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J. Biol. Chem., Vol. 278, Issue 39, 37658-37663, September 26, 2003

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Selective Inhibition of a Two-step Egress of Malaria Parasites from the Host Erythrocyte^*

Mark E. Wickham  , Janetta G. Culvenor ¶ and Alan F. Cowman  ||

From the The Walter and Eliza Hall Institute of Medical Research, and ^¶Department of Pathology, The University of Melbourne, Melbourne 3050, Australia

Escape from the host erythrocyte by the invasive stage of the malaria parasite Plasmodium falciparum is a fundamental step in the pathogenesis of malaria of which little is known. Upon merozoite invasion of the host cell, the parasite becomes enclosed within a parasitophorous vacuole, the compartment in which the parasite undergoes growth followed by asexual division to produce 16–32 daughter merozoites. These daughter cells are released upon parasitophorous vacuole and erythrocyte membrane rupture. To examine the process of merozoite release, we used P. falciparum lines expressing green fluorescent protein-chimeric proteins targeted to the compartments from which merozoites must exit: the parasitophorous vacuole and the host erythrocyte cytosol. This allowed visualization of merozoite release in live parasites. Herein we provide the first evidence in live, untreated cells that merozoite release involves a primary rupture of the parasitophorous vacuole membrane followed by a secondary rupture of the erythrocyte plasma membrane. We have confirmed, with the use of immunoelectron microscopy, that parasitophorous vacuole membrane rupture occurs before erythrocyte plasma membrane rupture in untransfected wild-type parasites. We have also demonstrated selective inhibition of each step in this two-step process of exit using different protease inhibitors, implicating the involvement of distinct proteases in each of these steps. This will facilitate the identification of the parasite and host molecules involved in merozoite release.

Received for publication, May 19, 2003 , and in revised form, July 10, 2003.

^* This work was supported by Grant R01-AI44008 from the National Institutes of Health and a grant from the National Health and Medical Research Council of Australia. 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 an Australian Postgraduate Research Award.

^|| Supported by an International Research Fellowship from the Howard Hughes Medical Institute. To whom correspondence should be addressed: 1G Royal Parade, Melbourne 3050, Australia. Tel.: 61-3-93452555; Fax: 61-3-93470852; E-mail: cowman{at}wehi.edu.au.

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