Abstract
BackgroundThe Plasmodium purine salvage enzyme, hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) can protect mice against Plasmodium yoelii pRBC challenge in a T cell-dependent manner and has, therefore, been proposed as a novel vaccine candidate. It is not known whether natural exposure to Plasmodium falciparum stimulates HGXPRT T cell reactivity in humans.MethodsPBMC and plasma collected from malaria-exposed Indonesians during infection and 7–28 days after anti-malarial therapy, were assessed for HGXPRT recognition using CFSE proliferation, IFNγ ELISPOT assay and ELISA.ResultsHGXPRT-specific T cell proliferation was found in 44% of patients during acute infection; in 80% of responders both CD4+ and CD8+ T cell subsets proliferated. Antigen-specific T cell proliferation was largely lost within 28 days of parasite clearance. HGXPRT-specific IFN-γ production was more frequent 28 days after treatment than during acute infection. HGXPRT-specific plasma IgG was undetectable even in individuals exposed to malaria for at least two years.ConclusionThe prevalence of acute proliferative and convalescent IFNγ responses to HGXPRT demonstrates cellular immunogenicity in humans. Further studies to determine minimal HGXPRT epitopes, the specificity of responses for Plasmodia and associations with protection are required. Frequent and robust T cell proliferation, high sequence conservation among Plasmodium species and absent IgG responses distinguish HGXPRT from other malaria antigens.
Highlights
The Plasmodium purine salvage enzyme, hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) can protect mice against Plasmodium yoelii parasitized red blood cells (pRBC) challenge in a T cell-dependent manner and has, been proposed as a novel vaccine candidate
HGXPRT-specific T cell proliferation during acute malaria and in convalescence To evaluate whether P. falciparum exposure induced T cell responses that recognize HGXPRT, cross-sectional PBMC collected during acute symptomatic malaria and one month after anti-malarial treatment were tested for proliferation in response to recombinant HGXPRT
During acute malaria HGXPRT was recognized by 44% (15/34) of subjects (Table 1)
Summary
The Plasmodium purine salvage enzyme, hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) can protect mice against Plasmodium yoelii pRBC challenge in a T cell-dependent manner and has, been proposed as a novel vaccine candidate. It is not known whether natural exposure to Plasmodium falciparum stimulates HGXPRT T cell reactivity in humans. The pre-erythrocytic stage vaccine RTS,S confers partial but not complete protection against clinical disease [6,7,8], and a DNA-MVA heterologous prime-boost regimen can protect against sporozoite challenge [9] All of these strategies elicit cellular immune responses, which contribute to protection [10,11]. Since T cell mediated protection has been demonstrated in the absence of antibodies [4,12,13,14,15,16,17], the identification of parasite antigens targeted by cellular responses is required to better understand the development of immunity to disease and to identify novel antigens that warrant consideration as potential vaccine candidates
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