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      Exoerythrocytic Plasmodium Parasites Secrete a Cysteine Protease Inhibitor Involved in Sporozoite Invasion and Capable of Blocking Cell Death of Host Hepatocytes

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          Abstract

          Plasmodium parasites must control cysteine protease activity that is critical for hepatocyte invasion by sporozoites, liver stage development, host cell survival and merozoite liberation. Here we show that exoerythrocytic P. berghei parasites express a potent cysteine protease inhibitor (PbICP, P. berghei inhibitor of cysteine proteases). We provide evidence that it has an important function in sporozoite invasion and is capable of blocking hepatocyte cell death. Pre-incubation with specific anti-PbICP antiserum significantly decreased the ability of sporozoites to infect hepatocytes and expression of PbICP in mammalian cells protects them against peroxide- and camptothecin-induced cell death. PbICP is secreted by sporozoites prior to and after hepatocyte invasion, localizes to the parasitophorous vacuole as well as to the parasite cytoplasm in the schizont stage and is released into the host cell cytoplasm at the end of the liver stage. Like its homolog falstatin/PfICP in P. falciparum, PbICP consists of a classical N-terminal signal peptide, a long N-terminal extension region and a chagasin-like C-terminal domain. In exoerythrocytic parasites, PbICP is posttranslationally processed, leading to liberation of the C-terminal chagasin-like domain. Biochemical analysis has revealed that both full-length PbICP and the truncated C-terminal domain are very potent inhibitors of cathepsin L-like host and parasite cysteine proteases. The results presented in this study suggest that the inhibitor plays an important role in sporozoite invasion of host cells and in parasite survival during liver stage development by inhibiting host cell proteases involved in programmed cell death.

          Author Summary

          Plasmodium sporozoites are transmitted by Anopheles mosquitoes to the vertebrate host. They migrate through the skin before entering blood vessels and being transported with the bloodstream to liver sinusoids. There the sporozoites transmigrate through Kupffer cells and several hepatocytes before they invade a final hepatocyte and develop into thousands of merozoites. These daughter parasites are transported inside host cell-derived vesicles (merosomes) back to the bloodstream where they are finally released and infect red blood cells. Most of these processes depend on the activity of proteases, which must be tightly controlled to avoid proteolytic destruction of the parasite. We have identified a potent cysteine protease inhibitor of the rodent parasite Plasmodium berghei, which is expressed throughout the life cycle of the parasite. The inhibitor appears to play a role in sporozoite invasion of host cells and in parasite survival during liver stage development by inhibiting host cell proteases involved in programmed cell death.

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          Most cited references59

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          Quantitative imaging of Plasmodium transmission from mosquito to mammal.

          Plasmodium, the parasite that causes malaria, is transmitted by a mosquito into the dermis and must reach the liver before infecting erythrocytes and causing disease. We present here a quantitative, real-time analysis of the fate of parasites transmitted in a rodent system. We show that only a proportion of the parasites enter blood capillaries, whereas others are drained by lymphatics. Lymph sporozoites stop at the proximal lymph node, where most are degraded inside dendritic leucocytes, but some can partially differentiate into exoerythrocytic stages. This previously unrecognized step of the parasite life cycle could influence the immune response of the host, and may have implications for vaccination strategies against the preerythrocytic stages of the parasite.
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            TRAP is necessary for gliding motility and infectivity of plasmodium sporozoites.

            Many protozoans of the phylum Apicomplexa are invasive parasites that exhibit a substrate-dependent gliding motility. Plasmodium (malaria) sporozoites, the stage of the parasite that invades the salivary glands of the mosquito vector and the liver of the vertebrate host, express a surface protein called thrombospondin-related anonymous protein (TRAP) that has homologs in other Apicomplexa. By gene targeting in a rodent Plasmodium, we demonstrate that TRAP is critical for sporozoite infection of the mosquito salivary glands and the rat liver, and is essential for sporozoite gliding motility in vitro. This suggests that in Plasmodium sporozoites, and likely in other Apicomplexa, gliding locomotion and cell invasion have a common molecular basis.
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              Secretory lysosomes.

              Regulated secretion of stored secretory products is important in many cell types. In contrast to professional secretory cells, which store their secretory products in specialized secretory granules, some secretory cells store their secretory proteins in a dual-function organelle, called a secretory lysosome. Functionally, secretory lysosomes are unusual in that they serve both as a degradative and as a secretory compartment. Recent work shows that cells with secretory lysosomes use new sorting and secretory pathways. The importance of these organelles is highlighted by several genetic diseases, in which immune function and pigmentation--two processes that normally involve secretory lysosomes--are impaired.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                March 2010
                March 2010
                26 March 2010
                : 6
                : 3
                : e1000825
                Affiliations
                [1 ]Bernhard Nocht Institute for Tropical Medicine, Department of Molecular Parasitology, Hamburg, Germany
                [2 ]Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany
                [3 ]Josef Stefan Institute, Department of Biochemistry, Molecular and Structural Biology, Ljubljana, Slovenia
                Case Western Reserve University, United States of America
                Author notes

                Conceived and designed the experiments: AR VTH. Performed the experiments: AR CL AH TW CD. Analyzed the data: AR CL AH GH VTH. Contributed reagents/materials/analysis tools: KN VT RH. Wrote the paper: AR VTH. Corrected the manuscript: GH VT RH.

                Article
                09-PLPA-RA-1218R4
                10.1371/journal.ppat.1000825
                2845656
                20361051
                7b599402-8ed8-4d0d-bc0f-80304f65c82f
                Rennenberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 17 July 2009
                : 18 February 2010
                Page count
                Pages: 18
                Categories
                Research Article
                Cell Biology
                Infectious Diseases/Protozoal Infections

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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