ldentification of PfAP2-HS as the master regulator of the heat shock response in the human malaria parasites Plasmodium falciparum
[eng] Malaria disease is caused by protozoan Plasmodium sp. parasites. Among the species of Plasmodium that produce infection in humans, P. falciparum is the responsible for the majority of cases and deaths worldwide. The main mode of transmission in humans is through the bite of an infected female...
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| Tipo de recurso: | tesis doctoral |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/180609 |
| Acceso en línea: | https://hdl.handle.net/2445/180609 http://hdl.handle.net/10803/672615 |
| Access Level: | acceso abierto |
| Palabra clave: | Malària Plasmodium falciparum Regulació genètica Malaria Genetic regulation |
| Sumario: | [eng] Malaria disease is caused by protozoan Plasmodium sp. parasites. Among the species of Plasmodium that produce infection in humans, P. falciparum is the responsible for the majority of cases and deaths worldwide. The main mode of transmission in humans is through the bite of an infected female Anopheles mosquito. The invasion of erythrocytes and the developmental cycle occurring within this cells (intraerythrocytic developmental cycle) are responsible of the symptomatology associated to malaria disease. The hallmark of symptomatic malaria is periodic fever, which in P. falciparum infections typically occurs every 48 h and can reach to more than 40ºC. Consequently, parasites are periodically exposed to changes of temperature, suggesting that they may have developed mechanisms to survive to such conditions, although the related mechanism is not clear. In this thesis, we used heat shock assays to mimic physiological fever episodes in vitro and study the mechanism of response to heat shock by which P. falciparum parasites can survive to such stress. On the one hand, we have identified the PfAP2-HS transcription factor as the main regulator of the protective heat shock response, characterized by a rapid induction of the expression of a reduced group of genes (hsp70-1, hsp90 and PF3D7_1421800). HSP70-1 and HSP90 are known chaperones involved in the heat shock response in model organisms. Moreover, both genes have two highly conserved copies of the PfAP2-HS DNA binding motif in their promoter region, suggesting that a direct regulation of hsp70-1 and hsp90 may be driven by this transcription factor. On the other hand, we have characterized the transcriptional alterations occurring independently of PfAP2-HS, mainly related with cellular damage or further mechanisms of stress response. PfAP2-HS role in the heat shock response is analogous to HSF1, a transcription factor highly conserved among eukaryotes. Although both proteins are structurally divergent, they play similar functions not only during the heat shock response, but also under basal conditions. HSF1 is involved in development, metabolism and protein homeostasis, among other cellular processes. Similarly, we have found that PfAP2-HS is also involved in the developmental cycle, being essential for the correct growth and replication of the parasite under basal conditions. In such cases, PfAP2-HS target genes are mostly related with translation, metabolism, invasion and protein homeostasis maintenance. Related with this latter role, we have determined that the correct PfAP2-HS activity is necessary to ensure survival to drugs that are known to alter protein homeostasis, such as the frontline antimalarial drug dihydroartemisinin. Directed responses play a key role in model eukaryotes, but it was unclear whether such mechanisms are also present in Plasmodium sp. With the present thesis, we corroborate the capacity of parasites to both sense and external change and drive a specific transcriptional response to ensure survival. Indeed, we describe the mechanism of heat shock response in P. falciparum parasites, an adaptive strategy that relies on the PfAP2-HS transcription factor to drive the protective response. |
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