anopheles vectors in response to insecticides used either as adulticides (focussing on insecticide-treated bed nets (ITNs)) or as larvicides (either for the control of malaria or, as an inadvertent side-product, in agriculture).Results: We show that indoor use of insecticides leads to considerably less selection pressure than their use as larvicides, supporting the idea that most resistance of malaria vectors is due to the agricultural use of the insecticides that are also used for malaria control. The reasons for the relatively low selection pressure posed by adulticides are (i) that males are not affected by the ITNs and, in particular, (ii) that the insecticides are also repellents, keeping mosquitoes at bay from contacting the insecticide but also driving them to bite either people who do not use the insecticide or alternative hosts.Conclusion: We conclude by discussing the opposing public health benefits of high repellency at an epidemiological and an evolutionary timescale: whereas repellency is beneficial to delay the evolution of resistance, other models have shown that it decreases the population-level protection of the insecticide.     

Transmission Risk from Imported Plasmodium vivax Malaria in the China–Myanmar Border Region

Malaria importation and local vector susceptibility to imported Plasmodium vivax infection are a continuing risk along the China–Myanmar border. Malaria transmission has been prevented in 3 border villages in Tengchong County, Yunnan Province, China, by use of active fever surveillance, integrated vector control measures, and intensified surveillance and response.     

Differential antibody recognition of FC27-like Plasmodium falciparum merozoite surface protein MSP2 antigens which lack 12 amino acid repeats

Three alleles of the FC27-type allelic family of the MSP2 gene of the malaria parasite Plasmodium falciparum have been sequenced from parasites from the field (The Gambia and Tanzania). These alleles lack the 12 amino acid repeat units which are usual in this family of MSP2 alleles. We have investigated the recognition by sera from an endemic area (The Gambia) of three recombinant MSP2 proteins that have 5, 1 and no copies of this repeat region. Antibody recognition of these recombinant proteins varied according to the number of repeats present. High titre antibody levels were seen with most sera using the recombinant protein with 5 × 12-mer repeats, whereas only low responses were measured using proteins containing 1 or no 12-mer repeats. Several sera entirely failed to recognise the protein which lacked 12-mer repeats. The data suggest that variation in the number of tandem repeat sequences could allow the parasite to avoid high avidity antibody binding and this may allow escape from immune recognition.     

The roles of the glycosylphosphatidylinositol anchor on the production and immunogenicity of recombinant ookinete surface antigen Pbs21 of Plasmodium berghei when prepared in a baculovirus expression system

Malarial ookinetes express an immunodominant surface protein (P28) that is a priority candidate for the development of transmission-blocking vaccines. The full length P28 gene from Plasmodium berghei [Pbs21(1-213)] and a deletion construct [Pbs21(1-188)] encoding a protein that lacks the 25 C-terminal amino acids, including the glycosylphosphatidylinositol (GPI) anchor signal, were expressed in insect cells using baculovirus vectors. Pbs21(1-213) protein is strongly hydrophobic, found in the cytoplasm and on the surface of Spodoptera Sf21 cells, and in the culture medium. Pbs21(1-188) protein was largely found in the aqueous phase of the medium and in the cytoplasm of Sf21 cells, but was not detected on the cell surface. The presence of 25 C-terminal amino acids is therefore critical to the attachment of recombinant Pbs21 to the parasite plasma membrane. Mice were immunized subcutaneously or intramuscularly with affinity purified recombinant Pbs21(1-213), Pbs21(1-188) or native Pbs21 proteins. Following two immunizations, native Pbs21 induces higher titres when administered by either route, than the recombinant protein bearing an insect GPI anchor, which in turn is markedly more immunogenic than the recombinant polypeptide lacking a GPI anchor. When specific anti Pbs21 antibody titres exceeded 1 mg/ml all three antigens were capable of inducing transmission blockade > or = 90%, below 1 mg/ml blockade did not correlate with antibody concentration.     

Reversible suppression of bone marrow response to erythropoietin in Plasmodium falciparum malaria

To study the importance of bone marrow inhibition in the pathogenesis of malarial anaemia, haematological and parasitological parameters were followed in patients with acute malaria. Three patient categories were studied, severe malarial anaemia (SA), cerebral malaria (CM) and uncomplicated malaria (UM). Red cell distribution width (RDW) was used as a surrogate marker of release of young erythrocytes and reticulocytes. Initially RDW was low in all patients in spite of markedly increased concentrations of erythropoietin (EPO). 3 d after institution of treatment and coinciding with parasite clearance RDW increased dramatically, reaching the highest levels 1–2 weeks later. Although severe anaemia was corrected by blood transfusion during the first 3 d of treatment, the peak RDW correlated significantly with the initial EPO levels. This suggests that Plasmodium falciparum infection causes a rapidly reversible suppression of the bone marrow response to EPO. Furthermore, the inhibition of bone marrow response was a general finding irrespective of initial haemoglobin levels suggesting that the severity of anaemia depends upon the degree of peripheral erythrocyte destruction in patients with suppressed bone marrow response to EPO.     

Massive Plasmodium falciparum visceral sequestration: a cause of maternal death in Africa

Sequestration of Plasmodium falciparum-infected erythrocytes (PfIE) in the capillaries of the central nervous system (CNS) is the pathognomonic feature of cerebral malaria, a condition frequently leading to death. Sequestration of PfIE in the placental intervillous spaces is the characteristic feature of malaria in pregnancy and is associated with low birthweight and prematurity. Although both patterns of sequestration are thought to result from the expression of different parasite proteins involved in cytoadhesion to human receptors, scant information exists on whether both conditions can coexist and whether this can lead to death. We conducted a prospective autopsy study including all consecutive pregnancy-related deaths in a tertiary-level referral hospital in Maputo, Mozambique, between October 2002 and December 2006. Extensive sampling of all major viscera was performed. All cases showing parasites in any of the viscera were included in the analysis. From 317 complete autopsies PfIEs were identified in ten women (3.2%). All cases showed massive accumulation of PfIE in small capillaries of the CNS but also in most visceral capillaries (heart, lung, kidney, uterus). Placental tissue, available in four cases, showed a massive accumulation of maternal PfIE in the intervillous space. Coma (six women) and dyspnoea (five women) were the most frequent presenting clinical symptoms. In conclusion, massive visceral sequestration of PfIE with significant involvement of the CNS is an infrequent but definite direct cause of maternal death in endemic areas of Africa. The PfIE sequestered in cerebral capillaries and the placenta coexist in these fatal cases.