Genetic Mapping of Pathogenesis Determinants in<i>Toxoplasma gondii</i>

Behnke, Michael S.; Dubey, J. P.; Sibley, L. David

doi:10.1146/annurev-micro-091014-104353

Cited by 60 publications

(55 citation statements)

References 127 publications

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“…These studies have taken advantage of the capacity for genetic crosses along with linkage analysis (214) to identify genes that underlie phenotypes that differ among the major strains types of T. gondii. This approach has been exploited to identify genes that mediate acute virulence as well as augment immune signaling (197,215).…”

Section: Defining Pathogenesis Determinantsmentioning

confidence: 99%

ToxoplasmaEffectors Targeting Host Signaling and Transcription

2017

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Early electron microscopy studies revealed the elaborate cellular features that define the unique adaptations of apicomplexan parasites. Among these were bulbous rhoptry (ROP) organelles and small, dense granules (GRAs), both of which are secreted during invasion of host cells. These early morphological studies were followed by the exploration of the cellular contents of these secretory organelles, revealing them to be comprised of highly divergent protein families with few conserved domains or predicted functions. In parallel, studies on host-pathogen interactions identified many host signaling pathways that were mysteriously altered by infection. It was only with the advent of forward and reverse genetic strategies that the connections between individual parasite effectors and the specific host pathways that they targeted finally became clear. The current repertoire of parasite effectors includes ROP kinases and pseudokinases that are secreted during invasion and that block host immune pathways. Similarly, many secretory GRA proteins alter host gene expression by activating host transcription factors, through modification of chromatin, or by inducing small noncoding RNAs. These effectors highlight novel mechanisms by which has learned to harness host signaling to favor intracellular survival and will guide future studies designed to uncover the additional complexity of this intricate host-pathogen interaction.

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Section: Defining Pathogenesis Determinantsmentioning

confidence: 99%

ToxoplasmaEffectors Targeting Host Signaling and Transcription

2017

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“…1,2 The manipulation of host cells to enable evasion of the host immune defenses, and remodeling of the host cellular environment, are examples of mechanisms that this parasite can employ to sustain its intracellular survival. [3][4][5] This parasite also influences the host cell signaling and gene expression, alters vesicle trafficking and host cell cytoskeleton, and rearranges host cell organelles, such as the endoplasmic reticulum, lysosomes and mitochondria, 5,6 mainly through the secretion and export of T. gondii effector proteins including more than 50 protein kinases and pseudokinases. 7,8 T. gondii lytic cycle, which is essential for parasite survival within its host and progression of infection, starts with an active invasion of the parasite into the host cell, a process that is mediated by sequential secretion of proteins from three specialized secretory organelles, namely micronemes, rhoptries, and dense granules.…”

Section: Introductionmentioning

confidence: 99%

Novel roles of dense granule protein 12 (GRA12) inToxoplasma gondiiinfection

et al. 2020

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are contributed equally to this work. AbstractDense granule protein 12 (GRA12) is implicated in a range of processes related to the establishment of Toxoplasma gondii infection, such as the formation of the intravacuolar network (IVN) within the parasitophorous vacuole (PV). This protein is also thought to be important for T. gondii-host interaction, pathogenesis, and immune evasion, but their exact roles remain unknown. In this study, the contributions of GRA12 to the molecular pathogenesis of T. gondii infection were examined in vitro and in vivo. Deletion of GRA12 in type I RH and type II Pru T. gondii strains did not affect the parasite growth and replication in vitro, however, it caused a significant reduction in the parasite virulence and tissue cyst burden in vivo. T. gondii Δgra12 mutants were more vulnerable to be eliminated by host immunity, without the accumulation of immunity-related GTPase a6 (Irga6) onto the PV membrane.The ultrastructure of IVN in Δgra12 mutants appeared normal, suggesting that GRA12 is not required for biogenesis of the IVN. Combined deletion of GRA12 and ROP18 induced more severe attenuation of virulence compared to single Δgra12 or Δrop18 mutant strains. These data suggest a functional association between GRA12 and ROP18 that is revealed by the severe attenuation of virulence in a double mutant relative to the single individual mutations. Future studies are needed to define the molecular basis of this putative association. Collectively these findings indicate that although GRA12 is not essential for the parasite growth and replication in vitro, it contributes to the virulence and growth of T. gondii in mice. K E Y W O R D Sdense granule protein 12, immunity-related GTPases, intravacuolar network, rhoptry protein 18, Toxoplasma gondii, virulence 3166 | WANG et Al. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section. How to cite this article: Wang J-L, Bai M-J, Elsheikha HM, et al. Novel roles of dense granule protein 12 (GRA12) in Toxoplasma gondii infection.

