Disruption of Toxoplasma gondii-Induced Host Cell DNA Replication Is Dependent on Contact Inhibition and Host Cell Type

Pierre-Louis, Edwin; Etheridge, Menna G.; Baptista, Rodrigo P.; Khan, Asis; Chasen, Nathan M.; Etheridge, Ronald D.

doi:10.1128/msphere.00160-22

Cited by 5 publications

(5 citation statements)

References 80 publications

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“…To our best knowledge, available data on T. gondii -driven host cell cycle modulation currently refer to haplotype I tachyzoites (RH strain) and indicate that this clonal lineage might control host cell cycle progression to ease its intracellular asexual development ( Brunet et al, 2008 ; Molestina et al, 2008 ; Velásquez et al, 2019 ; Wong et al, 2020 ; Pierre-Louis et al, 2022 ). Since several typical and atypical clonal lineages of T. gondii occur worldwide and show variable pathogenicity ( Dardé et al, 2014 ; Miller et al, 2023 ), we aimed to compare recent RH data (haplotype I) ( Velásquez et al, 2019 ) with haplotypes II and III (Me49 and NED, respectively) by infecting the same host cell type.…”

Section: Discussionmentioning

confidence: 99%

“…Referring to parasite-mediated modulation of cell cycle progression, the current data showed that both NED and ME49 strains induced host cell cycle arrest in S-phase, but they differed in the control, thereby denying any haplotype-dependent reactions. Interestingly, S-phase arrest has been studied by other groups worldwide, suggesting that arrested cells were not able to incorporate new DNA molecules ( Pierre-Louis et al, 2022 ). Given that T. gondii arrests the host cell cycle equally in primary, immortalized, and tumor cells, we could suggest that it is a parasite strategy that has been maintained throughout haplotype evolution ( Brunet et al, 2008 ; Molestina et al, 2008 ; Kim et al, 2016 ; Velásquez et al, 2019 ; Pierre-Louis et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, S-phase arrest has been studied by other groups worldwide, suggesting that arrested cells were not able to incorporate new DNA molecules ( Pierre-Louis et al, 2022 ). Given that T. gondii arrests the host cell cycle equally in primary, immortalized, and tumor cells, we could suggest that it is a parasite strategy that has been maintained throughout haplotype evolution ( Brunet et al, 2008 ; Molestina et al, 2008 ; Kim et al, 2016 ; Velásquez et al, 2019 ; Pierre-Louis et al, 2022 ). The mitosis progression was shown to be modulated differently in NED- or ME49-infected cells compared to previous data published on the RH strain since infected cells displayed multipolar spindle formation ( Velásquez et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

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Toxoplasma gondii Me49 and NED strains arrest host cell cycle progression and alter chromosome segregation in a strain-independent manner

Rojas-Barón,

Hermosilla,

Taubert

et al. 2024

Front. Microbiol.

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Toxoplasma gondii is an obligate intracellular parasite that modulates a broad range of host cell functions to guarantee its intracellular development and replication. T. gondii includes three classical clonal lineages exhibiting different degrees of virulence. Regarding the genetic diversity of T. gondii circulating in Europe, type II strains and, to a lesser extent, type III strains are the dominant populations, both in humans and animals. Infections with the type I strain led to widespread parasite dissemination and death in mice, while type III is considered avirulent. Previously, we demonstrated that primary endothelial cells infected with the T. gondii RH strain (haplotype I) were arrested in the G2/M-phase transition, triggering cytokinesis failure and chromosome missegregation. Since T. gondii haplotypes differ in their virulence, we here studied whether T. gondii-driven host cell cycle perturbation is strain-dependent. Primary endothelial cells were infected with T. gondii Me49 (type II strain) or NED (type III strain), and their growth kinetics were compared up to cell lysis (6–30 h p. i.). In this study, only slight differences in the onset of full proliferation were observed, and developmental data in principle matched those of the RH strain. FACS-based DNA quantification to estimate cell proportions experiencing different cell cycle phases (G0/1-, S-, and G2/M-phase) revealed that Me49 and NED strains both arrested the host cell cycle in the S-phase. Cyclins A2 and B1 as key molecules of S- and M-phase were not changed by Me49 infection, while NED infection induced cyclin B1 upregulation. To analyze parasite-driven alterations during mitosis, we demonstrated that both Me49 and NED infections led to impaired host cellular chromosome segregation and irregular centriole overduplication. Moreover, in line with the RH strain, both strains boosted the proportion of binucleated cells within infected endothelial cell layers, thereby indicating enhanced cytokinesis failure. Taken together, we demonstrate that all parasite-driven host cell cycle arrest, chromosome missegregation, and binucleated phenotypes are T. gondii-specific but strain independent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Toxoplasma gondii Me49 and NED strains arrest host cell cycle progression and alter chromosome segregation in a strain-independent manner

