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J. Biol. Chem., Vol. 279, Issue 25, 26635-26644, June 18, 2004

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Plasmodium Ookinete-secreted Proteins Secreted through a Common Micronemal Pathway Are Targets of Blocking Malaria Transmission^*

Fengwu Li, Thomas J. Templeton, Vsevolod Popov¶, Jason E. Comer¶, Takafumi Tsuboi||, Motomi Torii||, and Joseph M. Vinetz**

From the Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0640, the Department of Microbiology and Immunology, Weill Medical College, Cornell University, New York, New York 10021, the ^¶Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609, and the ^||Department of Molecular Parasitology, Ehime University School of Medicine, Shigenobucho, Ehime 791-0295, Japan

The mosquito midgut ookinete stage of the malaria parasite, Plasmodium, possesses microneme secretory organelles that mediate locomotion and midgut wall egress to establish sporogonic stages and subsequent transmission. The purpose of this study was 2-fold: 1) to determine whether there exists a single micronemal population with respect to soluble and membrane-associated secreted proteins; and 2) to evaluate the ookinete micronemal proteins chitinase (PgCHT1), circumsporozoite and TRAP-related protein (CTRP), and von Willebrand factor A domain-related protein (WARP) as immunological targets eliciting sera-blocking malaria parasite infectivity to mosquitoes. Indirect immunofluorescence localization studies in Plasmodium gallinaceum using specific antisera showed that all three proteins are distributed intracellularly with a similar granular cytoplasmic appearance and with focal concentration of PgCHT1 and PgCTRP, but not PgWARP, at the ookinete apical end. Immunogold double-labeling electron microscopy, using antisera against the membrane-associated protein CTRP and the soluble WARP, showed that these two proteins co-localized to the same micronemal population. Within the microneme CTRP was associated peripherally at the microneme membrane, whereas PgCHT1 and WARP were diffuse within the micronemal lumen. Sera produced against Plasmodium falciparum WARP significantly reduced the infectivity of P. gallinaceum to Aedes aegypti and P. falciparum to Anopheles mosquitoes. Antisera against PgCTRP and PgCHT1 also significantly reduced the infectivity of P. gallinaceum for A. aegypti. These results support the concept that ookinete micronemal proteins may constitute a general class of malaria transmission-blocking vaccine candidates.

Received for publication, February 8, 2004 , and in revised form, March 23, 2004.

This work was presented at the Annual Meetings of the American Society of Tropical Medicine and Hygiene, November 2001, Atlanta, GA and Denver, CO, November 2002. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^* This work was supported by National Institutes of Health Grants R01AI45999 and K02AI50049, the Culpeper Scholarship of the Rockefeller Brothers Fund (to J. M. V.), and in part by Grants-in-aid for Scientific Research on Priority Areas 15019072 (to T. T.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

^** To whom correspondence and reprint requests should be addressed: Cellular and Molecular Medicine-East, Rm. 2052, University of California, San Diego, 9500 Gilman Dr.-0640, La Jolla, CA 92093-0640. Tel.: 858-822-4469; Fax: 858-552-4398; E-mail: jvinetz{at}ucsd.edu.

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