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Identifying host-pathogen interactions which cause severe malaria

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Title: Identifying host-pathogen interactions which cause severe malaria
Authors: Georgiadou, Athina
Item Type: Thesis or dissertation
Abstract: Infectious diseases pathogenesis is dependent on the interactions between the host and the pathogen. Being able to simultaneously assess the transcriptomes of both host and pathogen as we have shown here, using dual RNA sequencing of whole blood from Plasmodium falciparum malaria patients, can reveal these crucial interactions. Using Gambian children samples we tried to unravel the mechanisms leading to severe malaria. The main finding was the clear involvement of neutrophil related genes in severe malaria while host gene expression was mainly dependent on pathogen load. Identifying that parasite load imposes a huge effect on host gene expression while being a key determinant of severe disease, we aimed to develop a new method to identify the host mechanisms which constrain parasite growth. Using a mathematical model and RNA sequencing to discover genes positively associated with parasite growth inhibition, we identified Cathepsin G and matrix metallopeptidase 9 (MMP9). Using in vitro validation, I showed that both Cathepsin G and MMP9 decrease parasite growth. They do that using different mechanisms, cathepsin G cleaves red cell surface receptors crucial for the parasite invasion while MMP9 acts directly on the parasite. Our findings underline the importance of accounting for the interaction between host and pathogen when seeking to identify correlates of protection, and reveal novel mechanisms controlling parasite growth in humans. Finally, I used five different parasite strains P. berghei ANKA, P. berghei NK65, P. yoelii 17XL, P. yoelii 17XNL, and P. chabaudi AS to infect C57BL/6 mice and compare the transcriptome of these different malaria models with our human RNA dataset. This experiment revealed a new malarial hyperlactataemia model (P. yoelii 17XL). The mouse hyperlactataemia model also showed the greatest similarity of all the mouse models to the human hyperlactataemia phenotype at a transcriptional level.
Content Version: Open Access
Issue Date: Jan-2019
Date Awarded: Mar-2019
URI: http://hdl.handle.net/10044/1/82355
DOI: https://doi.org/10.25560/82355
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Cunnington, Aubrey
Levin, Michael
Sponsor/Funder: Medical Research Council (Great Britain)
Great Britain. Dept. for International Development
European Union
Funder's Grant Number: MR/L006529/1
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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