Abstract
We recently identified novel Plasmodium berghei (Pb) liver stage (LS) genes that as DNA vaccines significantly reduce Pb LS parasite burden (LPB) in C57Bl/6 (B6) mice through a mechanism mediated, in part, by CD8 T cells. In this study, we sought to determine fine antigen (Ag) specificities of CD8 T cells that target LS malaria parasites. Guided by algorithms for predicting MHC class I-restricted epitopes, we ranked sequences of 32 Pb LS Ags and selected ~400 peptides restricted by mouse H-2Kb and H-2Db alleles for analysis in the high-throughput method of caged MHC class I-tetramer technology. We identified a 9-mer H-2Kb restricted CD8 T cell epitope, Kb-17, which specifically recognized and activated CD8 T cell responses in B6 mice immunized with Pb radiation-attenuated sporozoites (RAS) and challenged with infectious sporozoites (spz). The Kb-17 peptide is derived from the recently described novel protective Pb LS Ag, PBANKA_1031000 (MIF4G-like protein). Notably, immunization with the Kb-17 epitope delivered in the form of a minigene in the adenovirus serotype 5 vector reduced LPB in mice infected with spz. On the basis of our results, Kb-17 peptide was available for CD8 T cell activation and recall following immunization with Pb RAS and challenge with infectious spz. The identification of a novel MHC class I-restricted epitope from the protective Pb LS Ag, MIF4G-like protein, is crucial for advancing our understanding of immune responses to Plasmodium and by extension, toward vaccine development against malaria.
Highlights
Malaria remains one of the most serious infectious diseases that plagues residents of tropical areas such as Sub-Saharan Africa, South-East Asia, and the Indian subcontinent
We have demonstrated that protracted protection induced by Plasmodium berghei (Pb) radiation-attenuated sporozoites (RAS) depends on liver stage (LS) Ag-specific effector and memory CD8 T cells [13]
Using transcriptome approach, we identified several LS Ags that confer partial protection against rodent malaria spz challenge and protection is enhanced by combining LS Ags with circumsporozoite protein (CSP) [17]
Summary
Malaria remains one of the most serious infectious diseases that plagues residents of tropical areas such as Sub-Saharan Africa, South-East Asia, and the Indian subcontinent. An effective malaria vaccine is still unavailable. The most advanced malaria vaccine, RTS,S, based on the Pf circumsporozoite protein (CSP), the major sporozoite (spz) surface antigen (Ag), induces but a modicum of protection from clinical malaria. P. berghei CD8 T Cell Epitope and protection is short-lived [2,3,4]. According to the majority of results from studies of immune responses induced by RTS,S, there appears to be an absence of CSP-specific CD8 T cells [5] and that alone may limit the effectiveness of the vaccine. Addition of antigenic targets to the CSP-based vaccine, and liver stage (LS) Ags that would be targeted by CD8 T cells, might rescue the modest efficacy of the otherwise well designed RTS,S vaccine
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