Pathogenesis of Plasmodium falciparum malaria: the roles of parasite adhesion and antigenic variation

Malaria results in up to 2.5 million deaths annually, with young children and pregnant women at greatest risk. The great majority of severe disease is caused by Plasmodium falciparum. A characteristic feature of infection with P. falciparum is the accumulation or sequestration of parasite-infected red blood cells (RBCs) in various organs, such as the brain, lung and placenta, and together with other factors is important in the pathogenesis of severe forms of malaria. Sequestration results from adhesive interactions between parasite-derived proteins expressed on the surface of infected RBCs and a number of host molecules on the surface of endothelial cells, placental cells and uninfected RBCs. Some receptors for parasite adhesion have been implicated in particular malaria syndromes, such as intercellular adhesion molecule 1 in cerebral malaria and chondroitin sulfate A and hyaluronic acid in placental infection. The principal parasite ligand and antigen on the RBC surface, P. falciparum erythrocyte membrane protein 1 encoded by a multigene family termed var, is clonally variant, enabling evasion of specific immune responses. An understanding of these host-parasite interactions in the context of clinical disease and immunity may reveal potential targets to prevent or treat severe forms of malaria. Received 25 June 2001; received after revision 22 August 2001; accepted 24 August 2001     

Malaria prophylaxis in travellers: The current position

Summary Malaria prevention is a main challenge for physicians, nurses, health officers and tour operators. The attack rate of malaria in travellers is 1–10/10,000 departures, and the case fatality rate of imported malaria is around 0.5/100. Travellers should be informed about the risk they are going to take, how to protect against mosquito bites, about the antimalarials they will have to take and about what to do when a malaria breakthrough should occur.The 4-aminoquinolines (chloroquine, amodiaquine) remain the drug of choice for the prevention ofPlasmodium vivax and of sensitiveP. falciparum infections. The problem is to find an effective and safe drug combination for travellers to areas whereP. falciparum is either resistant to chloroquine, to Fansidar (the combination of pyrimethamine plus sulfadoxine) or to both. These travellers will probably best be protected by an individually tailored drug combination, which includes amodiaquine or mefloquine as baseline drugs, and a supplementation with Fansidar, Maloprim (the combination of pyrimethamine with dapsone), paludrine or an antibiotic.     

具有迁移性质的Ross Macdonald系统的格子Boltzmann方法

用格子Boltzmann方法研究描述疟疾病疟蚊系统的具有迁移性质的Ross Macdonald方程, 先构建Ross-Macdonald方程的格子Boltzmann模型, 再用该模型对疟疾病疟蚊系统进行数值模拟, 并将格子Boltzmann方法与有限差分方法的数值解进行比较. 结果表明, 该方法可用于模拟疟疾病疟蚊系统.     

Malaria vaccine

Summary Among infectious diseases caused by protozoa, malaria is still the greatest killer of children. Mortality in adults living in endemic areas is significantly lower because they frequently acquire partial or complete immunity to the major pathogen,Plasmodium falciparum. This natural protection indicates that vaccination may be possible, and the first candidate antigens were cloned with the use of human immune sera as probes. Genetic and biochemical analysis of the parasite proteins revealed that they are polymorphic, and frequently gene sequences were discovered which were specific for a particular parasite isolate, which eliminated most antigens for purposes of vaccine development. The most promising candidate antigens today are the major surface proteins of sporozoites and blood stage parasites. However, the immune response against those is not sufficient for complete protection, and additional, intensive research is necessary to identify new molecules to be included in a vaccine cocktail against malaria. The current spread of the disease due to increasing drug resistance of parasites and mosquito vectors emphasizes the urgent need for a vaccine.     

Inhibition of invasion and intraerythrocytic development ofPlasmodium falciparum by kinase inhibitors

We have examined the effects of seven protein kinase inhibitors (staurosporine, genistein, methyl 2,5-dihydroxycinnamate, tyrphostins B44 and B46, lavendustin A and R03) on the erythrocytic cycle of the malaria parasite,Plasmodium falciparum. One (staurosporine) strongly inhibits serine/threonine kinases, but the remainder all exhibit a strong preference for tyrosine kinases. We have been able to discriminate between effects on invasion and on intraerythrocytic development. All reagents impeded development of intraerythrocytic parasites, though at widely differing concentrations, from the sub-micromolar to the millimolar. Several inhibitors, including staurosporine, also reduced invasion. The phosphatase inhibitor, okadaic acid, had a strong inhibitory effect both on invasion and development. The regulation of malaria development by phosphorylation or dephosphorylation reactions at several points in the blood-stage cycle is implied.     

Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance

Molecular determinants of antimalarial drug resistance are useful and informative tools that complement phenotypic assays for drug resistance. They also guide the design of strategies to circumvent such resistance once it has reached levels of clinical significance. Established resistance to arylaminoalcohols such as mefloquine and lumefantrine in SE Asia is mediated primarily by gene amplification of the P. falciparum drug transporter, pfmdr1. Single nucleotide polymorphisms in pfmdr1, whether assessed in field isolates or transfection experiments, are associated with changes in IC₅₀ values (to arylaminoalcohols and chloroquine), but not of such magnitude as to influence clinical treatment outcomes. Recently described emerging in vitro resistance to artemisinins in certain areas correlates with mutations in the SERCA-like sequence PfATP6 and supports PfATP6 as a key target for artemisinins. Received 13 February 2006; revised after revision 7 March 2006; accepted 29 March 2006