Host cell CRISPR genomics and modelling reveal shared metabolic vulnerabilities in the intracellular development of Plasmodium falciparum and related hemoparasites.
Plasmodium falciparum
/ genetics
Humans
Hepatocytes
/ parasitology
Malaria, Falciparum
/ parasitology
CRISPR-Cas Systems
Theileria
/ genetics
Genomics
/ methods
Heme
/ metabolism
Host-Parasite Interactions
/ genetics
Clustered Regularly Interspaced Short Palindromic Repeats
/ genetics
Animals
Gene Knockout Techniques
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 Jul 2024
21 Jul 2024
Historique:
received:
01
11
2023
accepted:
01
07
2024
medline:
22
7
2024
pubmed:
22
7
2024
entrez:
21
7
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39034325
doi: 10.1038/s41467-024-50405-x
pii: 10.1038/s41467-024-50405-x
doi:
Substances chimiques
Heme
42VZT0U6YR
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6145Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : 173972
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : CRSII5_198543
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : CRSII5_198543
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : CRSII5_198543
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : 189127
Informations de copyright
© 2024. The Author(s).
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