Targeted Disruption of the GRA2 Locus inToxoplasma gondii Decreases Acute Virulence in Mice

Mercier, Corinne; Howe, Daniel K.; Mordue, Dana G.; Lingnau, Maren; Sibley, L. David

doi:10.1128/.66.9.4176-4182.1998

Cited by 17 publications

(21 citation statements)

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“…Although the key function of most GRA proteins within the PV remains currently unknown, recent studies demonstrated that GRA2 and GRA7 are tubulogenic proteins essential in the formation of the MNN and HOSTs, respectively (14,16,32). GRA2 has also been shown to contribute to the parasite virulence in mice (33).…”

Section: The Pv Seems To Be a Main Final Destination For Many Toxoplamentioning

confidence: 99%

Apicomplexa in Mammalian Cells: Trafficking to the Parasitophorous Vacuole

Cesbron-Delauw

Gendrin

Travier

et al. 2008

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Most Apicomplexa reside and multiply in the cytoplasm of their host cell, within a parasitophorous vacuole (PV) originating from both parasite and host cell components. Trafficking of parasite-encoded proteins destined to membrane compartments beyond the confine of the parasite plasma membrane is a process that offers a rich territory to explore novel mechanisms of protein-membrane interactions. Here, we focus on the PVs formed by the asexual stages of two pathogens of medical importance, Plasmodium and Toxoplasma. We compare the PVs of both parasites, with a particular emphasis on their evolutionary divergent compartmentalization within the host cell. We also discuss the existence of peculiar export mechanisms and/or sorting determinants that are potentially involved in the post-secretory targeting of parasite proteins to the PV subcompartments.

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Section: The Pv Seems To Be a Main Final Destination For Many Toxoplamentioning

confidence: 99%

Apicomplexa in Mammalian Cells: Trafficking to the Parasitophorous Vacuole

Cesbron-Delauw

Gendrin

Travier

et al. 2008

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“…26 Disruption of either GRA2 or GRA6 did not affect the parasite growth in vitro cell culture, but resulted in a dramatically reduced virulence and a lower tissue cyst burden in a mouse model. [27][28][29] Two GRA12 genes (TGME49_275850 and TGME49_288650) were identified in the ToxoDB (https :// toxodb.org). 30 The TGME49_275850 gene was renamed as GRA12bis and was found non-essential for the parasites' lytic cycle and virulence.…”

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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“…Nonetheless, other dense granule proteins that traffic exclusively to the TVN of the PV are also critical for its formation (Mercier et al, 2002) but do not seem to appear to affect the same of processes influenced by GRA41. The loss of the TVN in parasites lacking GRA2 leads to a variety of phenotypes, including the formation of vacuoles containing poorly organised parasites that egress erratically (Muniz-Hernandez et al, 2011), altered presentation of antigens to the host immune system (Lopez et al, 2015), decreased ingestion of host cytosolic proteins (Dou, McGovern, Di Cristina, & Carruthers, 2014), and decreased virulence in mice (Mercier, Howe, Mordue, Lingnau, & Sibley, 1998). However, we have shown that the loss of GRA2 does not phenocopy the iiDeath resistance of the GRA41 knockout and forward genetic mutant, suggesting that the disruption of the TVN might not be the underlying reason for the iiDeath resistance of GRA41.…”

Section: Discussionmentioning

confidence: 99%

A novel dense granule protein, GRA41, regulates timing of egress and calcium sensitivity inToxoplasma gondii

LaFavers

Márquez-Nogueras

Coppens

et al. 2017

Cellular Microbiology

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SUMMARY Toxoplasma gondii is an obligate intracellular apicomplexan parasite with high seroprevalence in humans. Repeated lytic cycles of invasion, replication and egress drive both the propagation and the virulence of this parasite. Key steps in this cycle, including invasion and egress, depend on tightly regulated calcium fluxes and, while many of the calcium-dependent effectors have been identified, the factors that detect and regulate the calcium fluxes are mostly unknown. To address this knowledge gap, we used a forward genetic approach to isolate mutants resistant to extracellular exposure to the calcium ionophore A23187. Through whole genome sequencing and complementation we have determined that a nonsense mutation in a previously uncharacterized protein is responsible for the ionophore resistance of one of the mutants. The complete loss of this protein recapitulates the resistance phenotype and importantly shows defects in calcium regulation and in the timing of egress. The affected protein, GRA41, localizes to the dense granules and is secreted into the parasitophorous vacuole where it associates with the tubulovesicular network (TVN). Our findings support a connection between the TVN and ion homeostasis within the parasite, and thus a novel role for the vacuole of this important pathogen.

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Targeted Disruption of the GRA2 Locus inToxoplasma gondii Decreases Acute Virulence in Mice

Cited by 17 publications

References 0 publications

Apicomplexa in Mammalian Cells: Trafficking to the Parasitophorous Vacuole

Apicomplexa in Mammalian Cells: Trafficking to the Parasitophorous Vacuole

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

A novel dense granule protein, GRA41, regulates timing of egress and calcium sensitivity inToxoplasma gondii

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