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      Role for the flagellum attachment zone in Leishmania anterior cell tip morphogenesis

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          Abstract

          The shape and form of the flagellated eukaryotic parasite Leishmania is sculpted to its ecological niches and needs to be transmitted to each generation with great fidelity. The shape of the Leishmania cell is defined by the sub-pellicular microtubule array and the positioning of the nucleus, kinetoplast and the flagellum within this array. The flagellum emerges from the anterior end of the cell body through an invagination of the cell body membrane called the flagellar pocket. Within the flagellar pocket the flagellum is laterally attached to the side of the flagellar pocket by a cytoskeletal structure called the flagellum attachment zone (FAZ). During the cell cycle single copy organelles duplicate with a new flagellum assembling alongside the old flagellum. These are then segregated between the two daughter cells by cytokinesis, which initiates at the anterior cell tip. Here, we have investigated the role of the FAZ in the morphogenesis of the anterior cell tip. We have deleted the FAZ filament protein, FAZ2 and investigated its function using light and electron microscopy and infection studies. The loss of FAZ2 caused a disruption to the membrane organisation at the anterior cell tip, resulting in cells that were connected to each other by a membranous bridge structure between their flagella. Moreover, the FAZ2 null mutant was unable to develop and proliferate in sand flies and had a reduced parasite burden in mice. Our study provides a deeper understanding of membrane-cytoskeletal interactions that define the shape and form of an individual cell and the remodelling of that form during cell division.

          Author summary

          Leishmania are parasites that cause leishmaniasis in humans with symptoms ranging from mild cutaneous lesions to severe visceral disease. The life cycle of these parasites alternates between the human host and the sand fly vector, with distinct forms in both. These different forms have different cell shapes that are adapted for survival in these different environments. Leishmania parasites have an elongated cell shape with a flagellum extending from one end and this shape is due to a protein skeleton beneath the cell membrane. This skeleton is made up of different units one of which is called the flagellum attachment zone (FAZ), that connects the flagellum to the cell body. We have found that one of the proteins in the FAZ called FAZ2 is important for generating the shape of the cell at the point where the flagellum exits the cell. When we deleted FAZ2 we found that the cell membrane at the end of the cell was distorted resulting in unusual connections between the flagella of different cells. We found that the disruption to the cell shape reduces the ability of the parasite to infect mice and develop in the sand fly, which shows the importance of the parasite shape.

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          Most cited references 43

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          Leishmania development in sand flies: parasite-vector interactions overview

          Leishmaniases are vector-borne parasitic diseases with 0.9 – 1.4 million new human cases each year worldwide. In the vectorial part of the life-cycle, Leishmania development is confined to the digestive tract. During the first few days after blood feeding, natural barriers to Leishmania development include secreted proteolytic enzymes, the peritrophic matrix surrounding the ingested blood meal and sand fly immune reactions. As the blood digestion proceeds, parasites need to bind to the midgut epithelium to avoid being excreted with the blood remnant. This binding is strictly stage-dependent as it is a property of nectomonad and leptomonad forms only. While the attachment in specific vectors (P. papatasi, P. duboscqi and P. sergenti) involves lipophosphoglycan (LPG), this Leishmania molecule is not required for parasite attachment in other sand fly species experimentally permissive for various Leishmania. During late-stage infections, large numbers of parasites accumulate in the anterior midgut and produce filamentous proteophosphoglycan creating a gel-like plug physically obstructing the gut. The parasites attached to the stomodeal valve cause damage to the chitin lining and epithelial cells of the valve, interfering with its function and facilitating reflux of parasites from the midgut. Transformation to metacyclic stages highly infective for the vertebrate host is the other prerequisite for effective transmission. Here, we review the current state of knowledge of molecular interactions occurring in all these distinct phases of parasite colonization of the sand fly gut, highlighting recent discoveries in the field.
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            Establishment and maintenance of sand fly colonies.

             P Volf,  V Volfova (2011)
            Sand flies used to have a reputation for being difficult and labour-intensive to breed. Here we summarize our experience with establishment and maintenance of sand fly colonies and their use for infective experiments: techniques for collection and handling wild-caught females, rearing larvae and adults and experimental infections of sand flies by Leishmania using membrane feeding. In addition, we compare major life cycle parameters between various colonies maintained under standard laboratory conditions. The sand fly rearing is tricky but some species can be reared in large numbers with a minimum of space and equipment. Initiation of new colonies from endemic sites is a prerequisite for accurate studies on parasite-vector interaction but it is more difficult step than routine maintenance of colonies already established in laboratory for many generations. © 2011 The Society for Vector Ecology.
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              The trypanosome flagellar pocket.

              Trypanosomes are important disease agents and excellent models for the study of evolutionary cell biology. The trypanosome flagellar pocket is a small invagination of the plasma membrane where the flagellum exits the cytoplasm and participates in many cellular processes. It is the only site of exocytosis and endocytosis and part of a multiorganelle complex that is involved in cell polarity and cell division. Several flagellar pocket-associated proteins have been identified and found to contribute to trafficking and virulence. In this Review we discuss the contribution of the flagellar pocket to protein trafficking, immune evasion and other processes.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Visualization
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Visualization
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                22 October 2020
                October 2020
                : 16
                : 10
                Affiliations
                [1 ] Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
                [2 ] Shimoda Marine Research Center, University of Tsukuba, Shizuoka, Japan
                [3 ] York Biomedical Research Institute and Department of Biology, University of York, York, United Kingdom
                [4 ] Department of Parasitology, Charles University, Prague, Czech Republic
                University of California, Los Angeles, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PPATHOGENS-D-20-00556
                10.1371/journal.ppat.1008494
                7608989
                33091070
                © 2020 Halliday 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.

                Page count
                Figures: 8, Tables: 0, Pages: 26
                Product
                Funding
                Funded by: Wellcome Trust (GB)
                Award ID: 200807/Z/16/Z
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 104627/Z/14/Z
                CH was funded by a Nigel Groome studentship. RY was funded by a Fellowship from the Japan Society for the Promotion of Science. KP was funded by the Charles University Research Center (204072). PV was funded by the Czech Republic Ministry of Education, Youth and Sports (CZ.02.1.01/0.0/0.0/16_019/0000759). JCM was funded by the Wellcome Trust (200807/Z/16/Z). JDS initiated this work in the lab of Professor Keith Gull (University of Oxford), which is supported by the Wellcome Trust (104627/Z/14/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Flagella
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Virulence Factors
                Pathogen Motility
                Flagella
                Medicine and Health Sciences
                Medical Conditions
                Parasitic Diseases
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Leishmania
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Disease Vectors
                Insect Vectors
                Sand Flies
                Biology and Life Sciences
                Species Interactions
                Disease Vectors
                Insect Vectors
                Sand Flies
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cytoskeleton
                Microtubules
                Biology and Life Sciences
                Developmental Biology
                Life Cycles
                Protozoan Life Cycles
                Amastigotes
                Biology and Life Sciences
                Microbiology
                Protozoology
                Protozoan Life Cycles
                Amastigotes
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Biology and Life Sciences
                Developmental Biology
                Life Cycles
                Parasitic Life Cycles
                Biology and Life Sciences
                Parasitology
                Parasitic Life Cycles
                Custom metadata
                vor-update-to-uncorrected-proof
                2020-11-03
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology

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