<i>Toxoplasma</i> scavenges mammalian host organelles through usurpation of host ESCRT-III and Vps4

Coppens, Isabelle; Romano, Julia D.; Mayoral, Joshua; Guevara, Rebekah B.; Rivera-Cuevas, Yolanda; Carruthers, Vern B.; Weiss, Louis M.

doi:10.1101/2022.04.11.487923

Cited by 3 publications

(3 citation statements)

References 78 publications

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“…acquire amino acids from ingested hemoglobin [ 10 ]. The recruitment of the host Endosomal Sorting Complex Required for Transport (ESCRT) to the PVM, mediated by GRA14 and GRA64 [ 11 , 12 ], is likely necessary for the ingestion of host cytosolic proteins by promoting the budding and scission of host-derived vesicles into the PV lumen [ 13 ]. In Δ gra2 parasites, the ingestion of host cytosolic proteins, Rab-vesicles, and lipid droplets is significantly reduced [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide CRISPR screen identifies genes synthetically lethal with GRA17, a nutrient channel encoding gene in Toxoplasma

Paredes-Santos¹,

Bitew²,

Swale³

et al. 2023

PLoS Pathog

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Toxoplasma gondii is a parasite that replicates within a specialized compartment called the parasitophorous vacuole (PV), which is surrounded by the PV membrane (PVM). To obtain essential nutrients, Toxoplasma must transport molecules across the PVM, a process mediated by the secreted parasite proteins GRA17 and GRA23. These proteins form pores in the PVM through which small molecules can diffuse in and out of the PV. GRA17 and GRA23 are synthetically lethal, suggesting that at least one pore type is essential for parasite survival. In the ‘nutrient sensitized’ Δgra17 strain it is likely that other Toxoplasma genes become essential, because they mediate nutrient acquisition from the host or are involved in the trafficking of GRA23 to the PVM. To identify these genes, a genome-wide loss-of-function screen was performed in wild-type and Δgra17 parasites, which identified multiple genes that were synthetically sick/lethal with GRA17. Several of these genes were involved in the correct localization of GRAs, including GRA17/GRA23, to the PVM. One of the top hits, GRA72, was predicted to form a pore on the PVM, and its deletion led to the formation of enlarged “bubble vacuoles” with reduced PVM small molecule permeability, similar to what was previously observed for Δgra17 parasites. Furthermore, Δgra72 parasites had reduced in vitro growth and virulence in mice. These findings suggest that in the absence of GRA17, other genes become essential, likely because they play a role in the proper localization of GRA23 (and other GRAs) or because they determine host-derived nutrient acquisition at the PVM.

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Section: Introductionmentioning

confidence: 99%

Genome-wide CRISPR screen identifies genes synthetically lethal with GRA17, a nutrient channel encoding gene in Toxoplasma

Paredes-Santos¹,

Bitew²,

Swale³

et al. 2023

PLoS Pathog

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show abstract

“…3A ). Ongoing and future studies of GRA14 and GRA64 disruption will be essential to determine redundant and/or synergistic roles with host ESCRT in various aspects of nutrient uptake (e.g., recruitment, tethering/binding, ingestion) ( 53 ). Furthermore, GRA64 interacts with ESCRT-I, ESCRT-III, and ESCRT accessory proteins during bradyzoite infection of human foreskin fibroblasts ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Dense Granule Protein GRA64 Interacts with Host Cell ESCRT Proteins duringToxoplasma gondiiInfection

Mayoral

Guevara

Rivera-Cuevas

et al. 2022

mBio

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“…4O-P). T. gondii can trigger host autophagy to sequester host lipids through the recruitment of vesicles to the PV [85][86][87] . The buildup of MLBs and abnormal PVMs may therefore indicate an inability of these parasites to efficiently absorb host vesicles.…”

Section: Gra72 Is Required For Parasitophorous Vacuole Maintenance An...mentioning

confidence: 99%

Functional profiling of theToxoplasmagenome during acute mouse infection

Giuliano

Wei

Harling

et al. 2023

Preprint

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SUMMARYWithin 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 parasiteToxoplasma gondiiduring 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 againstT. gondiiandPlasmodium 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.

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Toxoplasma scavenges mammalian host organelles through usurpation of host ESCRT-III and Vps4

Cited by 3 publications

References 78 publications

Genome-wide CRISPR screen identifies genes synthetically lethal with GRA17, a nutrient channel encoding gene in Toxoplasma

Genome-wide CRISPR screen identifies genes synthetically lethal with GRA17, a nutrient channel encoding gene in Toxoplasma

Dense Granule Protein GRA64 Interacts with Host Cell ESCRT Proteins duringToxoplasma gondiiInfection

Functional profiling of theToxoplasmagenome during acute mouse infection

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