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Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin

Nature Microbiology volume 3, pages 1224–1233 (2018)Cite this article

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Abstract

The circumsporozoite protein (CSP) is the major surface protein of malaria sporozoites (SPZs), the motile and invasive parasite stage inoculated in the host skin by infected mosquitoes. Antibodies against the central CSP repeats of different plasmodial species are known to block SPZ infectivity1,2,3,4,5, but the precise mechanism by which these effectors operate is not completely understood. Here, using a rodent Plasmodium yoelii malaria model, we show that sterile protection mediated by anti-P. yoelii CSP humoral immunity depends on the parasite inoculation into the host skin, where antibodies inhibit motility and kill P. yoelii SPZs via a characteristic ‘dotty death’ phenotype. Passive transfer of an anti-repeat monoclonal antibody (mAb) recapitulates the skin inoculation-dependent protection, in a complement- and Fc receptor γ-independent manner. This purified mAb also decreases motility and, notably, induces the dotty death of P. yoelii SPZs in vitro. Cytotoxicity is species-transcendent since cognate anti-CSP repeat mAbs also kill Plasmodium berghei and Plasmodium falciparum SPZs. mAb cytotoxicity requires the actomyosin motor-dependent translocation and stripping of the protective CSP surface coat, rendering the parasite membrane susceptible to the SPZ pore-forming-like protein secreted to wound and traverse the host cell membrane6. The loss of SPZ fitness caused by anti-P. yoelii CSP repeat antibodies is thus a dynamic process initiated in the host skin where SPZs either stop moving7, or migrate and traverse cells to progress through the host tissues7,8,9 at the eventual expense of their own life.

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Fig. 1: Sterilizing anti-P. yoelii CSP humoral immunity is dependent on the host skin inoculation with SPZs.
Fig. 2: Decrease of motility and killing of parasites in the skin of CSP-immunized mice.
Fig. 3: Complement and FcRγ-independent cytotoxic antibody sterilizes SPZ infection.
Fig. 4: Motility, secretion and SPZ-specific wounding proteins play a critical role in the death mediated by the cytotoxic antibody.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank the team of the Centre of Production and Infection of Anopheles, Institut Pasteur, in particular M. Szatanik, C. Thouvenot, S. Golba, J. Pham and A. Lorthiois for providing mosquitoes and P. falciparum SPZs; the team of the Platform of Dynamic Imaging, Institut Pasteur, in particular Dr S. Shorte and M.-A. Nicola for the access to the confocal microscopes and IVIS system; Dr K. Kim from the Albert Einstein College of Medicine for providing the P. yoelii YM GFP-luciferase; Dr V. Nussenzweig from New York University for providing the P. berghei and falciparumnized P. berghei parasites; Dr M. Soares from the Instituto Gulbenkian for providing the JHT−/− mice; Dr P.-M. Lledo and Dr P. Bruhns from the Institut Pasteur for providing, respectively, the C3−/− and the FcRγ−/− mice; the team of the Clinical Investigation and Access to BioResources, in particular M.-N. Ungeheuer for providing the erythrocytes for the P. falciparum culture; Dr P. Baldacci and Dr P. Formaglio for their critical reading of the manuscript. This work was supported by funds from Institut Pasteur, Paris, the French National Research Agency (grant no. ANR-14-CE16-Im3alaria), the French Government’s ‘Investissement d’Avenir’ program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR-10-LABX-62-IBEID) and ‘ParaFrap’ (grant no. ANR-11-LABX-0024), the São Paulo Research Foundation (FAPESP, grant no. 2014/50631-0), the National Council for Scientific and Technological Development (CNPq), the BNP Paribas CIB, the Portuguese Science and Technology Foundation (FCT, grant no. IF/00881/2012/CP0158) and the European Social Fund (Human Potential Operational Programme).

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Authors and Affiliations

  1. Unit of Malaria Infection & Immunity, Institut Pasteur, Paris, France

    Eduardo Aliprandini, Raquel Hoffmann Panatieri, Sabine Thiberge & Rogerio Amino

  2. Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Joana Tavares

  3. Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

    Joana Tavares

  4. Parasitology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    Raquel Hoffmann Panatieri, Marcio Massao Yamamoto & Silvia Beatriz Boscardin

  5. Centre de Production et d’Infection des Anophèles, Institut Pasteur, Paris, France

    Sabine Thiberge

  6. Sorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses, CIMI, Paris, France

    Olivier Silvie

  7. Department of Molecular Parasitology, Ehime University, Ehime, Japan

    Tomoko Ishino

  8. Department of Medical Zoology, Mie University School of Medicine, Mie, Japan

    Masao Yuda

  9. Plateforme d’Ingénierie des Anticorps, Institut Pasteur, Paris, France

    Sylvie Dartevelle & François Traincard

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Contributions

R.A., S.B.B., E.A. and J.T. conceived and designed the experiments. E.A., J.T., S.T. and R.H.P performed the experiments. M.M.Y., S.D. and F.T. generated the hybridomas. O.S., T.I. and M.Y. contributed with the transgenic parasites. R.A., S.B.B., E.A., J.T., S.T. and R.H.P. analysed the data. R.A, E.A, J.T. and S.B.B. wrote the paper.

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Correspondence to Silvia Beatriz Boscardin or Rogerio Amino.

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Aliprandini, E., Tavares, J., Panatieri, R.H. et al. Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin. Nat Microbiol 3, 1224–1233 (2018). https://doi.org/10.1038/s41564-018-0254-z

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