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“…In contrast, RhopH3 and its partner proteins RhopH1/Clag and RhopH2 have additionally been shown to be involved in nutrient uptake during development of the intracellular parasite [22][23][24][25], whilst the rhoptry bulb low molecular weight (LMW) RAP1/RAP2 complex has been implicated in PVM formation [26]. In Toxoplasma (but not in Plasmodium) several rhoptry bulb proteins are enzymes, including proteases, phosphatases and kinases or pseudokinases, the latter two groups of which dramatically modulate host cell STAT signalling and the immunity-related GTPase (IRG) pathway involved in controlling parasite replication, and play key roles in virulence [27,28]. Collectively, the current evidence points to multiple diverse roles for rhoptry proteins, with a general theme being that rhoptry neck proteins are often but not exclusively involved in host cell entry whilst rhoptry bulb proteins usually fulfil subsequent roles in the life cycle (see [29][30][31] for excellent reviews of this subject).…”

Section: Introductionmentioning

confidence: 99%

The Plasmodium falciparum rhoptry bulb protein RAMA plays an essential role in rhoptry neck morphogenesis and host red blood cell invasion

et al. 2019

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The malaria parasite Plasmodium falciparum invades, replicates within and destroys red blood cells in an asexual blood stage life cycle that is responsible for clinical disease and crucial for parasite propagation. Invasive malaria merozoites possess a characteristic apical complex of secretory organelles that are discharged in a tightly controlled and highly regulated order during merozoite egress and host cell invasion. The most prominent of these organelles, the rhoptries, are twinned, club-shaped structures with a body or bulb region that tapers to a narrow neck as it meets the apical prominence of the merozoite. Different protein populations localise to the rhoptry bulb and neck, but the function of many of these proteins and how they are spatially segregated within the rhoptries is unknown. Using conditional disruption of the gene encoding the only known glycolipid-anchored malarial rhoptry bulb protein, rhoptry-associated membrane antigen (RAMA), we demonstrate that RAMA is indispensable for blood stage parasite survival. Contrary to previous suggestions, RAMA is not required for trafficking of all rhoptry bulb proteins. Instead, RAMA-null parasites display selective mislocalisation of a subset of rhoptry bulb and neck proteins (RONs) and produce dysmorphic rhoptries that lack a distinct neck region. The mutant parasites undergo normal intracellular development and egress but display a fatal defect in invasion and do not induce echinocytosis in target red blood cells. Our results indicate that distinct pathways regulate biogenesis of the two main rhoptry sub-compartments in the malaria parasite. Author summaryDespite improved control measures over recent decades, malaria is still a considerable health burden across much of the globe. The disease is caused by a single-celled parasite PLOS Pathogens | https://doi.

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Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

Cited by 60 publications

References 127 publications

ToxoplasmaEffectors Targeting Host Signaling and Transcription

ToxoplasmaEffectors Targeting Host Signaling and Transcription

Novel roles of dense granule protein 12 (GRA12) inToxoplasma gondiiinfection

The Plasmodium falciparum rhoptry bulb protein RAMA plays an essential role in rhoptry neck morphogenesis and host red blood cell invasion

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