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Dissertation
Plasmodium yoelii orthologue of macrophage migration inhibitory factor alters the course of blood stage malaria infection
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2009
DOI:
https://doi.org/10.17918/00002069
Abstract
Severe malaria is being recognized as a systemic inflammatory condition with increased production of inflammatory cytokines playing a major part in disease pathogenesis. Macrophage migration inhibitory factor (MIF) is an immune mediator that promotes a sustained pro-inflammatory response by inhibiting glucocorticoid-mediated down-regulation of inflammation, in addition to its role in the pathogenesis of malarial anemia. Plasmodium species were found to contain a conserved orthologue of MIF with significant similarity to mammalian MIF (30%). We used P. yoelii murine model to study the potential role of parasite-encoded MIF in the pathogenesis of malaria. Initial characterization of PyMIF using bacterially expressed recombinant protein in functional assays showed that PyMIF could actively induce chemotaxis of macrophages but did not show enzymatic activity or ability to induce or enhance TNF-[alpha] production from macrophages. Localization studies showed that PyMIF was expressed during infection and was detected in parasitized erythrocytes and in the extracellular medium. Neutralization of PyMIF by immunization-induced antibody during infection resulted in a low-persistent parasitemia and longer period of anemia. To further evaluate the role of PyMIF, two transgenic parasite lines that constitutively overexpress PyMIF on a nonlethal P. voelii 17X (PyMIFcon, PyMIF-OE 17X) and lethal P. yoelii I7XL background (PyMIF-OE 17XL) were generated. Challenge studies with transgenic parasites in mice showed that over-expression of PyMIF resulted in a modest decrease in disease severity. The non-lethal transgenic parasites showed a slight decrease in mean peak parasitemia and anemia. In infections with lethal transgenic parasites, a delay in mortality was observed, the extent of which was dependent on expression level of PyMIF. Overall, PyMIF over-expressing parasites showed lower parasite burdens indicating a trend towards attenuation. We studied early cytokine responses during challenge infection with PyMIF-OE 17XL parasites to determine the possible mechanism of PyMIF-based attenuation and saw increased IFN-[gamma] responses in the PyMIF-OE 17XL infected mice but no significant changes in other pro or anti-inflammatory cytokines. These data show that PyMIF has a protective role during infection and can modulate blood-stage malaria by inducing early IFN-[gamma] production and possibly, by increasing macrophage migration to the spleen to aid the clearance of parasites.
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Details
- Title
- Plasmodium yoelii orthologue of macrophage migration inhibitory factor alters the course of blood stage malaria infection
- Creators
- Swati Thorat
- Contributors
- James M. Burns Jr. (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 193 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Drexel University
- Other Identifier
- 991021889057804721