Rojas-Barón,

Hermosilla,

Taubert

et al. 2024

Front. Microbiol.

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“…Immortalized human fibroblasts, HFF, were arrested in the S-phase after 6 h p.i. with T. gondii tachyzoites (Pierre-Louis et al, 2022). The G2 phase arrest in human dermal fibroblasts or a human trophoblast cell line was linked to the downregulation of cyclin B1 (Brunet et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii infection-induced host cellular DNA damage is strain-dependent and leads to the activation of the ATM-dependent homologous recombination pathway

Rojas-Barón,

Hermosilla,

Taubert

et al. 2024

Front. Cell. Infect. Microbiol.

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Toxoplasma gondii is a globally occurring apicomplexan parasite that infects humans and animals. Globally, different typical and atypical haplotypes of T. gondii induce varying pathologies in hosts. As an obligate intracellular protozoon, T. gondii was shown to interfere with host cell cycle progression, leading to mitotic spindle alteration, chromosome segregation errors and cytokinesis failure which all may reflect chromosomal instability. Referring to strain-dependent virulence, we here studied the potential of different T. gondii strains (RH, Me49 and NED) to drive DNA damage in primary endothelial host cells. Utilizing microscopic analyses, comet assays and γ-H2AX quantification, we demonstrated a strain-dependent induction of binucleated host cells, DNA damage and DNA double strand breaks, respectively, in T. gondii-infected cells with the RH strain driving the most prominent effects. Interestingly, only the NED strain significantly triggered micronuclei formation in T. gondii-infected cells. Focusing on the RH strain, we furthermore demonstrated that T. gondii-infected primary host cells showed a DNA damage response by activating the ATM-dependent homologous recombination (HR) pathway. In contrast, key molecules of the nonhomologous DNA end joining (NHEJ) pathway were either not affected or downregulated in RH-infected host cells, suggesting that this pathway is not activated by infection. In conclusion, current finding suggests that T. gondii infection affects the host cell genome integrity in a strain-dependent manner by causing DNA damage and chromosomal instability.

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“…T. gondii is able to influence the progression of the cell cycle of the host cell and to promote its transition to the S phase, followed however by an arrest in the G2/M phase [ [58] , [59] , [60] ]. Recently, separate studies have also revealed the ability of the parasite protein TEEGR to be exported to the host cell nucleus to induce cyclin E [ [61] , [62] , [63] ]. In addition, GRA16, another parasite effector protein, is able to positively modulate the expression of genes involved in cell cycle progression, as well as p53, via its interaction with the HAUSP protein [ 64 ].…”

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii, a plea for a thorough investigation of its oncogenic potential

Dupont,

Robert,

Brenier-Pinchart

et al. 2023

Heliyon

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Disruption of Toxoplasma gondii-Induced Host Cell DNA Replication Is Dependent on Contact Inhibition and Host Cell Type

Cited by 5 publications

References 80 publications

Toxoplasma gondii Me49 and NED strains arrest host cell cycle progression and alter chromosome segregation in a strain-independent manner

Toxoplasma gondii Me49 and NED strains arrest host cell cycle progression and alter chromosome segregation in a strain-independent manner

Toxoplasma gondii infection-induced host cellular DNA damage is strain-dependent and leads to the activation of the ATM-dependent homologous recombination pathway

Toxoplasma gondii, a plea for a thorough investigation of its oncogenic potential

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