Characterisation of the role of epigenetic variation in the adaptation of malaria parasites to changes in the conditions of the human host
[eng] Malaria is a vector-borne disease transmitted by female Anopheles mosquitoes and caused by Plasmodium parasites. The deadliest species, Plasmodium falciparum, is responsible for over 200 million cases and almost half a million deaths per year. These parasites possess a complex life cycle that...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/181643 |
| Acceso en línea: | https://hdl.handle.net/2445/181643 |
| Access Level: | acceso abierto |
| Palabra clave: | Malària Epigenètica Adaptació (Fisiologia) Heterocromatina Malaria Epigenetics Adaptation (Physiology) Heterochromatin |
| Sumario: | [eng] Malaria is a vector-borne disease transmitted by female Anopheles mosquitoes and caused by Plasmodium parasites. The deadliest species, Plasmodium falciparum, is responsible for over 200 million cases and almost half a million deaths per year. These parasites possess a complex life cycle that takes place between the human and mosquito hosts and involves many different stages that develop within different tissues and cells. As a result, malaria parasites are exposed to a wide variety of environments which has led them to develop a huge adaptive capacity. An example of this is the fact that Plasmodium parasites have developed resistance against nearly all known antimalarial drugs, constituting a major challenge for malaria control and eradication programs. In general, slow, long-term adaptation involves irreversible changes at the genetic level. However, within the human host circulation malaria parasites are exposed to fluctuating conditions that can vary both within the same or between different hosts. Adaptation to these fluctuations requires a speed and reversibility that can only be provided by changes at the transcriptional and posttranscriptional levels. Consequently, in addition to directed transcriptional responses, malaria parasites present a characteristic adaptive mechanism that revolves around the spontaneous generation of transcriptional diversity by the means of clonally variant gene expression. Clonally variant genes (CVGs) are located in facultative heterochromatin and are regulated at the epigenetic level so that they can stochastically switch between transcriptionally active or silent states. In this manner, within a genetically homogenous parasite population, different individual parasites can present different active or silent CVGs resulting in transcriptional and phenotypic diversity. Upon an environmental change, natural selection can act upon this pre-existing populational diversity and select those subpopulations of parasites with the most fit CVG expression patterns under the new set of conditions. This constitutes the basis of a bet-hedging adaptive strategy as the transcriptional diversity that precedes the selective pressure is what enables the population to survive. CVGs participate in many host-parasite interactions and have been found to play an important role in two bet-hedging adaptive strategies: immune evasion through antigenic variation mediated by var genes and resistance to toxic compounds due to changes in the permeability of the membrane of infected red blood cells mediated by clag3 genes. In this thesis, we have further characterised the role of CVGs in the adaptation of P. falciparum to the fluctuating conditions of the human host circulation and their involvement in bet-hedging adaptive strategies. Firstly, we have continued with the study of the adaptive role of clag3 genes by identifying new antimalarial compounds that are susceptible to the resistance mechanism mediated by changes in the expression patterns of these genes and also by generating a triple transgenic parasite line that can be used to analyse the expression dynamics of clag3 genes under different conditions. Secondly, we have determined how malaria parasites use their CVGs at the onset of a blood infection in a new human host and how the epigenetic memory behind the expression patterns of many of these genes is lost and re-established during the passage of parasites through transmission stages. Finally, we have found a new adaptation mechanism that enables malaria parasites to adapt to fluctuations in the availability of lipids in the culture medium simulating those they may encounter in the human circulation. This mechanism involves the loss of functional PfNDH2, a protein that forms part of the mitochondrial electron transport chain, suggesting at a possible link between the mitochondria and lipid metabolism under these conditions. In summary, we have further demonstrated the adaptive potential of CVGs as well as the huge adaptive plasticity of P. falciparum. |
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