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Quantitative analysis of P lasmodium ookinete motion in three dimensions suggests a critical role for cell shape in the biomechanics of malaria parasite gliding motility

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      Summary

      Motility is a fundamental part of cellular life and survival, including for P lasmodium parasites – single‐celled protozoan pathogens responsible for human malaria. The motile life cycle forms achieve motility, called gliding, via the activity of an internal actomyosin motor. Although gliding is based on the well‐studied system of actin and myosin, its core biomechanics are not completely understood. Currently accepted models suggest it results from a specifically organized cellular motor that produces a rearward directional force. When linked to surface‐bound adhesins, this force is passaged to the cell posterior, propelling the parasite forwards. Gliding motility is observed in all three life cycle stages of P lasmodium: sporozoites, merozoites and ookinetes. However, it is only the ookinetes – formed inside the midgut of infected mosquitoes – that display continuous gliding without the necessity of host cell entry. This makes them ideal candidates for invasion‐free biomechanical analysis. Here we apply a plate‐based imaging approach to study ookinete motion in three‐dimensional (3 D) space to understand P lasmodium cell motility and how movement facilitates midgut colonization. Using single‐cell tracking and numerical analysis of parasite motion in 3 D, our analysis demonstrates that ookinetes move with a conserved left‐handed helical trajectory. Investigation of cell morphology suggests this trajectory may be based on the ookinete subpellicular cytoskeleton, with complementary whole and subcellular electron microscopy showing that, like their motion paths, ookinetes share a conserved left‐handed corkscrew shape and underlying twisted microtubular architecture. Through comparisons of 3 D movement between wild‐type ookinetes and a cytoskeleton‐knockout mutant we demonstrate that perturbation of cell shape changes motion from helical to broadly linear. Therefore, while the precise linkages between cellular architecture and actomyosin motor organization remain unknown, our analysis suggests that the molecular basis of cell shape may, in addition to motor force, be a key adaptive strategy for malaria parasite dissemination and, as such, transmission.

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      We have developed a computer software package, IMOD, as a tool for analyzing and viewing three-dimensional biological image data. IMOD is useful for studying and modeling data from tomographic, serial section, and optical section reconstructions. The software allows image data to be visualized by several different methods. Models of the image data can be visualized by volume or contour surface rendering and can yield quantitative information.
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        A Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle.

        Green fluorescent protein (GFP) is a well-established reporter protein for the examination of biological processes. This report describes a recombinant Plasmodium berghei, PbGFPCON, that constitutively expresses GFP in a growth responsive manner in its cytoplasm from a transgene that is integrated into the genome and controlled by the strong promoter from a P. berghei elongation factor-1alpha gene. All life cycle forms of PbGFPCON except for male gametes can be easily visualized by fluorescent microscopy. PbGFPCON showed similar growth characteristics to wild type P. berghei parasites throughout the whole life cycle and can therefore be used as a reference line for future investigations of parasite-host cell interactions. The principle of automated fluorescence-based counting and sorting of live parasites from host cell backgrounds and different parasite forms from complex mixtures such as asynchronous blood stages is established. PbGFPCON allows the visualization and investigation of live parasite stages that are difficult and labor-intensive to observe, such as the liver and mosquito stages. PbGFPCON can be employed to establish the phenotype of independent mutant parasites. With the recent development of a second, independent selectable marker in P. berghei, PbGFPCON is a useful tool to investigate the effect of further genetic modifications on host-parasite interactions.
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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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            Author and article information

            Affiliations
            [ 1 ] Victoria Research Laboratory, National ICT Australia (NICTA) Department of Computing and Information SystemsUniversity of Melbourne Melbourne Vic. 3010Australia
            [ 2 ] Infection and Immunity DivisionThe Walter and Eliza Hall of Institute of Medical Research Parkville Vic. 3052Australia
            [ 3 ] Centre for Dynamic ImagingThe Walter and Eliza Hall of Institute of Medical Research Parkville Vic. 3052Australia
            [ 4 ] Department of Medical BiologyUniversity of Melbourne Vic. 3052Australia
            [ 5 ] Electron Microscopy Unit Bio21 Molecular Science and Biotechnology Institute and Department of Biochemistry and Molecular Biology University of Melbourne Parkville Vic. 3010Australia
            [ 6 ] School of BotanyThe University of Melbourne Parkville Vic. 3010Australia
            [ 7 ] Department of Life SciencesImperial College of Science, Technology and Medicine London SW7 2AZUK
            [ 8 ] Department of Life Sciences Sir Alexander Fleming BuildingImperial College London South Kensington London SW7 2AZUK
            Author notes
            [* ]For correspondence. E‐mail jake.baum@ 123456imperial.ac.uk ; Tel. (+61) 393452476; Fax (+61) 393470852.

            These authors contributed equally.

            Journal
            Cell Microbiol
            Cell. Microbiol
            10.1111/(ISSN)1462-5822
            CMI
            Cellular Microbiology
            Wiley-Blackwell
            1462-5814
            1462-5822
            28 March 2014
            May 2014
            : 16
            : 5 , Malaria ( doiID: 10.1111/cmi.2014.16.issue-5 )
            : 734-750
            24612056
            4286792
            10.1111/cmi.12283
            CMI12283
            © 2014 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd.

            This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

            Counts
            Pages: 18
            Product
            Funding
            Funded by: National Health and Medical Research Council of Australia (NHMRC)
            Award ID: 637341
            Award ID: APP1055246
            Funded by: Human Frontier Science Program (HFSP) Young Investigator Program
            Award ID: RGY0071/2011
            Funded by: National ICT Australia (NICTA)
            Funded by: Australian Research Council (ARC)
            Award ID: FT100100112
            Funded by: Wellcome Trust
            Award ID: 100993/Z/13/Z
            Categories
            Special Issue on Malaria
            Read here for publications from the European Virtual Institute for Malaria Research and the world wide malaria research community commemorating the 10th annual ‘BioMalPar’ meeting on the biology and pathology of the malaria parasite
            Original Articles
            Original Article
            Custom metadata
            2.0
            cmi12283
            May 2014
            Converter:WILEY_ML3GV2_TO_NLM version:4.0.7 mode:remove_FC converted:25.07.2014
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