The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites

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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Correspondence to Kota Arun Kumar.

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