IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50770-7.html
   My bibliography  Save this article

A broadly cross-reactive i-body to AMA1 potently inhibits blood and liver stages of Plasmodium parasites

Author

Listed:
  • Dimuthu Angage

    (La Trobe University)

  • Jill Chmielewski

    (The University of Adelaide)

  • Janesha C. Maddumage

    (La Trobe University)

  • Eva Hesping

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Sabrina Caiazzo

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Keng Heng Lai

    (The University of Adelaide)

  • Lee Ming Yeoh

    (Burnet Institute
    The University of Melbourne)

  • Joseph Menassa

    (La Trobe University)

  • D. Herbert Opi

    (Burnet Institute
    The University of Melbourne
    Monash University)

  • Callum Cairns

    (La Trobe University)

  • Hamsa Puthalakath

    (La Trobe University)

  • James G. Beeson

    (Burnet Institute
    Monash University
    The University of Melbourne)

  • Marc Kvansakul

    (La Trobe University)

  • Justin A. Boddey

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Danny W. Wilson

    (The University of Adelaide
    Burnet Institute
    University of Adelaide)

  • Robin F. Anders

    (La Trobe University)

  • Michael Foley

    (La Trobe University
    AdAlta)

Abstract

Apical membrane antigen-1 (AMA1) is a conserved malarial vaccine candidate essential for the formation of tight junctions with the rhoptry neck protein (RON) complex, enabling Plasmodium parasites to invade human erythrocytes, hepatocytes, and mosquito salivary glands. Despite its critical role, extensive surface polymorphisms in AMA1 have led to strain-specific protection, limiting the success of AMA1-based interventions beyond initial clinical trials. Here, we identify an i-body, a humanised single-domain antibody-like molecule that recognises a conserved pan-species conformational epitope in AMA1 with low nanomolar affinity and inhibits the binding of the RON2 ligand to AMA1. Structural characterisation indicates that the WD34 i-body epitope spans the centre of the conserved hydrophobic cleft in AMA1, where interacting residues are highly conserved among all Plasmodium species. Furthermore, we show that WD34 inhibits merozoite invasion of erythrocytes by multiple Plasmodium species and hepatocyte invasion by P. falciparum sporozoites. Despite a short half-life in mouse serum, we demonstrate that WD34 transiently suppressed P. berghei infections in female BALB/c mice. Our work describes the first pan-species AMA1 biologic with inhibitory activity against multiple life-cycle stages of Plasmodium. With improved pharmacokinetic characteristics, WD34 could be a potential immunotherapy against multiple species of Plasmodium.

Suggested Citation

  • Dimuthu Angage & Jill Chmielewski & Janesha C. Maddumage & Eva Hesping & Sabrina Caiazzo & Keng Heng Lai & Lee Ming Yeoh & Joseph Menassa & D. Herbert Opi & Callum Cairns & Hamsa Puthalakath & James G, 2024. "A broadly cross-reactive i-body to AMA1 potently inhibits blood and liver stages of Plasmodium parasites," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50770-7
    DOI: 10.1038/s41467-024-50770-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50770-7
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-50770-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Palak N. Patel & Thayne H. Dickey & Ababacar Diouf & Nichole D. Salinas & Holly McAleese & Tarik Ouahes & Carole A. Long & Kazutoyo Miura & Lynn E. Lambert & Niraj H. Tolia, 2023. "Structure-based design of a strain transcending AMA1-RON2L malaria vaccine," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Sean Yanik & Varsha Venkatesh & Michelle L. Parker & Raghavendran Ramaswamy & Ababacar Diouf & Deepti Sarkar & Kazutoyo Miura & Carole A. Long & Martin J. Boulanger & Prakash Srinivasan, 2023. "Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Wai Kwan Tang & Nichole D. Salinas & Surendra Kumar Kolli & Shulin Xu & Darya V. Urusova & Hirdesh Kumar & John R. Jimah & Pradeep Annamalai Subramani & Madison M. Ogbondah & Samantha J. Barnes & John, 2024. "Multistage protective anti-CelTOS monoclonal antibodies with cross-species sterile protection against malaria," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50770-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.