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J. Biol. Chem., Vol. 280, Issue 8, 6752-6760, February 25, 2005

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A Surface Phospholipase Is Involved in the Migration of Plasmodium Sporozoites through Cells^*

Purnima Bhanot, Kristine Schauer, Isabelle Coppens¶, and Victor Nussenzweig||

From the Department of Pathology, New York University School of Medicine, New York, New York 10016 and ^¶Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205

Plasmodium sporozoites, injected by mosquitoes into the skin of the host, traverse cells during their migration to hepatocytes where they continue their life cycle. The mechanisms used by the parasite to rupture the plasma membrane of the host cells are not known. Here we report the presence of a phospholipase on the surface of Plasmodium berghei sporozoites (P. berghei phospholipase; Pb PL) and demonstrate that it is involved in the establishment of a malaria infection in vivo. Pb PL is highly conserved among the Plasmodium species. The protein is about 750 amino acids, with a predicted signal sequence and a carboxyl terminus that is 32% identical to the vertebrate lecithin:cholesterol acyltransferase, a secreted phospholipase. Pb PL contains a motif characteristic of lipases and a catalytic triad of a serine, aspartate, and histidine that is found in several phospholipases. We have verified its lipase and membrane lytic activity in vitro, using recombinant baculovirus-expressed protein. To study its role in vivo, we have disrupted the P. berghei PL open reading frame and generated mutants in its active site. During an infection through mosquito bite, the infectivity of the knock-out parasites in the liver is decreased by 90%. The prepatent period of the resulting blood infection is 1 day longer as compared with wild type. Further, the mutant sporozoites are impaired in their ability to cross epithelial cell layers. Thus, the Pb PL functions as a lipase to damage cell membranes and facilitates sporozoite passage through cells during their migration from the skin to the bloodstream.

Received for publication, October 7, 2004 , and in revised form, December 3, 2004.

^* 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.

^|| Supported by National Institutes of Health Grant NIHAI04997.

William T. Golden fellow of the Life Sciences Research Foundation. To whom correspondence should be addressed: Public Health Research Institute, 225 Warren St., W250H, Newark, NJ 07103. Tel.: 973-854-3218; Fax: 973-854-3101; E-mail: bhanot{at}phri.org.

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