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Dissertation
Characterization of merozoite surface protein-8 and evaluation of its potential as a blood-stage malaria vaccine candidate
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2006
DOI:
https://doi.org/10.17918/00008767
Abstract
Plasmodium yoelii merozoite surface protein-8 ( PyMSP-8) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with a C-terminal double epidermal growth factor (EGF)-like domain. PyMSP-8 is expressed throughout the blood-stage and co-localizes with merozoite surface protein-1 (MSP-1), a major vaccine candidate, on the merozoite surface in the late-stage schizont. Immunization with recombinant PyMSP-8 (rPyMSP-8) induced protection against normocyte-associated but not reticulocyte-associated P. yoelii malaria. This protection is antibody-dependent and requires non-polymorphic conformational B-cell epitopes. Interestingly, rPyMSP-8 binds to the surface of both mouse normocytes and reticulocytes, but not human erythrocytes. Moreover, this binding cannot be inhibited by protective antibodies, suggesting that PyMSP-8 plays a role in merozoite invasion, but that MSP-8 specific neutralizing antibodies may not confer protection by disrupting a specific receptor-ligand interaction. Because the double EGF-like domains of MSP-1 and MSP-8 have been proposed to play similar function(s) during blood-stage parasite development, presumably in merozoite invasion process, a chimeric antigen composed of the C-terminus of PyMSP-1 and the full-length PyMSP-8 was constructed in order to improve overall vaccine efficacy. As expected, immunization with this chimeric antigen induced solid protection against lethal P. yoelii 17XL infection. However, no improvement in protection against reticulocyte-restricted nonlethal P. yoelii 17X challenge was observed. Therefore, MSP-specific antibodies seem to only suppress P. yoelii parasite growth in normocytes but not reticulocytes. By comparing gene expression patterns of P. yoelii 17XL parasites from PyMSP-8 immunized animals versus adjuvant control animals, we conclude that these parasites altered their host cell preference to reticulocytes by the differential expression of sets of parasite proteins expressed on the merozoite surface as well as the surface of infected erythrocytes, and therefore escaped the MSP-8 specific neutralizing antibodies. In conclusion, MSP-8 is a promising vaccine candidate. Inclusion of MSP-8 improves the protective efficacy of an MSP-1 based vaccine against normocyte-associated parasites. However, parasites may limit efficacy of MSP-based vaccines by alternation of their host cell preference. Thus, additional targets such as antigens expressed on the surface of infected erythrocytes or antigens associated with reticulocyte invasion may need to be included in future multivalent vaccine trials.
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Details
- Title
- Characterization of merozoite surface protein-8 and evaluation of its potential as a blood-stage malaria vaccine candidate
- Creators
- Qifang Shi
- 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
- xii, 173 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021888940904721