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The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites

Nature volume 444, pages 937–940 (2006)Cite this article

Abstract

Malaria infection starts when mosquitoes inject sporozoites into the skin. The parasites enter the blood stream and make their way to the liver where they develop into the exo-erythrocytic forms (EEFs). Immunization with irradiated sporozoites (IrSp) leads to robust protection against malaria infection in rodents1, monkeys2 and humans3 by eliciting antibodies to circumsporozoite protein (CS) that inhibit sporozoite infectivity, and T cells that destroy the EEFs4. To study the role of non-CS antigens in protection, we produced CS transgenic mice that were tolerant to CS T-cell epitopes. Here we show that in the absence of T-cell-dependent immune responses to CS, protection induced by immunization with two doses of IrSp was greatly reduced. Thus, although hundreds of other Plasmodium genes are expressed in sporozoites5 and EEFs6, CS is a dominant protective antigen. Nevertheless, sterile immunity could be obtained by immunization of CS transgenics with three doses of IrSp.

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Figure 1: Expression of CS in transgenic mice.
Figure 2: Circulating CS in the transgenic mice inhibits infectivity of sporozoites.
Figure 3: CS-Tg mice are tolerant to the H-2K d restricted CTL epitope of P. yoelii CS.
Figure 4: CS-Tg mice produce T-cell-independent antibodies to CS.
Figure 5: Protection mediated by immunization with IrSp in BALB/c and C57BL/6 CS-Tg mice.

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Acknowledgements

V.N. is supported by the Gates Foundation, R.S.N by the Starr Foundation, F.Z. by the NIH, and M.C.N. is a Howard Hughes Investigator. We thank A. Nussenzweig for suggestions. S.B. is supported by the Pew Foundation.

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Author notes

  1. Kota Arun Kumar and Gen-ichiro Sano: These authors contributed equally to this work.

Authors and Affiliations

  1. Michael Heidelberger Division of Immunology, Department of Pathology, New York University School of Medicine, New York, New York, 10016, USA

    Kota Arun Kumar & Victor Nussenzweig

  2. Department of Microbiology and Immunology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Gen-ichiro Sano

  3. Laboratory of Molecular Immunology and Howard Hughes Institute, Rockefeller University, New York, New York, 10021, USA

    Silvia Boscardin & Michel C. Nussenzweig

  4. Department of Medical and Molecular Parasitology, and Department of Pathology, New York University School of Medicine, New York, New York, 10016, USA

    Ruth S. Nussenzweig

  5. Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA

    Fidel Zavala

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Correspondence to Kota Arun Kumar.

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Supplementary Methods

The file contains Supplementary Methods which include the experimental details that have not been elaborated in the main text of the manuscript and Supplementary Figures 1-5 and legends (PDF 3713 kb)

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Arun Kumar, K., Sano, Gi., Boscardin, S. et al. The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites. Nature 444, 937–940 (2006). https://doi.org/10.1038/nature05361

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