IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50405-x.html
   My bibliography  Save this article

Host cell CRISPR genomics and modelling reveal shared metabolic vulnerabilities in the intracellular development of Plasmodium falciparum and related hemoparasites

Author

Listed:
  • Marina Maurizio

    (University of Bern)

  • Maria Masid

    (University of Lausanne and Lausanne University Teaching Hospital (CHUV)
    École Polytechnique Fédérale de Lausanne (EPFL))

  • Kerry Woods

    (University of Bern)

  • Reto Caldelari

    (University of Bern)

  • John G. Doench

    (Broad Institute of MIT and Harvard)

  • Arunasalam Naguleswaran

    (University of Bern)

  • Denis Joly

    (École Polytechnique Fédérale de Lausanne (EPFL))

  • Martín González-Fernández

    (University of Bern)

  • Jonas Zemp

    (University of Bern
    University of Bern)

  • Mélanie Borteele

    (École Polytechnique Fédérale de Lausanne (EPFL))

  • Vassily Hatzimanikatis

    (École Polytechnique Fédérale de Lausanne (EPFL))

  • Volker Heussler

    (University of Bern)

  • Sven Rottenberg

    (University of Bern)

  • Philipp Olias

    (University of Bern
    Justus Liebig University)

Abstract

Parasitic diseases, particularly malaria (caused by Plasmodium falciparum) and theileriosis (caused by Theileria spp.), profoundly impact global health and the socioeconomic well-being of lower-income countries. Despite recent advances, identifying host metabolic proteins essential for these auxotrophic pathogens remains challenging. Here, we generate a novel metabolic model of human hepatocytes infected with P. falciparum and integrate it with a genome-wide CRISPR knockout screen targeting Theileria-infected cells to pinpoint shared vulnerabilities. We identify key host metabolic enzymes critical for the intracellular survival of both of these lethal hemoparasites. Remarkably, among the metabolic proteins identified by our synergistic approach, we find that host purine and heme biosynthetic enzymes are essential for the intracellular survival of P. falciparum and Theileria, while other host enzymes are only essential under certain metabolic conditions, highlighting P. falciparum’s adaptability and ability to scavenge nutrients selectively. Unexpectedly, host porphyrins emerge as being essential for both parasites. The shared vulnerabilities open new avenues for developing more effective therapies against these debilitating diseases, with the potential for broader applicability in combating apicomplexan infections.

Suggested Citation

  • Marina Maurizio & Maria Masid & Kerry Woods & Reto Caldelari & John G. Doench & Arunasalam Naguleswaran & Denis Joly & Martín González-Fernández & Jonas Zemp & Mélanie Borteele & Vassily Hatzimanikati, 2024. "Host cell CRISPR genomics and modelling reveal shared metabolic vulnerabilities in the intracellular development of Plasmodium falciparum and related hemoparasites," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50405-x
    DOI: 10.1038/s41467-024-50405-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50405-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-50405-x?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. Maria Masid & Meric Ataman & Vassily Hatzimanikatis, 2020. "Author Correction: Analysis of human metabolism by reducing the complexity of the genome-scale models using redHUMAN," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    2. Adil Mardinoglu & Rasmus Agren & Caroline Kampf & Anna Asplund & Mathias Uhlen & Jens Nielsen, 2014. "Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease," Nature Communications, Nature, vol. 5(1), pages 1-11, May.
    3. Andrea Galmozzi & Bernard P. Kok & Arthur S. Kim & J. Rafael Montenegro-Burke & Jae Y. Lee & Roberto Spreafico & Sarah Mosure & Verena Albert & Rigo Cintron-Colon & Cristina Godio & William R. Webb & , 2019. "PGRMC2 is an intracellular haem chaperone critical for adipocyte function," Nature, Nature, vol. 576(7785), pages 138-142, December.
    4. Maria Masid & Meric Ataman & Vassily Hatzimanikatis, 2020. "Analysis of human metabolism by reducing the complexity of the genome-scale models using redHUMAN," Nature Communications, Nature, vol. 11(1), pages 1-12, 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. Marco Sciacovelli & Aurelien Dugourd & Lorea Valcarcel Jimenez & Ming Yang & Efterpi Nikitopoulou & Ana S. H. Costa & Laura Tronci & Veronica Caraffini & Paulo Rodrigues & Christina Schmidt & Dylan Ge, 2022. "Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. André Schultz & Amina A Qutub, 2016. "Reconstruction of Tissue-Specific Metabolic Networks Using CORDA," PLOS Computational Biology, Public Library of Science, vol. 12(3), pages 1-33, March.
    3. Oveis Jamialahmadi & Sameereh Hashemi-Najafabadi & Ehsan Motamedian & Stefano Romeo & Fatemeh Bagheri, 2019. "A benchmark-driven approach to reconstruct metabolic networks for studying cancer metabolism," PLOS Computational Biology, Public Library of Science, vol. 15(4), pages 1-29, April.
    4. Chaitra Sarathy & Marian Breuer & Martina Kutmon & Michiel E Adriaens & Chris T Evelo & Ilja C W Arts, 2021. "Comparison of metabolic states using genome-scale metabolic models," PLOS Computational Biology, Public Library of Science, vol. 17(11), pages 1-25, November.

    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_s41467-024-50405-x. 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.