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Investigating the role of the bone marrow stroma in the response of haematopoietic stem cells to Plasmodium berghei infection

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Title: Investigating the role of the bone marrow stroma in the response of haematopoietic stem cells to Plasmodium berghei infection
Authors: Haltalli, Myriam Luydmila Rachelle
Item Type: Thesis or dissertation
Abstract: Haematopoietic stem cells (HSCs) maintain the turnover of all blood cell lineages and reside within the bone marrow (BM), where they are critically dependant on interactions with complex and specialised niches. Severe infections can have profound effects on haematopoiesis and HSCs will adapt their progeny output to promptly cope with the increased demand for immune cells. This can often lead to exhaustion of the stem cell pool. BM niches have been shown to be altered during ageing and haematopoietic malignancies, but whether they play a role in mediating the effects of infection on HSCs remains an open question. Using a murine model of malaria infection, I established, through phenotypic analysis and mathematical modelling, that the entire haematopoietic stem and progenitor cell (HSPC) compartment is affected and activated by Plasmodium berghei infection, with significant changes in their proliferation rates (Chapter 3). Transplantation assays demonstrated a loss of long-term function of HSCs exposed to P. berghei and this was accompanied by an overall loss of the transcriptional HSC signature and rewiring of haematopoiesis assessed by single cell RNA sequencing (Chapter 4). I also show that, as well as a global interferon (IFN) response by HSPCs, IFN dramatically affects the BM microenvironment with diffuse disruption of BM vascular integrity and a systemic loss of osteoblasts over the course of P. berghei infection (Chapter 5). By targeting the osteolineage with parathyroid hormone, I was able to reduce osteoblast loss, lower local and systemic IFN levels and prevent HSC proliferation. Together, this thesis provides an insight into how severe infection affects both haematopoiesis and the BM microenvironment and opens up new avenues for further research and therapeutic interventions that may improve the health of survivors of severe infection.
Content Version: Open Access
Issue Date: Apr-2019
Date Awarded: Aug-2019
URI: http://hdl.handle.net/10044/1/81684
DOI: https://doi.org/10.25560/81684
Copyright Statement: Creative Commons Attribution NonCommercial NoDerivatives Licence
Supervisor: Lo Celso, Cristina
Blagborough, Andrew
Sponsor/Funder: Wellcome Trust (London, England)
Funder's Grant Number: 105398/Z/14/Z
Department: Department of Life Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Life Sciences PhD theses

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