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• W75468268 abstract "Despite many years of research, malaria remains a major public health problem with 300-500 million clinical cases and one to two million deaths per year. Malaria is caused by species of the protozoan parasite Plasmodium. Four species of Plasmodium infect humans but the most severe morbidity and mortality is caused by infection with Plasmodium falciparum. Development of new drugs and vaccines has been impeded by a lack of knowledge of basic parasite biology. Sequencing of the genome of the P. falciparum laboratory strain 3D7 was completed in late 2002 and many of the annotated genes were found to display no homology to other eukaryotic organisms. A major factor associated with the severe pathology observed with P. falciparum is the phenomenon of cytoadherence or sequestration, where infected red blood cells (RBCs) adhere to endothelial cells in the capillaries of all organs including the brain. It is generally accepted that P. falciparum sequesters to avoid clearance of infected RBCs by the spleen. This is a successful strategy for the parasite but deleterious to the host and this process can lead to severe syndromes such as cerebral malaria. The mechanism by which cytoadherence causes such severe pathology may have an immunological basis, be due to mechanical blockage of blood flow or a combination of both. RBCs are highly specialized cells lacking organelles and trafficking machinery. The parasite thus faces a unique challenge in infecting these cells and must set up its own trafficking machinery in order to import nutrients, export waste and insert parasitederived proteins on the surface of the infected RBC. Proteins involved in trafficking cytoadherence proteins and the proteins directly involved in cytoadherence on the surface of the RBC are all parasite-derived and therefore prime therapeutic candidates as they are unique to the parasite and so distinct from the host. A drug targeting cytoadherence, while not treating the actual infection, may reduce some of the severe pathology seen with P. falciparum infection. A vaccine that prevents infection is probably many years away so the possibility of treating severe symptoms of P. falciparum should be investigated. In addition, as it is accepted that P. falciparum parasites sequester to avoid clearance by the spleen; by preventing cytoadherence an infection may be cleared more efficiently by the host immune system. P. falciparum erythrocyte membrane protein 1 (PfEMP1) is a parasite protein which has been found to be the major adhesion ligand for cytoadherence on the surface of the infected RBC. PfEMP1 is a unique parasite protein but it is encoded by a large gene family known as var and the parasite regularly exchanges the expressed var gene generating antigenic variation of the PfEMP1 protein on the infected RBC surface. Antigenic variation enables P. falciparum to avoid immune clearance and diminishes the usefulness of PfEMP1 as a drug candidate designed to prevent the severe disease caused by cytoadherence. However, proteins involved in trafficking cytoadherence proteins such as PfEMP1 to the surface are more attractive targets for chemotherapeutic intervention as they are less likely to be modulated by immune evasion mechanisms than parasite proteins located on the surface of the RBC. P. falciparum develops asexually within RBCs over 48 hours progressing from the ring stage, to the trophozoite stage and finally to the schizont stage, after which the infected RBC ruptures, releasing merozoite stage parasites that infect new RBCs. Cytoadherence and rapid growth of the parasite occurs in the later trophozoite and schizont stages. The ring stage lasts almost half the asexual cycle and is characterized by low metabolic and biosynthetic activity. The ring stage parasite is thought to modify the RBC during this “lag” phase in preparation for the rapid growth and cytoadherence observed in the later stages of infection of the RBC. Proteins encoded by genes transcribed in ring stages are therefore likely candidates with involvement in the trafficking of cytoadherence proteins to the surface of the RBC. Investigation of ring stage specific genes in recent years has demonstrated that many show no homologies to proteins in other organisms and in conjunction many are exported into the host RBC where they may play a role in trafficking and host cell modification. In this thesis the ability to grow and genetically manipulate P. falciparum in vitro has been used to investigate the role of novel genes transcribed in ring stages in the trafficking of cytoadherence proteins. It has been shown that a number of independent clones and isolates lose cytoadherence to C32 melanoma cells, presumably via the receptor CD36, after passage in culture. This loss of cytoadherence was mapped to a 55 kb region on the right arm of chromosome 9. Sequencing of the genome of 3D7 revealed there are thirteen genes located in this region. Gene expression profiling and northern blotting has revealed three genes located in the region of chromosome 9 linked to cytoadherence have ring stage specific transcription. This thesis describes the investigation of these three ring stage specific genes in the region of chromosome 9 linked to cytoadherence. All three of the proteins encoded by these genes are exported into the host RBC cytoplasm, with two of the proteins localizing to the Maurer’s clefts. The Maurer’s clefts are unique parasite derived membranous structures found in the infected RBC, they have been implicated in protein trafficking but their exact function has not been completely elucidated. Maurer’s clefts are thought to be involved in the trafficking of PfEMP1, as PfEMP1 is observed to transiently associate with the clefts before reaching the infected RBC surface. Export of all three proteins beyond the parasite into the host RBC and localization of two of these proteins to the Maurer’s clefts indicates they may have a role in trafficking parasite proteins in the infected RBC. Loss of these genes does not affect growth in vitro which may point to a specific role of these genes in trafficking cytoadherence proteins in vivo in P. falciparum. To date, database searching has revealed no homologs of these three genes in other species of Plasmodium or other organisms. The Maurer’s clefts themselves are a novel organelle in terms of trafficking and investigation of these proteins in this thesis adds to the depth of knowledge about these unique parasite organelles. It is hoped that the work on these novel proteins encoded by genes transcribed in ring stages, which is described in this thesis, will further knowledge about the biology of P. falciparum and in the future may lead to the development of novel treatments for the severe pathology caused by cytoadherence." @default.
• W75468268 created "2016-06-24" @default.
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• W75468268 date "2006-01-01" @default.
• W75468268 modified "2023-09-27" @default.
• W75468268 title "Investigation of Ring Exported Proteins in Plasmodium falciparum" @default.
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