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      Possible roles of amyloids in malaria pathophysiology


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          The main therapeutic and prophylactic tools against malaria have been locked for more than a century in the classical approaches of using drugs targeting metabolic processes of the causing agent, the protist Plasmodium spp., and of designing vaccines against chosen antigens found on the parasite's surface. Given the extraordinary resources exhibited by Plasmodium to escape these traditional strategies, which have not been able to free humankind from the scourge of malaria despite much effort invested in them, new concepts have to be explored in order to advance toward eradication of the disease. In this context, amyloid-forming proteins and peptides found in the proteome of the pathogen should perhaps cease being regarded as mere anomalous molecules. Their likely functionality in the pathophysiology of Plasmodium calls for attention being paid to them as a possible Achilles’ heel of malaria. Here we will give an overview of Plasmodium-encoded amyloid-forming polypeptides as potential therapeutic targets and toxic elements, particularly in relation to cerebral malaria and the blood–brain barrier function. We will also discuss the recent finding that the genome of the parasite contains an astonishingly high proportion of prionogenic domains.

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          Pathogenesis, clinical features, and neurological outcome of cerebral malaria.

          Cerebral malaria is the most severe neurological complication of Plasmodium falciparum malaria. Even though this type of malaria is most common in children living in sub-Saharan Africa, it should be considered in anybody with impaired consciousness that has recently travelled in a malaria-endemic area. Cerebral malaria has few specific features, but there are differences in clinical presentation between African children and non-immune adults. Subsequent neurological impairments are also most common and severe in children. Sequestration of infected erythrocytes within cerebral blood vessels seems to be an essential component of the pathogenesis. However, other factors such as convulsions, acidosis, or hypoglycaemia can impair consciousness. In this review, we describe the clinical features and epidemiology of cerebral malaria. We highlight recent insights provided by ex-vivo work on sequestration and examination of pathological specimens. We also summarise recent studies of persisting neurocognitive impairments in children who survive cerebral malaria and suggest areas for further research.
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            Transcriptional variation in the malaria parasite Plasmodium falciparum

            Malaria genetic variation has been extensively characterized, but the level of epigenetic plasticity remains largely unexplored. Here we provide a comprehensive characterization of transcriptional variation in the most lethal malaria parasite, Plasmodium falciparum , based on highly accurate transcriptional analysis of isogenic parasite lines grown under homogeneous conditions. This analysis revealed extensive transcriptional heterogeneity within genetically homogeneous clonal parasite populations. We show that clonally variant expression controlled at the epigenetic level is an intrinsic property of specific genes and gene families, the majority of which participate in host–parasite interactions. Intrinsic transcriptional variability is not restricted to genes involved in immune evasion, but also affects genes linked to lipid metabolism, protein folding, erythrocyte remodeling, or transcriptional regulation, among others, indicating that epigenetic variation results in both antigenic and functional variation. We observed a general association between heterochromatin marks and clonally variant expression, extending previous observations for specific genes to essentially all variantly expressed gene families. These results suggest that phenotypic variation of functionally unrelated P. falciparum gene families is mediated by a common mechanism based on reversible formation of H3K9me3-based heterochromatin. In changing environments, diversity confers fitness to a population. Our results support the idea that P. falciparum uses a bet-hedging strategy, as an alternative to directed transcriptional responses, to adapt to common fluctuations in its environment. Consistent with this idea, we found that transcriptionally different isogenic parasite lines markedly differed in their survival to heat-shock mimicking febrile episodes and adapted to periodic heat-shock with a pattern consistent with natural selection of pre-existing parasites.
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              Emerging principles of conformation-based prion inheritance.

              The prion hypothesis proposes that proteins can act as infectious agents. Originally formulated to explain transmissible spongiform encephalopathies (TSEs), the prion hypothesis has been extended with the finding that several non-Mendelian traits in fungi are due to heritable changes in protein conformation, which may in some cases be beneficial. Although much remains to be learned about the specific role of cellular cofactors, mechanistic parallels between the mammalian and yeast prion phenomena point to universal features of conformation-based infection and inheritance involving propagation of ordered beta-sheet-rich protein aggregates commonly referred to as amyloid. Here we focus on two such features and discuss recent efforts to explain them in terms of the physical properties of amyloid-like aggregates. The first is prion strains, wherein chemically identical infectious particles cause distinct phenotypes. The second is barriers that often prohibit prion transmission between different species. There is increasing evidence suggesting that both of these can be manifestations of the same phenomenon: the ability of a protein to misfold into multiple self-propagating conformations. Even single mutations can change the spectrum of favored misfolded conformations. In turn, changes in amyloid conformation can shift the specificity of propagation and alter strain phenotypes. This model helps explain many common and otherwise puzzling features of prion inheritance as well as aspects of noninfectious diseases involving toxic misfolded proteins.

                Author and article information

                Future Sci OA
                Future Sci OA
                Future Science OA
                Future Science Ltd (London, UK )
                September 2015
                01 September 2015
                : 1
                : 2
                : FSO43
                [1 ]Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10–12, ES-08028 Barcelona, Spain
                [2 ]Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149–153, ES-08036 Barcelona, Spain
                [3 ]Department of Biochemistry & Molecular Biology IV, Universidad Complutense de Madrid, Ciudad Universitaria, ES-28040 Madrid, Spain
                [4 ]Research Institute Hospital 12 de Octubre, Universidad Complutense de Madrid, Ciudad Universitaria, ES-28040 Madrid, Spain
                [5 ]Department of Cell Biology, Immunology & Neurosciences, University of Barcelona School of Medicine & Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), ES-08036 Barcelona, Spain
                [6 ]Institut de Biotecnologia i Biomedicina & Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, ES-08193 Bellaterra, Spain
                Author notes
                *Author for correspondence: xfernandez_busquets@ 123456ub.edu

                Authors contributed equally

                © Xavier Fernàndez-Busquets

                This work is licensed under a Creative Commons Attribution 4.0 License

                Special Report

                amyloids,intrinsically unstructured proteins,malaria,prions


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