Calcium Signaling throughout the Toxoplasma gondii Lytic Cycle

Borges-Pereira, Lucas; Budu, Alexandre; McKnight, Ciara Anderson; Moore, Christina A.; Vella, Stephen A.; Triana, Miryam Andrea Hortua; Liu, Jing; Garcia, Célia Regina da Silva; Pace, Douglas A.; Moreno, Silvia N.J.

doi:10.1074/jbc.m115.652511

Cited by 69 publications

(61 citation statements)

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“…The redox reagent DTT is proposed to induce egress by activating NTPases located in the PV since it is capable of activating isolated enzyme (Bermudes et al , 1994). Treatment with DTT has also been shown to lead to calcium fluxes within the parasite, resulting in induced egress, which can be blocked by chelating calcium, indicating that DTT-induced egress is also calcium dependent (Stommel et al , 1997, Borges-Pereira et al , 2015). Unlike calcium ionophores such as A23187, DTT is not capable of inducing egress at early stages of parasite vacuole formation and requires longer growth times (~36 hours) for vacuoles to consistently egress.…”

Section: Discussionmentioning

confidence: 99%

“…Many of the events in Toxoplasma’s lytic cycle such as egress, motility, invasion and micronemal protein secretion are accompanied by and dependent on calcium fluxes within both the parasite and the host cell (Arrizabalaga et al , 2004a). Calcium levels increase in the host cell, the PV and the parasite cytoplasm just prior to the initiation of parasite egress from its host cell (Borges-Pereira et al , 2015). Oscillations in parasite calcium, which are enhanced in the presence of extracellular calcium, have been observed during periods of parasite motility using both chemical and genetically encoded calcium indicators, (Lovett et al , 2003, Borges-Pereira et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Calcium levels increase in the host cell, the PV and the parasite cytoplasm just prior to the initiation of parasite egress from its host cell (Borges-Pereira et al , 2015). Oscillations in parasite calcium, which are enhanced in the presence of extracellular calcium, have been observed during periods of parasite motility using both chemical and genetically encoded calcium indicators, (Lovett et al , 2003, Borges-Pereira et al , 2015). Secretion of the proteins from the micronemes, which are required for parasite attachment to a host cell, can be stimulated by artificially inducing calcium fluxes (Carruthers et al , 1999b).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…It is also possible that a number of Ca 2+ regulated proteins are involved in the replication of the parasite. There is evidence for the presence of a higher concentration of Ca 2+ within the PV [122] and host Ca 2+ oscillation do cause oscillations in the parasite [123]. It is still not clear how host cytosolic Ca 2+ impacts the biological functions of the parasite.…”

Section: Microneme Secretion Motility Host Cell Invasion and Egressmentioning

confidence: 99%

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Triana

Márquez-Nogueras

Vella

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Toxoplasma gondii has a complex life cycle involving different hosts and is dependent on fast responses, as the parasite reacts to changing environmental conditions. T. gondii causes disease by lysing the host cells that it infects and it does this by reiterating its lytic cycle, which consists of host cell invasion, replication inside the host cell, and egress causing host cell lysis. Calcium ion (Ca2+) signaling triggers activation of molecules involved in the stimulation and enhancement of each step of the parasite lytic cycle. Ca2+ signaling is essential for the cellular and developmental changes that support T. gondii parasitism. The characterization of the molecular players and pathways directly activated by Ca2+ signaling in Toxoplasma is sketchy and incomplete. The evolutionary distance between Toxoplasma and other eukaryotic model systems makes the comparison sometimes not informative. The advent of new genomic information and new genetic tools applicable for studying Toxoplasma biology is rapidly changing this scenario. The Toxoplasma genome reveals the presence of many genes potentially involved in Ca2+ signaling, even though the role of most of them is not known. The use of Genetically Encoded Calcium Indicators (GECIs) has allowed studies on the role of novel calcium-related proteins on egress, an essential step for the virulence and dissemination of Toxoplasma. In addition, the discovery of new Ca2+ players is generating novel targets for drugs, vaccines, and diagnostic tools and a better understanding of the biology of these parasites.

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“…Ca 2ϩ fluxes precede egress and are directly linked to parasite motility and invasion (8,9). Moreover, Ca 2ϩ signaling controls microneme secretion (10,11) and is essential to trigger parasite motility, which is regulated by Ca 2ϩ -mediated phosphorylation of parasite motility motor components (12,13).…”

mentioning

confidence: 99%

Serial Dissection of Parasite Gene Families

Bzik

2016

Infect Immun

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Calcium ion signaling regulates central aspects of the biology controlling stage and life cycle transitions of apicomplexan parasites. In the current issue ofInfection and Immunity, Long and coworkers (S. Long, Q. Wang, and L. D. Sibley, Infect Immun 84:1262–1273, 2016,http://dx.doi.org/10.1128/IAI.01173-15) describe a powerful genetic system enabling reliable serial genetic dissection of a large gene family encoding novel calcium-dependent protein kinases (CDPKs) that provides new insights into the roles of CDPKs duringToxoplasma gondiiinfection.

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Calcium Signaling throughout the Toxoplasma gondii Lytic Cycle

Cited by 69 publications

References 50 publications

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

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

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Serial Dissection of Parasite Gene Families

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