Source: http://www.asmscience.org/content/book/10.1128/9781555816872.ch29
Timestamp: 2019-04-22 22:29:37+00:00

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This chapter focuses on the pathogenesis of malaria caused by Plasmodium falciparum and Plasmodium vivax. It talks about two factors, parasite multiplication rate and cytoadherence of parasitized Red Blood Cells (RBCs), both of which enable parasites to achieve high densities and induce microvascular inflammation. The chapter considers several cytoadherence interactions between parasitized RBCs and host cells to better understand how parasites cause microvascular obstruction, inflammation, and dysfunction in vivo. Additional evidence for endothelial dysfunction in severe malaria has now been reported from a study of Indonesian adults. In this study, cell-free hemoglobin and arginase levels were elevated in patients with severe malaria, compared to those with moderately severe malaria or those who were healthy. The chapter presents the pathogenesis of vivax malaria, and discusses human genetic resistance to vivax malaria. It also describes working models of malaria pathogenesis which the authors believe provide useful frameworks for future studies. The authors propose that the levels of parasitemia and the strength of pathogen-host cell interactions are critically involved in the pathogenesis of malaria, and that host factors which interfere with parasite multiplication and sequestration are centrally important in ameliorating the severity of malaria. They suggest that RBC polymorphisms other than Duffy-negativity may reduce P. vivax infection of RBCs or impair cytoadherence interactions between P. vivax-infected RBCs and host cells. Like Duffy negativity, RBC polymorphisms that are found to protect against P. vivax may teach the important aspects of the pathogenesis of this fascinating and sometimes deadly parasite.
Life cycle of Plasmodium spp. Sporozoites injected into the dermis by female anopheline mosquitoes are carried through the blood and lymph to the liver, where they invade hepatocytes and form liver schizonts. After an incubation period of 7 to 14 days, each liver schizont releases tens of thousands of merozoites, which invade red blood cells (RBCs) and form ring-stage parasites. These forms are found freely circulating in the bloodstream until they mature to trophozoites, which sequester in microvessels while developing into schizonts. Merozoites released from schizonts establish rounds of asexual replication every 48 hours. Some ringstage parasites develop into sexualstage gametocytes, which circulate in the bloodstream and are taken up by female mosquitoes during a blood meal. After a cycle of sexual development in the mosquito, sporozoites enter the mosquito’s salivary gland and are injected into another host at the next blood meal. Image kindly reproduced with permission from Cell Press.
A new model of falciparum malaria pathogenesis and protection. The sequestration of P. falciparum-infected red blood cells (RBCs) in microvessels is believed to activate microvascular endothelial cells (MVECs) and monocytes, which contribute to the microvessel inflammation associated with severe malaria. Hemoglobin (Hb) C and sickle HbS reduce the risk of severe malaria in sub-Saharan Africa. HbC and HbS are associated with abnormal display of P. falciparum erythrocyte membrane protein-1 (PfEMP-1), a family of antigenically variant cytoadherence ligands that serves as the parasite’s main virulence factor on the surface of parasitized RBCs. Reduced levels and abnormal distributions of PfEMP-1 are associated with impaired adherence of parasitized HbC and HbS RBCs to MVECs and monocytes (this is shown schematically at right as less intimate interactions between these parasitized RBCs, MVECs, and monocytes). By lowering the avidity of cytoadherence interactions, HbC and HbS may reduce the level of MVEC and monocyte activation in vivo and prevent the progression from uncomplicated to severe malaria. PfEMP-1-specific antibodies that reduce the avidity of these interactions may work in concert with Hb variants to dampen inflammation and ameliorate disease severity.
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