Functional profiling of the Toxoplasma genome during acute mouse infection.

Autor:	Giuliano CJ; Whitehead Institute, Cambridge, MA.; Biology Department, MIT, Cambridge, MA., Wei KJ; Whitehead Institute, Cambridge, MA.; Biology Department, MIT, Cambridge, MA., Harling FM; Whitehead Institute, Cambridge, MA.; Biology Department, MIT, Cambridge, MA., Waldman BS; Whitehead Institute, Cambridge, MA.; Biology Department, MIT, Cambridge, MA., Farringer MA; Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.; Biological Sciences in Public Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Boydston EA; Whitehead Institute, Cambridge, MA., Lan TCT; Whitehead Institute, Cambridge, MA., Thomas RW; Whitehead Institute, Cambridge, MA.; Biology Department, MIT, Cambridge, MA., Herneisen AL; Whitehead Institute, Cambridge, MA.; Biology Department, MIT, Cambridge, MA., Sanderlin AG; Biology Department, MIT, Cambridge, MA., Coppens I; Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD., Dvorin JD; Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA., Lourido S; Whitehead Institute, Cambridge, MA.; Biology Department, MIT, Cambridge, MA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 06. Date of Electronic Publication: 2023 Mar 06.
DOI:	10.1101/2023.03.05.531216
Abstrakt:	Within a host, pathogens encounter a diverse and changing landscape of cell types, nutrients, and immune responses. Examining host-pathogen interactions in animal models can therefore reveal aspects of infection absent from cell culture. We use CRISPR-based screens to functionally profile the entire genome of the model apicomplexan parasite Toxoplasma gondii during mouse infection. Barcoded gRNAs were used to track mutant parasite lineages, enabling detection of bottlenecks and mapping of population structures. We uncovered over 300 genes that modulate parasite fitness in mice with previously unknown roles in infection. These candidates span multiple axes of host-parasite interaction, including determinants of tropism, host organelle remodeling, and metabolic rewiring. We mechanistically characterized three novel candidates, including GTP cyclohydrolase I, against which a small-molecule inhibitor could be repurposed as an antiparasitic compound. This compound exhibited antiparasitic activity against T. gondii and Plasmodium falciparum, the most lethal agent of malaria . Taken together, we present the first complete survey of an apicomplexan genome during infection of an animal host, and point to novel interfaces of host-parasite interaction that may offer new avenues for treatment. Competing Interests: DECLARATION OF INTERESTS A patent application has been filled by the Whitehead Institute based on these results with C.J.G. and S.L. as inventors. C.J.G. is a scientific advisor at Meliora Therapeutics, a company not related to this study.
Databáze:	MEDLINE
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