Abstract
Plasmodium species produce an ortholog of the cytokine macrophage migration inhibitory factor, PMIF, which modulates the host inflammatory response to malaria. Using a novel RNA replicon-based vaccine, we show the impact of PMIF immunoneutralization on the host response and observed improved control of liver and blood-stage Plasmodium infection, and complete protection from re-infection. Vaccination against PMIF delayed blood-stage patency after sporozoite infection, reduced the expression of the Th1-associated inflammatory markers TNF-α, IL-12, and IFN-γ during blood-stage infection, augmented Tfh cell and germinal center responses, increased anti-Plasmodium antibody titers, and enhanced the differentiation of antigen-experienced memory CD4 T cells and liver-resident CD8 T cells. Protection from re-infection was recapitulated by the adoptive transfer of CD8 or CD4 T cells from PMIF RNA immunized hosts. Parasite MIF inhibition may be a useful approach to promote immunity to Plasmodium and potentially other parasite genera that produce MIF orthologous proteins.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity / drug effects*
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Adoptive Transfer
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Animals
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Antibodies, Protozoan / biosynthesis*
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / parasitology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / parasitology
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Female
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Gene Expression
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Germinal Center / drug effects
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Germinal Center / immunology
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Germinal Center / parasitology
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Immunologic Memory / drug effects
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
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Macrophage Migration-Inhibitory Factors / genetics
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Macrophage Migration-Inhibitory Factors / immunology
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Malaria / immunology
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Malaria / parasitology
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Malaria / prevention & control*
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Malaria Vaccines / administration & dosage*
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Malaria Vaccines / biosynthesis
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Mice
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Mice, Inbred BALB C
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Plasmodium berghei / drug effects
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Plasmodium berghei / genetics
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Plasmodium berghei / immunology
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / genetics
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Protein Isoforms / immunology
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / genetics
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Protozoan Proteins / immunology
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RNA, Protozoan / genetics
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RNA, Protozoan / immunology
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
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Vaccines, DNA / administration & dosage*
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Vaccines, DNA / biosynthesis
Substances
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Antibodies, Protozoan
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Macrophage Migration-Inhibitory Factors
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Malaria Vaccines
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Protein Isoforms
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Protozoan Proteins
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RNA, Protozoan
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Tumor Necrosis Factor-alpha
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Vaccines, DNA
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macrophage-migration inhibitory factor, Plasmodium falciparum
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Interleukin-12
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Interferon-gamma