Infection with Toxoplasma gondii results in dysregulation of the host cell cycle

Molestina, Robert E.; El-Guendy, Nadia; Sinai, Anthony P.

doi:10.1111/j.1462-5822.2008.01117.x

Cited by 85 publications

(107 citation statements)

References 65 publications

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“…Interestingly, many of the Toxoplasma-induced c-Myc targets in our data set have been shown to be positive regulators of cell survival and viability and negative regulators of apoptosis and cell cycling (specifically, genes regulating the G 2 /M checkpoint were enriched [P ϭ 0.00132]), which is consistent with previous reports on the regulation of apoptosis and cell cycle by this parasite (43)(44)(45). Altogether, these data suggest that the upregulation of c-Myc in Toxoplasma-infected cells has a substantial impact on the host transcriptome and, likely, the overall phenotype of the infected cell.…”

Section: Toxoplasma Infection Results In Specific Upregulation Of Hossupporting

confidence: 80%

“…Another possibility is that Toxoplasma co-opts c-Myc to regulate the host cell cycle. Our findings using IPA of gene expression changes in Toxoplasma-infected cells are consistent with previous reports that have shown that Toxoplasma can induce host cell cycle arrest at a G 2 /M checkpoint (43,44). Restricting the proliferation ability of the host cell could be a strategy to ensure that enough nutrients are available for the parasite instead of being utilized by the host cell.…”

Section: Figsupporting

confidence: 79%

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Infection by Toxoplasma gondii Specifically Induces Host c-Myc and the Genes This Pivotal Transcription Factor Regulates

2014

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Toxoplasma gondii infection has previously been described to cause dramatic changes in the host transcriptome by manipulating key regulators, including STATs, NF-B, and microRNAs. Here, we report that Toxoplasma tachyzoites also mediate rapid and sustained induction of another pivotal regulator of host cell transcription, c-Myc. This induction is seen in cells infected with all three canonical types of Toxoplasma but not the closely related apicomplexan parasite Neospora caninum. Coinfection of cells with both Toxoplasma and Neospora still results in an increase in the level of host c-Myc, showing that c-Myc is actively upregulated by Toxoplasma infection (rather than repressed by Neospora). We further demonstrate that this upregulation may be mediated through c-Jun N-terminal protein kinase (JNK) and is unlikely to be a nonspecific host response, as heat-killed Toxoplasma parasites do not induce this increase and neither do nonviable parasites inside the host cell. Finally, we show that the induced c-Myc is active and that transcripts dependent on its function are upregulated, as predicted. Hence, c-Myc represents an additional way in which Toxoplasma tachyzoites have evolved to specifically alter host cell functions during intracellular growth.T oxoplasma gondii is a ubiquitous parasite that infects and reproduces in virtually any nucleated cell of warm-blooded animals. It is of great medical importance as infections in immunocompromised humans often lead to life-threatening disease. The ability of Toxoplasma to replicate in a wide host range is likely dependent on the capacity of the parasite to regulate conserved host cell pathways via its secreted factors. For example, the secreted protein ROP16 regulates immunologically important host transcription factors, STAT3 (1), STAT6 (2), and STAT5 (3), causing profound transcriptional changes shortly after invasion. Although many of the changes observed in infected host cells are strain specific and are important for the differences in virulence between the major strains of Toxoplasma (4), it is likely that there is also remodeling of host cells that occurs independently of strain type. Parasite effectors whose function is conserved across the three major types of Toxoplasma (e.g., Toxoplasma protein GRA16, which regulates the host p53 pathway [5]) have previously been identified. Such is likely an effective solution for those instances where the same need is faced by all strains, e.g., disarming defenses common to many hosts and/or meeting a survival challenge encountered in all cells.We have previously reported that infection with Toxoplasma tachyzoites specifically upregulates microRNAs that belong to transcriptional loci miR-17ϳ92 and miR-106bϳ25 (6). These microRNAs play an important role in the cell cycle and apoptosis of a host cell (7) and thereby likely affect the interplay between host and parasite. It has been reported that c-Myc is a direct transcriptional regulator of miR-17ϳ92 and miR-106bϳ25 (8), and so we hypothesized that Toxoplasma induces this tr...

