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Investigating the role of interferon—γ signalling for malaria dyserythropoiesis

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Nwoke2020.pdf (37.30Mb)
Date
30/11/2020
Item status
Restricted Access
Embargo end date
30/11/2021
Author
Nwoke, Eze Chukwunyere
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Abstract
In innate and adaptive immunity, the proinflammatory type 1 cytokine interferon gamma (IFN-γ), is well known for its protective role particularly against intracellular pathogens. However, this type 2 interferon has been implicated in the pathology of several diseases. In malaria, it has been demonstrated that IFN-γ exerts both protective and pathological roles. In humans and in mouse models, the acute infection results in aberrant erythroid differentiation termed dyserythropoiesis which contributes to the development of severe malarial anaemia. The mechanism that drives this process is poorly understood. However, recent data from our lab suggests a role for IFN-γ as the one candidate to mediate the manifestation of early dyserythropoiesis. This study aimed to determine the stages of erythropoiesis in the bone marrow (BM) and spleen that are perturbed by malaria, and investigate if IFN-γ signalling in the haematopoietic compartment alone, is sufficient to promote suppression of erythropoiesis during malaria. To address the first aim, I used three murine models of experimental malaria which differ in virulence, parasite burden, proinflammatory cytokine induction and elicited immune response. In all malaria models, I observed an expansion of the erythroid progenitors in the bone marrow and spleen, nevertheless, this expansion failed to reflect in the number of downstream precursors. Early in infection, there was no change in the absolute number of erythroid precursors in infected mice, in comparison to naive gender and age matched controls, but at peak parasitaemia at the time points sampled, there was a significant contraction in the number of all erythroid precursor stages, from the proerythroblast to the orthochromatic erythroblast. Furthermore, I observed that this aberration of erythropoiesis in the BM and spleen manifests independently of the degree of peripheral parasite burden, suggesting a role for proinflammatory cytokines, in particular, IFN-γ in mediating this process. To further decipher the role of IFN-γ for malaria dyserythropoiesis, I made use of the Vav1::iCre/Ifngr2fl/fl mice, which are deficient in IFN-γ signalling specifically in haematopoietic cells. I observed that the absolute number of BM lineage negative (LIN—) cells, erythroid progenitors and erythroid precursors was significantly higher in Vav1::iCre/Ifngr2fl/fl mice, in comparison to control mice. Interestingly, the absolute number of basophilic and polychromatic erythroblasts in infected Vav1::iCre/Ifngr2fl/fl mice was significantly higher than in naive mice which was not the case for infected control mice. Based on these observations, my results suggest that IFN-γ plays a key role in malaria dyserythropoiesis by inhibiting the expansion and differentiation of erythroid progenitors and precursors, through a direct signalling in haematopoietic cells. In this study, I have demonstrated a novel and unpublished method for the identification and isolation of erythroid progenitor subsets at high purity and showed for the first time in an in vivo setting, that IFN-γ signalling in the haematopoietic compartment alone is crucial for malaria dyserythropoiesis.
URI
https://hdl.handle.net/1842/37547

http://dx.doi.org/10.7488/era/830
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  • Biological Sciences thesis and dissertation collection

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