| Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites. | |
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MedLine Citation:
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PMID: 20657824 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Radiation-attenuated Plasmodium sporozoites (RAS) are the only vaccine shown to induce sterilizing protection against malaria in both humans and rodents. Importantly, these "whole-parasite" vaccines are currently under evaluation in human clinical trials. Studies with inbred mice reveal that RAS-induced CD8 T cells targeting liver-stage parasites are critical for protection. However, the paucity of defined T cell epitopes for these parasites has precluded precise understanding of the specific characteristics of RAS-induced protective CD8 T cell responses. Thus, it is not known whether quantitative or qualitative differences in RAS-induced CD8 T cell responses underlie the relative resistance or susceptibility of immune inbred mice to sporozoite challenge. Moreover, whether extraordinarily large CD8 T cell responses are generated and required for protection following RAS immunization, as has been described for CD8 T cell responses following single-antigen subunit vaccination, remains unknown. Here, we used surrogate T cell activation markers to identify and track whole-parasite, RAS-vaccine-induced effector and memory CD8 T cell responses. Our data show that the differential susceptibility of RAS-immune inbred mouse strains to Plasmodium berghei or P. yoelii sporozoite challenge does not result from host- or parasite-specific decreases in the CD8 T cell response. Moreover, the surrogate activation marker approach allowed us for the first time to evaluate CD8 T cell responses and protective immunity following RAS-immunization in outbred hosts. Importantly, we show that compared to a protective subunit vaccine that elicits a CD8 T cell response to a single epitope, diversifying the targeted antigens through whole-parasite RAS immunization only minimally, if at all, reduced the numerical requirements for memory CD8 T cell-mediated protection. Thus, our studies reveal that extremely high frequencies of RAS-induced memory CD8 T cells are required, but may not suffice, for sterilizing anti-Plasmodial immunity. These data provide new insights into protective CD8 T cell responses elicited by RAS-immunization in genetically diverse hosts, information with relevance to developing attenuated whole-parasite vaccines. |
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Authors:
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Nathan W Schmidt; Noah S Butler; Vladimir P Badovinac; John T Harty |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-07-15 |
Journal Detail:
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Title: PLoS pathogens Volume: 6 ISSN: 1553-7374 ISO Abbreviation: PLoS Pathog. Publication Date: 2010 |
Date Detail:
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Created Date: 2010-07-26 Completed Date: 2010-10-19 Revised Date: 2011-01-27 |
Medline Journal Info:
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Nlm Unique ID: 101238921 Medline TA: PLoS Pathog Country: United States |
Other Details:
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Languages: eng Pagination: e1000998 Citation Subset: IM |
Affiliation:
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Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antimalarials / immunology CD8-Positive T-Lymphocytes / immunology* Immunity Immunization* Immunologic Memory Liver / immunology, parasitology* Malaria Vaccines / administration & dosage, immunology* Mice Sporozoites / immunology*, radiation effects Vaccines, Attenuated / immunology |
| Grant Support | |
ID/Acronym/Agency:
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1-F32-AI084329/AI/NIAID NIH HHS; 5-T32-AI0726024/AI/NIAID NIH HHS; AI83286/AI/NIAID NIH HHS; R01 AI085515-02/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antimalarials; 0/Malaria Vaccines; 0/Vaccines, Attenuated |
| Comments/Corrections | |
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