Dissertation
Analysis of vaccine- and infection-induced immune responses contributing to suppression of blood-stage malaria in the Plasmodium yoelii Robert model
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2008
DOI:
https://doi.org/10.17918/00009268
Abstract
Immunization with Plasmodium yoelii merozoite surface protein-8 (PyMSP-8) protects mice from lethal malaria but does not prevent infection. Using this MSP-based vaccine model, vaccine- and infection-induced immune responses that contribute to protection were investigated. Analysis of prechallenge sera from rPyMSP-8 immunized C57BL/6 and BALB/c mice revealed high and comparable levels of antigen-specific IgG but differences in isotype profile and specificity for conformational epitopes were noted. As both strains of mice were similarly protected against P. yoelii, vaccine-induced responses did not correlate with protection. However, passive immunization studies suggested that protection resulted from differing immune responses. Studies with cytokine-deficient mice showed that protection was induced by immunization of C57BL/6 mice only when IL-4 and IFN-[gamma] were both present. In BALB/c mice, the absence of either IL-4 or IFN-[gamma] led to predictable shifts in the IgG isotype profile but did not reduce the magnitude of the antibody response induced by rPyMSP-8 immunization. Immunized IL-4^[-/-] BALB/c mice were protected against P. yoelii. Surprisingly, immunized IFN-[gamma]^[-/-] BALB/c mice initially controlled parasite growth but eventually succumbed to infection. Analysis of cytokine production revealed that P. yoelii infection induced two distinct peaks of IFN-[gamma] in rPyMSP-8 immunized BALB/c mice. Further evaluation determined that it was the early production of IFN-[gamma] that was necessary for protection in immunized and challenged mice. Maximal parasite growth in rPyMSP-8 immunized mice occurred during a period of sustained TGF-[beta] production. TGF-[beta] neutralization did not lead to an uncontrolled, pathologic proinflammatory response but resulted in modestly improved protection in rPyMSP-8 immunized mice. There were no significant differences in antibody or cytokine responses between isotype- and anti-TGF-[beta]-treated, rPyMSP-8 immunized mice. Interestingly, rPyMSP-8 immunized IFN-[gamma]^[-/-] BALB/c mice, which normally succumb to lethal P. yoelii malaria, were protected when TGF-[beta] was neutralized. These data suggest that in rPyMSP-8 immunized mice, TGF-[beta] is not necessary for downmodulating inflammatory responses and is detrimental to disease outcome in the absence of IFN-[gamma]. Combined, the data indicate that suppression of lethal P. yoelii in rPyMSP-8 immunized mice requires high titers of PyMSP-8 antibody and infection-induced IFN-[gamma] which is associated with development of the protective response to additional parasite antigens.
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Details
- Title
- Analysis of vaccine- and infection-induced immune responses contributing to suppression of blood-stage malaria in the Plasmodium yoelii Robert model
- Creators
- Patricia M. Petritus
- 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, 147 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021889104904721