Dataset Information

Humoral and cellular immunity to Plasmodium falciparum merozoite surface protein 1 and protection from infection with blood-stage parasites.

ABSTRACT:

Background

?Acquired immunity to malaria develops with increasing age and repeated infections. Understanding immune correlates of protection from malaria would facilitate vaccine development and identification of biomarkers that reflect changes in susceptibility resulting from ongoing malaria control efforts.

Methods

?The relationship between immunoglobulin G (IgG) antibody and both interferon ? (IFN-?) and interleukin 10 (IL-10) responses to the 42-kD C-terminal fragment of Plasmodium falciparum merozoite surface protein 1 (MSP142) and the risk of (re)infection were examined following drug-mediated clearance of parasitemia in 94 adults and 95 children in an area of holoendemicity of western Kenya.

Results

?Positive IFN-? enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot assay (ELISPOT) responses to MSP142 3D7 were associated with delayed time to (re)infection, whereas high-titer IgG antibodies to MSP142 3D7 or FVO alleles were not independently predictive of the risk of (re)infection. When IFN-? and IL-10 responses were both present, the protective effect of IFN-? was abrogated. A Cox proportional hazard model including IFN-?, IL-10, MSP142 3D7 IgG antibody responses, hemoglobin S genotype, age, and infection status at baseline showed that the time to blood-stage infection correlated positively with IFN-? responses and negatively with IL-10 responses, younger age, and asymptomatic parasitemia.

Conclusions

?Evaluating combined allele-specific cellular and humoral immunity elicited by malaria provides a more informative measure of protection relative to evaluation of either measure alone.

SUBMITTER: Moormann AM

PROVIDER: S-EPMC3666139 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Publications

Humoral and cellular immunity to Plasmodium falciparum merozoite surface protein 1 and protection from infection with blood-stage parasites.

Moormann Ann M AM Sumba Peter Odada PO Chelimo Kiprotich K Fang Hua H Tisch Daniel J DJ Dent Arlene E AE John Chandy C CC Long Carole A CA Vulule John J Kazura James W JW

The Journal of infectious diseases 20130328 1

<h4>Background</h4> Acquired immunity to malaria develops with increasing age and repeated infections. Understanding immune correlates of protection from malaria would facilitate vaccine development and identification of biomarkers that reflect changes in susceptibility resulting from ongoing malaria control efforts.<h4>Methods</h4> The relationship between immunoglobulin G (IgG) antibody and both interferon γ (IFN-γ) and interleukin 10 (IL-10) responses to the 42-kD C-terminal fragment of Plasm ...[more]

PMID: 23539744

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Project description:Concerted efforts to fight malaria have caused significant reductions in global malaria cases and mortality. Sustaining this will be critical to avoid rebound and outbreaks of seasonal malaria. Identifying predictive attributes that define clinical malaria will be key to guide development of second-generation tools to fight malaria. Broadly reactive antibodies against variable surface antigens that are expressed on the surface of infected erythrocytes and merozoites stage antigens are targets of naturally acquired immunity and prime candidates for anti-malaria therapeutics and vaccines. However, predicting the relationship between the antigen-specific antibodies and protection from clinical malaria remains unresolved. Here, we used new datasets and multiple approaches combined with re-analysis of our previous data to assess the multi-dimensional and complex relationship between antibody responses and clinical malaria outcomes. We observed 22 antigens (17 PfEMP1 domains, 3 RIFIN family members, merozoite surface protein 3 (PF3D7_1035400), and merozoites-associated armadillo repeats protein (PF3D7_1035900) that were selected across three different clinical malaria definitions (1,000/2,500/5,000 parasites/µl plus fever). In addition, Principal Components Analysis (PCA) indicated that the first three components (Dim1, Dim2 and Dim3 with eigenvalues of 306, 48, and 29, respectively) accounted for 66.1% of the total variations seen. Specifically, the Dim1, Dim2 and Dim3 explained 52.8%, 8.2% and 5% of variability, respectively. We further observed a significant relationship between the first component scores and age with antibodies to PfEMP1 domains being the key contributing variables. This is consistent with a recent proposal suggesting that there is an ordered acquisition of antibodies targeting PfEMP1 proteins. Thus, although limited, and further work on the significance of the selected antigens will be required, these approaches may provide insights for identification of drivers of naturally acquired protective immunity as well as guide development of additional tools for malaria elimination and eradication.

Project description:BackgroundThree members of the Plasmodium vivax merozoite surface protein-3 (PvMSP3) family (PvMSP3-α, PvMSP3-β and PvMSP3-γ) were initially characterized and later shown to be part of a larger highly diverse family, encoded by a cluster of genes arranged head-to-tail in chromosome 10. PvMSP3-α and PvMSP3-β have become genetic markers in epidemiological studies, and are being evaluated as vaccine candidates. This research investigates the gene and protein expression of the entire family and pertinent implications.Methodology/principal findingsA 60 kb multigene locus from chromosome 10 in P. vivax (Salvador 1 strain) was studied to classify the number of pvmsp3 genes present, and compare their transcription, translation and protein localization patterns during blood-stage development. Eleven pvmsp3 paralogs encode an N-terminal NLRNG signature motif, a central domain containing repeated variable heptad sequences, and conserved hydrophilic C-terminal features. One additional ORF in the locus lacks these features and was excluded as a member of the family. Transcripts representing all eleven pvmsp3 genes were detected in trophozoite- and schizont-stage RNA. Quantitative immunoblots using schizont-stage extracts and antibodies specific for each PvMSP3 protein demonstrated that all but PvMSP3.11 could be detected. Homologs were also detected by immunoblot in the closely related simian species, P. cynomolgi and P. knowlesi. Immunofluorescence assays confirmed that eight of the PvMSP3s are present in mature schizonts. Uniquely, PvMSP3.7 was expressed exclusively at the apical end of merozoites.Conclusion/significanceSpecific proteins were detected representing the expression of 10 out of 11 genes confirmed as members of the pvmsp3 family. Eight PvMSP3s were visualized surrounding merozoites. In contrast, PvMSP3.7 was detected at the apical end of the merozoites. Pvmsp3.11 transcripts were present, though no corresponding protein was detected. PvMSP3 functions remain unknown. The ten expressed PvMSP3s are predicted to have unique and complementary functions in merozoite biology.

Dataset Information

Humoral and cellular immunity to Plasmodium falciparum merozoite surface protein 1 and protection from infection with blood-stage parasites.

Background

Methods

Results

Conclusions

Publications

Humoral and cellular immunity to Plasmodium falciparum merozoite surface protein 1 and protection from infection with blood-stage parasites.

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