Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection

Nat Commun. 2018 Jul 13;9(1):2714. doi: 10.1038/s41467-018-05041-7.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / drug effects*
  • Adoptive Transfer
  • Animals
  • Antibodies, Protozoan / biosynthesis*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / parasitology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / parasitology
  • Female
  • Gene Expression
  • Germinal Center / drug effects
  • Germinal Center / immunology
  • Germinal Center / parasitology
  • Immunologic Memory / drug effects
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / genetics
  • Macrophage Migration-Inhibitory Factors / immunology
  • Malaria / immunology
  • Malaria / parasitology
  • Malaria / prevention & control*
  • Malaria Vaccines / administration & dosage*
  • Malaria Vaccines / biosynthesis
  • Mice
  • Mice, Inbred BALB C
  • Plasmodium berghei / drug effects
  • Plasmodium berghei / genetics
  • Plasmodium berghei / immunology
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / immunology
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / immunology
  • RNA, Protozoan / genetics
  • RNA, Protozoan / immunology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Vaccines, DNA / administration & dosage*
  • Vaccines, DNA / biosynthesis

Substances

  • Antibodies, Protozoan
  • Macrophage Migration-Inhibitory Factors
  • Malaria Vaccines
  • Protein Isoforms
  • Protozoan Proteins
  • RNA, Protozoan
  • Tumor Necrosis Factor-alpha
  • Vaccines, DNA
  • macrophage-migration inhibitory factor, Plasmodium falciparum
  • Interleukin-12
  • Interferon-gamma