Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors

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Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths each year1. Plasmodium falciparum causes most life-threatening cases of malaria. Acquired immunity to malaria is inefficient, even after repeated exposure to P. falciparum2, but the immune regulatory mechanisms used by P. falciparum remain largely unknown. Here we show that P. falciparum uses immune inhibitory receptors to achieve immune evasion. RIFIN proteins are products of a polymorphic multigene family comprising approximately 150–200 genes per parasite genome3 that are expressed on the surface of infected erythrocytes. We found that a subset of RIFINs binds to either leucocyte immunoglobulin-like receptor B1 (LILRB1) or leucocyte-associated immunoglobulin-like receptor 1 (LAIR1). LILRB1-binding RIFINs inhibit activation of LILRB1-expressing B cells and natural killer (NK) cells. Furthermore, P. falciparum-infected erythrocytes isolated from patients with severe malaria were more likely to interact with LILRB1 than erythrocytes from patients with non-severe malaria, although an extended study with larger sample sizes is required to confirm this finding. Our results suggest that P. falciparum has acquired multiple RIFINs to evade the host immune system by targeting immune inhibitory receptors.

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We thank T. Mitamura for discussions, K. Saito for mass spectrometry analysis, M. Matsumoto and S. Matsuoka for technical assistance, the Thai and Tanzanian donors and the Japanese Red Cross Society for providing human erythrocytes and human plasma. This work was partly supported by the Japanese Initiative for Progress of Research on Infectious Disease for Global Epidemic from the Japan Agency for Medical Research and Development (AMED) (H.A.), the Platform Project for Supporting Drug Discovery and Life Science Research from AMED (J.T.), JSPS KAKENHI grant numbers JP16K08839 (K.H.), JP16H05195 (T.Su.), JP15K08531 (M.K.), MEXT KAKENHI grant numbers JP26117714 (H.A.), JP23117008 (T.T.), JP24115005 (H.A.), the Senri Life Science Foundation (K.H.), the Kato Memorial Bioscience Foundation (K.H.), the Danish Council for Independent Research grants 1333-00220 (C.W.W.) and 4004-00624B (T.L.), The Lundbeck Foundation (T.L.) and the United States National Institutes of Health (NIH R01HL130678, T.L.). F.S was supported by the Taniguchi Memorial Fellowship program.

Author information

Author notes

    • Takeshi Satoh

    Present address: Division of Systems Immunology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.

    • Fumiji Saito
    •  & Kouyuki Hirayasu

    These authors contributed equally to this work.


  1. Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan

    • Fumiji Saito
    • , Takeshi Satoh
    • , Masako Kohyama
    • , Tadahiro Suenaga
    •  & Hisashi Arase
  2. Laboratory of Immunochemistry, WPI Immunology Frontier Research Centre, Osaka University, Suita, Osaka 565-0871, Japan

    • Kouyuki Hirayasu
    • , Kyoko Shida
    • , Masako Kohyama
    • , Tadahiro Suenaga
    •  & Hisashi Arase
  3. Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark

    • Christian W. Wang
    •  & Thomas Lavstsen
  4. Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark

    • Christian W. Wang
    •  & Thomas Lavstsen
  5. National Institute for Medical Research, Tanga Research Centre, Tanga, Tanzania

    • John Lusingu
  6. Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan

    • Takao Arimori
    •  & Junichi Takagi
  7. Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan

    • Nirianne Marie Q. Palacpac
    • , Sawako Itagaki
    •  & Toshihiro Horii
  8. Department of Medical Zoology, School of Medicine, Mie University, Tsu, Mie 514-8507, Japan

    • Shiroh Iwanaga
  9. Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

    • Shiroh Iwanaga
  10. Division of Malaria Research, Proteo-Science Centre, Ehime University, Matsuyama, Ehime, 790-8577, Japan

    • Eizo Takashima
    •  & Takafumi Tsuboi
  11. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Marco Colonna


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F.S. and K.H. performed most of the binding and functional experiments, and analysed and discussed the data. T.Sa. performed limiting dilution experiments and assisted with ligand identification. C.W.W. performed binding and serological analyses in Tanzania. J.L. assisted with experiments in Tanzania. T.A. performed CD spectral analysis. K.S. prepared recombinant plasmids. N.M.Q.P. assisted with P. falciparum culture and cloning. S.It. assisted with P. falciparum culture. S.Iw. assisted with transgenic parasite experiments and provided Thai P. falciparum isolates. E.T. prepared wheat germ cell-free proteins. T.T. designed wheat germ cell-free protein expression system and discussed the data. M.K. assisted with functional experiments. T.Su. assisted with ligand identification. M.C. assisted with LILR analyses. J.T. assisted with protein experiments and discussed the data. T.L. assisted with experiments in Tanzania and discussed the data. T.H. assisted with P. falciparum experimental design and discussed the data. H.A. designed the study and analysed the data. All authors contributed to the writing of the manuscript.

Competing interests

Competing financial interests: Osaka university has filed a provisional patent application that covers the use of LILRB1-binding RIFINs as a possible target for malaria vaccine. F.S., K.H. and H.A. are listed as inventors.

Corresponding author

Correspondence to Hisashi Arase.

Reviewer Information Nature thanks P. Preiser and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Information

    This file contains original gel images, gating strategy for flow cytometry analysis and sequence chromatogram of cloned rif genes.

Excel files

  1. 1.

    Supplementary Table 1

    This file contains information on peptides identified by mass spectrometry analyses.

  2. 2.

    Supplementary Table 2

    This file contains information on 33 different rif genes used for generating RIFIN-transgenic parasites.

  3. 3.

    Supplementary Table 3

    This file contains information on primers used to clone rif genes.


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