Artikel
The effect of protease inhibitors on parasite transmission
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Autoren
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Tim Weißbach
- Institute for Cellular and Applied Infectionbiology, RWTH-Aachen University, Aachen, Germany
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Ludmilla Sologub
- Research Center for Infectious Diseases, University of Würzburg, Würzburg, Germany
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Urska Repnik
- Department of Molecular Biosciences, University of Oslo, Oslo, Norway
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Anna Olivieri
- Istituto Superiore di Sanità, Rom, Italy
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Matthew Bogyo
- Department of Pathology, Stanford University School of Medicine, Stanford, USA
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Jude M. Przyborski
- Parasitology, Faculty of Biology, University of Marburg, Marburg, Germany
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Martha Ponzi
- Istituto Superiore di Sanità, Rom, Italy
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Mike Blackman
- Division of Parasitology, MRC National Institute for Medical Research, London, UK
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Gareth Griffiths
- Department of Molecular Biosciences, University of Oslo, Oslo, Norway
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Rainer Fischer
- Fraunhofer Institute of Molecular Biology and Applied Ecology, Aachen, Germany
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Gabriele Pradel
- Institute for Cellular and Applied Infectionbiology, RWTH-Aachen University, Aachen, Germany
| Veröffentlicht: | 17. Dezember 2014 |
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Gliederung
Text
The transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito is mediated by sexual precursor cells, the intraerythrocytic gametocytes, which become activated in the mosquito midgut by environmental stimuli and then undergo gametogenesis. Because gametocytes are the only life-cycle stages of the parasite that are able to establish an infection in the mosquito, they play an important role in spreading the tropical disease. Gametocyte egress from the enveloping erythrocyte is a crucial step for the parasite to prepare for fertilization, but the molecular mechanisms are not well understood. We previously showed that P. falciparum gametocytes exit the erythrocyte by an inside-out mode of egress, during which the parasitophorous vacuole membrane (PVM) ruptures at multiple sites within less than a minute after activation, while the erythrocyte membrane (EM) opens by a single pore approximately 10 min later. EM rupture can be inhibited by the cysteine/serine protease inhibitors TLCK and TPCK. Inhibitors directed against the cysteine protease family like E64d, on the other hand, prevent the rupture of the PVM. Here we tested two antiparasitic cysteine protease inhibitors, the PfDPAP3-inhibitor ML4118S and inhibitor K11777.HCl, previously shown to act against Trypanosoma brucei, for their effects on gametocyte egress. In vitro exflagellation assays and electron microscopy studies demonstrated that both inhibitors specifically impaired PVM rupture. Moreover we started to investigate, which plasmodial proteases are present in gametocytes and released during egress using mass spectrometry and immunohistochemistry. Identifying the role of proteases will lead to a better understanding of the molecular mechanisms behind gametocyte egress and may point to new targets for transmission blocking intervention strategies.
