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Title: Study of the mechanisms responsible for anemia and thrombocytopenia in an experimental mouse model of visceral leishmaniasis
Author: Preham, Olivier
ISNI:       0000 0004 5921 3916
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2016
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Visceral leishmaniasis (VL) is a neglected tropical disease caused by protozoan parasites of the Leishmania genus causing between 20 000 and 50 000 deaths per annum. The parasites have developed a range of mechanisms to avoid the host’s immunity and establish chronic infection of the spleen, liver and bone marrow as intracellular parasites of macrophages. The non-exhaustive list of syndromes associated with VL include hepatomegaly, splenomegaly, fever and pancytopenia. The causes for the reduction of red blood cells, platelets or leukocytes are still unclear. Many studies have focused on the immunological aspects of VL, both in humans and experimental models, but the mechanisms causing haematological disorders remain unclear. In this study, it is shown that mice chronically infected with Leishmania donovani (L. donovani) develop haematological abnormalities, namely anaemia and thrombocytopenia. Erythropoiesis was quantified in the bone marrow, the main site of haematopoiesis in adult mammals. The number of late erythroid precursors was severely reduced in infected animals. Reduction of medullar erythropoiesis was associated with a reduction of stromal support in the bone marrow shown by a reduction of stromal macrophages expressing high levels of CD169 and a loss of CXCL12-producing stromal fibroblasts. The granulocyte-colony stimulating factor (G-CSF) known to deplete stromal macrophages and inhibit CXCL12 expression was systematically up-regulated in infected mice. Splenomegaly correlated with compensatory extramedullary erythropoiesis confined to the red pulp. Infection of splenectomised mice demonstrated that anaemia was independent of the spleen since medullar erythropoiesis was still impaired in these mice. Infection caused an increase in CD4 and CD8 T cells in the bone marrow and infected B6 RAG2-/- mice lacking mature T and B cells were not anaemic and had no repression of medullar erythropoiesis nor splenomegaly. Alterations of bone marrow stromal cells or up-regulation of G-CSF did not occur in these mice. Splenomegaly was relevant because it was shown to be responsible for thrombocytopenia. Megakaryopoiesis was unaltered by chronic infection and infected splenectomised mice had higher platelet counts than their sham-operated counterparts. Platelet production could be stimulated by injections of recombinant thrombopoietin (TPO) in chronically infected mice. Efficacy of TPO treatment in curing thrombocytopenia correlated negatively with the severity of splenomegaly. The original contribution of this work is the demonstration of a complex immunopathological mechanism causing haematological changes in an experimental model of VL. Better understanding of haematological alterations of VL is a step forward for the improvement of VL therapy, in which these alterations have been associated with the lethality of the disease.
Supervisor: Kaye, P. M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available