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Title: Impact of Leishmania donovani infection on early events in haematopoiesis
Author: Pinto, Ana Isabel
ISNI:       0000 0004 5918 8415
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2016
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Visceral leishmaniasis (VL) in humans and in animal models is associated with, among other factors, parasite persistence in the bone marrow (BM) and significant changes in haematological function. However, the mechanisms underlying haematologic dysregulation are largely unknown. Using a panel of stem cell markers, we characterized murine haematopoietic stem and precursor cells in the BM over the course of L. donovani-infection in C57BL/6 (B6) mice. In steady-state, the majority of LT-HSCs (Long-term haematopoietic stem cells) (LSK CD150+ CD34- CD48- cells) were found in a quiescent state, representing cells with the highest degree of reconstitution potential. In contrast, during chronic infection, most LT-HSCs were found to have progressed to cell-cycle and this correlated with a reduced potential to engraft into syngeneic recipients. The loss of quiescent LT-HSCs was associated with expansion of cells displaying a phenotype attributed to early, and uncommitted progenitors. However this increase in uncommitted progenitors did not result in an increase in effective haematopoiesis, but rather chronically infected mice displayed signs of anaemia and thrombocytopenia. The loss of quiescent HSCs and other alterations in the haematopoietic compartment were absent in infected RAG2 KO mice, but adoptive transfer of CD4+ T cells restored this phenotype. In subsequent experiments, we transferred IFNγ-deficient CD4+ T cells into RAG KO recipients and established that this pro-inflammatory cytokines was pivotal for the depletion of the reservoir of LT-HSCs in quiescence, as well as for the establishment of anaemia and thrombocytopenia. Subsequently, using mixed BM chimeras, we established that IFNγ signalling and TNF signalling pathways converge to induce an expansion of BM T cells, suggesting that both cytokines are required to drive the development of CD4+ T cells with the potential to cause alterations in haematopoiesis and haematological dysfunction in the periphery. These data suggest new avenues for clinical research into the pathogenesis of VL and have relevance for the development of new therapeutic strategies and clinical follow-up.
Supervisor: Kaye, Paul M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available