Impact of Engineered Expression of Mitochondrial Association Factor 1b on<i>Toxoplasma gondii</i>Infection and the Host Response in a Mouse Model

English, Elizabeth D.; Boyle, Jon P.

doi:10.1128/msphere.00471-18

Cited by 11 publications

(12 citation statements)

References 35 publications

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“…Cysts are also strongly associated with ER, Golgi complex and endolysosomal vesicles, while host mitochondria were not observed near the cyst membrane. Notably, type II strains are not able to recruit mitochondria to the vicinity of the PVM (Paredes-Santos et al, 2017) due to a lack of expression of the dense granule protein MAF-1b (Pernas et al, 2014; English and Boyle, 2018). Even though the proximity of host organelles with the cyst wall was demonstrated, it is not known if this organization around the cyst is related to nutrient acquisition by bradyzoites.…”

Section: Introductionmentioning

confidence: 99%

The GRA17 Parasitophorous Vacuole Membrane Permeability Pore Contributes to Bradyzoite Viability

Paredes-Santos

Wang

Waldman

et al. 2019

Front. Cell. Infect. Microbiol.

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The Toxoplasma gondii parasitophorous vacuole membrane (PVM) offers protection from the host immune system but is also a barrier for uptake of nutrients from the host. Previously, we showed that GRA17 mediates the tachyzoite PVM permeability to small molecules. During the conversion from tachyzoites to encysted bradyzoites, the PVM become the cyst membrane that is the outer layer of the cyst wall. Little is known about how small molecules, such as nutrients, enter cysts. To characterize GRA17's role in cysts, we deleted GRA17 in the type II ME49 cyst-forming strain. ME49Δgra17 parasites have reduced growth and formed grossly enlarged “bubble vacuoles,” which have reduced PVM small molecule permeability. ME49Δgra17 parasites formed cysts in vitro at rates comparable to the wild-type, but the viability of the bradyzoites inside these cysts was significantly reduced compared to wild-type bradyzoites. Genetic complementation of ME49Δgra17 with GRA17 expressed from the endogenous or tachyzoite-specific SAG1 promoter recovered the viability of bradyzoites. Complementation with the bradyzoite-specific SRS9 promoter drastically increased the viability of bradyzoites, demonstrating the importance of GRA17 in regulating bradyzoite viability inside cysts. Mice infected with a high dose of ME49Δgra17 parasites did not contain parasites in their brain nor did mice infected with ME49Δgra17 complemented with GRA17 expressed from a bradyzoite-specific promoter. Our results suggest that the ME49Δgra17 strain is avirulent and is cleared before it can reach the brain and that GRA17 not only plays an important role during acute infections but is also needed for viability of bradyzoites inside cysts.

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Section: Introductionmentioning

confidence: 99%

The GRA17 Parasitophorous Vacuole Membrane Permeability Pore Contributes to Bradyzoite Viability

Paredes-Santos

Wang

Waldman

et al. 2019

Front. Cell. Infect. Microbiol.

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“…Our observation that mROS also played a role in parasite restriction is in keeping with several studies that have shown that mROS plays an important role in macrophage killing of phagosomally localized bacteria ( 46 , 47 ) and extends this work to suggest that mROS may play in important role in pathogen defense in nonimmune cells as well. This finding is especially interesting given that type I and III strains, but not type II strains, show high levels of host mitochondrion association with the PV, the host membrane-derived structure, which surrounds intracellular parasites and avoids fusion with the phagolysosome ( 50 – 59 ). Host mitochondria associating with the PV might be able to deliver mitochondrion-derived vesicles harboring ROS ( 47 ) to the underlying parasites.…”

Section: Discussionmentioning

confidence: 99%

ROP16-Mediated Activation of STAT6 Suppresses Host Cell Reactive Oxygen Species Production, Facilitating Type III Toxoplasma gondii Growth and Survival

