CRISPR-based Functional Profiling of the Toxoplasma Gondii Genome During Acute Murine Infection

Overview

Journal Nat Microbiol

Specialties Microbiology
Parasitology

Date 2024 Jul 8

PMID 38977907

Authors

Christopher J Giuliano

Kenneth J Wei

Faye M Harling

Benjamin S Waldman

Madeline A Farringer

Elizabeth A Boydston

Tammy C T Lan

Raina W Thomas

Alice L Herneisen

Allen G Sanderlin

Isabelle Coppens

Jeffrey D Dvorin

Sebastian Lourido

Affiliations

Soon will be listed here.

Abstract

Examining host-pathogen interactions in animals can capture aspects of infection that are obscured in cell culture. Using CRISPR-based screens, we functionally profile the entire genome of the apicomplexan parasite Toxoplasma gondii during murine infection. Barcoded gRNAs enabled bottleneck detection and mapping of population structures within parasite lineages. Over 300 genes with previously unknown roles in infection were found to modulate parasite fitness in mice. Candidates span multiple axes of host-parasite interaction. Rhoptry Apical Surface Protein 1 was characterized as a mediator of host-cell tropism that facilitates repeated invasion attempts. GTP cyclohydrolase I was also required for fitness in mice and druggable through a repurposed compound, 2,4-diamino-6-hydroxypyrimidine. This compound synergized with pyrimethamine against T. gondii and malaria-causing Plasmodium falciparum parasites. This work represents a complete survey of an apicomplexan genome during infection of an animal host and points to novel interfaces of host-parasite interaction.

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