P. falciparum ligand binding to erythrocytes induce alterations in deformability essential for invasion

  1. Xavier Sisquella
  2. Thomas Nebl
  3. Jennifer K Thompson
  4. Lachlan Whitehead
  5. Brian M Malpede
  6. Nichole D Salinas
  7. Kelly Rogers
  8. Niraj H Tolia
  9. Andrea Fleig
  10. Joseph O'Neill
  11. Wai-Hong Tham
  12. F David Horgen
  13. Alan F Cowman  Is a corresponding author
  1. The Walter and Eliza Hall Institute of Medical Research, Australia
  2. Washington University School of Medicine, United States
  3. Hawaii Pacific University, United States
  4. University of Hawaii, United States

Abstract

The most lethal form of malaria in humans is caused by Plasmodium falciparum. These parasites invade erythrocytes, a complex process involving multiple ligand-receptor interactions. The parasite makes initial contact with the erythrocyte followed by dramatic deformations linked to the function of the Erythrocyte binding antigen family and P. falciparum reticulocyte binding-like families. We show EBA-175 mediates substantial changes in deformability of erythrocytes by binding to glycophorin A and activating a phosphorylation cascade that includes erythrocyte cytoskeletal proteins resulting in changes in the viscoelastic properties of the host cell. TRPM7 kinase inhibitors FTY720 and waixenicin A block the changes in deformability of erythrocytes and inhibit merozoite invasion by directly inhibiting the phosphorylation cascade. Therefore, binding of P. falciparum parasites to the erythrocyte directly activate a signaling pathway through a phosphorylation cascade and this alters the viscoelastic properties of the host membrane conditioning it for successful invasion.

Article and author information

Author details

  1. Xavier Sisquella

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Thomas Nebl

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennifer K Thompson

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Lachlan Whitehead

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Brian M Malpede

    Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nichole D Salinas

    Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kelly Rogers

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Niraj H Tolia

    Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2689-1337
  9. Andrea Fleig

    Department of Natural Sciences, Hawaii Pacific University, Kaneohe, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Joseph O'Neill

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Wai-Hong Tham

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. F David Horgen

    The Queen's Medical Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Alan F Cowman

    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    For correspondence
    cowman@wehi.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5145-9004

Funding

Howard Hughes Medical Institute (HHMI International Scholar Award 55007645)

  • Alan F Cowman

National Health and Medical Research Council (NHMRc Program Grant 637406)

  • Alan F Cowman

Australian Research Council (Australian Research Council Future Fellowship)

  • Wai-Hong Tham

National Health and Medical Research Council (IRIISS grant)

  • Xavier Sisquella
  • Thomas Nebl
  • Jennifer K Thompson
  • Lachlan Whitehead
  • Kelly Rogers
  • Joseph O'Neill
  • Wai-Hong Tham
  • Alan F Cowman

National Health and Medical Research Council (1026581)

  • Alan F Cowman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Stephen C. Harrison, Harvard Medical School, United States

Publication history

  1. Received: August 30, 2016
  2. Accepted: February 9, 2017
  3. Accepted Manuscript published: February 22, 2017 (version 1)
  4. Version of Record published: March 2, 2017 (version 2)
  5. Version of Record updated: March 3, 2017 (version 3)

Copyright

© 2017, Sisquella et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Xavier Sisquella
  2. Thomas Nebl
  3. Jennifer K Thompson
  4. Lachlan Whitehead
  5. Brian M Malpede
  6. Nichole D Salinas
  7. Kelly Rogers
  8. Niraj H Tolia
  9. Andrea Fleig
  10. Joseph O'Neill
  11. Wai-Hong Tham
  12. F David Horgen
  13. Alan F Cowman
(2017)
P. falciparum ligand binding to erythrocytes induce alterations in deformability essential for invasion
eLife 6:e21083.
https://doi.org/10.7554/eLife.21083

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