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The role of human Hsp70 for survival and development of the human malaria parasite Plasmodium falciparum

Engels, Sonja

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Abstract

Plasmodium falciparum is one of the most deadly malaria parasites and causes the tropical disease “malaria tropica”. Most of the pathology can be explained by the drastic host cell modifications which are initiated by the parasite shortly after invasion. Moreover, upon the invasion of the mature human erythrocyte, the parasite encases itself with a parasitophorous vacuole (PV). It is known that the parasite exports 300-400 proteins to the host cell, to change the biophysical properties of the infected erythrocytes. However, up to date little is known about how the parasite sets up its own protein export machinery in a host cell devoid of any infrastructure. Scientific knowledge was significantly boosted with the discovery that ATP, a factor in the host cell cytoplasm and protein unfolding was pivotal to protein export across the PV membrane (PVM). Further, the discovery of the parasite-encoded protein translocon called PTEX (Plasmodium Translocon of EXported proteins) in the PVM shed more light on the underlying mechanism. In 2016, data was obtained that the human heat-shock protein 70 (HsHsp70) is essential for the transport across the PVM. Based on this observation, this study focussed on the question whether HsHsp70 is vital to the parasite’s intra-erythrocytic development. For this purpose, a resealing approach commonly used in pharmacology was established. Since the mature human erythrocyte cannot be easily genetically modified, the resealing approach was used to achieve a classic dominant negative effect by pre-loading the mature human erythrocytes with an excess amount of mutated recombinant HsHsp70. Afterwards the resealed erythrocytes were infected with P. falciparum parasites. Interestingly, the growth was not altered by the presence of the excess amount of the mutated HsHsp70. In addition, the protein export in the presence of the mutant protein was analysed using parasites encoding green fluorescently labelled, known exported, proteins. Surprisingly, the protein transport was not inhibited by the presence of the mutant, as well. Last, parasites depleted of a parasite-exported Hsp70 called Hsp70x, were used to infect the resealed cells pre-loaded with the mutated protein. The growth and protein export were not altered for the ΔHsp70x parasite. In conclusion, under the given experimental setup, no essential function of HsHsp70 for the growth and protein export of P. falciparum was revealed.

Item Type: Dissertation
Supervisor: Lanzer, Prof. Dr. Michael
Date of thesis defense: 10 July 2019
Date Deposited: 06 Aug 2019 09:39
Date: 2020
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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