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Section: Toxoplasma Infection Results In Specific Upregulation Of Hossupporting

confidence: 80%

Section: Figsupporting

confidence: 79%

Infection by Toxoplasma gondii Specifically Induces Host c-Myc and the Genes This Pivotal Transcription Factor Regulates

2014

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“…By stalling host cell division prior to cytokinesis, the parasites may ensure a stable and spacious environment for replication, as offered by a multinucleated cell. To this point, infection of quiescent cells with T. gondii induces an increase in D and E cyclins, thus promoting progression through G 1 and transition into S phase, respectively (90). Therefore, in Toxoplasma-infected cells, there is not only an induction of entry into S phase triggered by the parasite but also an arrest in cell cycle progression in the S/G 2 transition, based on host cyclin expression levels and accumulation in the infected cells.…”

Section: Discussionmentioning

confidence: 99%

Neospora caninum Recruits Host Cell Structures to Its Parasitophorous Vacuole and Salvages Lipids from Organelles

et al. 2015

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Toxoplasma gondii and Neospora caninum, which cause the diseases toxoplasmosis and neosporosis, respectively, are two closely related apicomplexan parasites. They have similar heteroxenous life cycles and conserved genomes and share many metabolic features. Despite these similarities, T. gondii and N. caninum differ in their transmission strategies and zoonotic potential. Comparative analyses of the two parasites are important to identify the unique biological features that underlie the basis of host preference and pathogenicity. T. gondii and N. caninum are obligate intravacuolar parasites; in contrast to T. gondii, events that occur during N. caninum infection remain largely uncharacterized. We examined the capability of N. caninum (Liverpool isolate) to interact with host organelles and scavenge nutrients in comparison to that of T. gondii (RH strain). N. caninum reorganizes the host microtubular cytoskeleton and attracts endoplasmic reticulum (ER), mitochondria, lysosomes, multivesicular bodies, and Golgi vesicles to its vacuole though with some notable differences from T. gondii. For example, the host ER gathers around the N. caninum parasitophorous vacuole (PV) but does not physically associate with the vacuolar membrane; the host Golgi apparatus surrounds the N. caninum PV but does not fragment into ministacks. N. caninum relies on plasma lipoproteins and scavenges cholesterol from NPC1-containing endocytic organelles. This parasite salvages sphingolipids from host Golgi Rab14 vesicles that it sequesters into its vacuole. Our data highlight a remarkable degree of conservation in the intracellular infection program of N. caninum and T. gondii. The minor differences between the two parasites related to the recruitment and rearrangement of host organelles around their vacuoles likely reflect divergent evolutionary paths.

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“…As cell cycle progression is a fundamentally important biological process that leads to many functional alterations in cells, it is not surprising that numerous intracellular pathogens manipulate the cell cycle progression of their host cells. While important and well-studied examples arise from viral and bacterial infections (reviewed in references 1 and 2), protozoan parasites, such as Toxoplasma gondii (3)(4)(5), Trypanosoma cruzi (6), Eimeria bovis (7), Encephalitozoon spp. (8), and Leishmania major (9), have all been suggested to modulate host cell cycle progression.…”

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confidence: 99%

In Vitro Alterations Do Not Reflect a Requirement for Host Cell Cycle Progression during Plasmodium Liver Stage Infection

Hanson

March

et al. 2015

Eukaryot Cell

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f Prior to invading nonreplicative erythrocytes, Plasmodium parasites undergo their first obligate step in the mammalian host inside hepatocytes, where each sporozoite replicates to generate thousands of merozoites. While normally quiescent, hepatocytes retain proliferative capacity and can readily reenter the cell cycle in response to diverse stimuli. Many intracellular pathogens, including protozoan parasites, manipulate the cell cycle progression of their host cells for their own benefit, but it is not known whether the hepatocyte cell cycle plays a role during Plasmodium liver stage infection. Here, we show that Plasmodium parasites can be observed in mitotic hepatoma cells throughout liver stage development, where they initially reduce the likelihood of mitosis and ultimately lead to significant acquisition of a binucleate phenotype. However, hepatoma cells pharmacologically arrested in S phase still support robust and complete Plasmodium liver stage development, which thus does not require cell cycle progression in the infected cell in vitro. Furthermore, murine hepatocytes remain quiescent throughout in vivo infection with either Plasmodium berghei or Plasmodium yoelii, as do Plasmodium falciparum-infected primary human hepatocytes, demonstrating that the rapid and prodigious growth of liver stage parasites is accomplished independent of host hepatocyte cell cycle progression during natural infection.

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Infection with Toxoplasma gondii results in dysregulation of the host cell cycle

Cited by 85 publications

References 65 publications

Infection by Toxoplasma gondii Specifically Induces Host c-Myc and the Genes This Pivotal Transcription Factor Regulates

Infection by Toxoplasma gondii Specifically Induces Host c-Myc and the Genes This Pivotal Transcription Factor Regulates

Neospora caninum Recruits Host Cell Structures to Its Parasitophorous Vacuole and Salvages Lipids from Organelles

In Vitro Alterations Do Not Reflect a Requirement for Host Cell Cycle Progression during Plasmodium Liver Stage Infection

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