Kochanowsky

Thomas

Koshy

2021

mBio

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Polymorphic effector proteins determine the susceptibility of Toxoplasma gondii strains to IFN-γ-mediated clearance mechanisms deployed by murine host cells. However, less is known about the influence of these polymorphic effector proteins on IFN-γ-independent clearance mechanisms. Here, we show that deletion of one such polymorphic effector protein, ROP16, from a type III background leads to a defect in parasite growth and survival in unstimulated human fibroblasts and murine macrophages. Rescue of these defects requires a ROP16 with a functional kinase domain and the ability to activate a specific family of host cell transcription factors (STAT3, 5a, and 6). The growth and survival defects correlate with an accumulation of host cell reactive oxygen species (ROS) and are prevented by treatment with an ROS inhibitor. Exogenous activation of STAT3 and 6 suppresses host cell ROS production during infection with ROP16-deficient parasites and depletion of STAT6, but not STAT3 or 5a, causes an accumulation of ROS in cells infected with wild-type parasites. Pharmacological inhibition of NOX2 and mitochondrially derived ROS also rescues growth and survival of ROP16-deficient parasites. Collectively, these findings reveal an IFN-γ-independent mechanism of parasite restriction in human cells that is subverted by injection of ROP16 by type III parasites. IMPORTANCE Toxoplasma gondii is an obligate intracellular parasite that infects up to one-third of the world’s population. Control of the parasite is largely accomplished by IFN-γ-dependent mechanisms that stimulate innate and adaptive immune responses. Parasite suppression of IFN-γ-stimulated responses has been linked to proteins that the parasite secretes into its host cell. These secreted proteins vary by T. gondii strain and determine strain-specific lethality in mice. How these strain-specific polymorphic effector proteins affect IFN-γ-independent parasite control mechanisms in human and murine cells is not well known. This study shows that one such secreted protein, ROP16, enables efficient parasite growth and survival by suppressing IFN-γ-independent production of ROS by human and mouse cells.

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“…The associating mitochondria may also be somewhat dysfunctional (Syn et al., 2017). Regardless of which impact is most important, the data are clear that this association is of substantial importance in vivo during the acute and, possibly, chronic stages of the infection (English & Boyle, 2018).…”

Section: Maf1 Is a Pvm‐associating Effector That Mediates Associationmentioning

confidence: 99%

Seizing control: How dense granule effector proteins enable Toxoplasma to take charge

Panas

Boothroyd

2021

Molecular Microbiology

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Control of the host cell is crucial to the Apicomplexan parasite, Toxoplasma gondii, while it grows intracellularly. To achieve this goal, these single-celled eukaryotes export a series of effector proteins from organelles known as "dense granules" that interfere with normal cellular processes and responses to invasion. While some effectors are found attached to the outer surface of the parasitophorous vacuole (PV) in which Toxoplasma tachyzoites reside, others are found in the host cell's cytoplasm and yet others make their way into the host nucleus, where they alter host transcription. Among the processes that are severely altered are innate immune responses, host cell cycle, and association with host organelles. The ways in which these crucial processes are altered through the coordinated action of a large collection of effectors is as elegant as it is complex, and is the central focus of the following review; we also discuss the recent advances in our understanding of how dense granule effector proteins are trafficked out of the PV. K E Y W O R D Sdense granule, effector protein, innate immunity, toxoplasma | 467 PANAS ANd BOOTHROYd Effector Host cell location Summary of function MYR-dependent GRA16 Nucleus Binds HAUSP, PP2AB55, leads to c-Myc induction, p53 activation, cyclin A degradation, alterations in sterol pathways GRA18 Cytoplasm Binds B-catenin degradation complex preventing B-catenin degradation, upregulates CCL17 and CCL22 GRA24 Nucleus Binds and triggers autophosphorylation of p38 MAPkinase, triggering cytokine production GRA28 Nucleus Upregulates CCL22 HCE1/TEEGR Nucleus Binds to E2F3/4, upregulates cell cycle genes, reduces chromatin access, limits cytokine production TgIST Nucleus Binds STAT1 and Mi2-NuRD complex silencing IGNg responses.

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Impact of Engineered Expression of Mitochondrial Association Factor 1b onToxoplasma gondiiInfection and the Host Response in a Mouse Model

Cited by 11 publications

References 35 publications

The GRA17 Parasitophorous Vacuole Membrane Permeability Pore Contributes to Bradyzoite Viability

The GRA17 Parasitophorous Vacuole Membrane Permeability Pore Contributes to Bradyzoite Viability

ROP16-Mediated Activation of STAT6 Suppresses Host Cell Reactive Oxygen Species Production, Facilitating Type III Toxoplasma gondii Growth and Survival

Seizing control: How dense granule effector proteins enable Toxoplasma to take charge

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