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

Marina Maurizio, Maria Masid, Kerry Woods, Reto Caldelari, John G. Doench, Arunasalam Naguleswaran, Denis Joly, Martín González-Fernández, Jonas Zemp, Mélanie Borteele, Vassily Hatzimanikatis, Volker Heussler, Sven Rottenberg () and Philipp Olias ()
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Marina Maurizio: University of Bern
Maria Masid: University of Lausanne and Lausanne University Teaching Hospital (CHUV)
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
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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50405-x

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