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

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

Author information

1
Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06520, USA.
2
Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA.
3
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, 06520, USA.
4
Institut für Schlaganfall- und Demenzforschung, Klinikum der Universität München Ludwig-Maximilians-Universität München, D-81377, München, Germany.
5
Novartis Vaccines, Inc., 350 Massachusetts Avenue, Cambridge, MA, 02139, USA.
6
Leiden Malaria Research Group, Department of Parasitology, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands.
7
Slaoui Center for Vaccines Research, GSK Vaccines, 14200 Shady Grove Rd., Rockville MD, 20850, USA.
8
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, 06520, CT, USA.
9
Howard Hughes Medical Institute, Chevy Chase, 20815, MD, USA.
10
Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06520, USA. richard.bucala@yale.edu.
11
Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA. richard.bucala@yale.edu.
12
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, 06520, USA. richard.bucala@yale.edu.

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.

PMID:
30006528
PMCID:
PMC6045615
DOI:
10.1038/s41467-018-05041-7
[Indexed for MEDLINE]
Free PMC Article

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