Toxoplasma gondii-induced host cellular cell cycle dysregulation is linked to chromosome missegregation and cytokinesis failure in primary endothelial host cells

Velásquez, Zahady D.; Conejeros, Iván; Larrazabal, Camilo; Kerner, Katharina; Hermosilla, Carlos; Taubert, Anja

doi:10.1038/s41598-019-48961-0

Cited by 28 publications

(71 citation statements)

References 52 publications

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“…This finding contrasts with data on T. gondii infections which were reported either to dampen host cell proliferation in non-endothelial cell types (Brunet et al 2008;Molestina et al 2008;Kim et al 2016) or to trigger proliferation in the same endothelial cell type we used (Velásquez et al 2019). Accordingly, we could also not state an infection-driven increase of bi-or multi-nucleated host cells as previously reported for T. gondii infections (Velásquez et al 2019). In this respect, the combination of DRAQ5 staining with live cell 3D-holotomographic microscopy easily allowed nuclear phenotype estimation and nicely illustrated B. besnoiti development in BUVEC.…”

Section: Discussioncontrasting

confidence: 99%

“…Bars represent the median ± SD against the non-infected cells control. **** = p < 0.0001 recently published T. gondii data (Velásquez et al 2019), the current study was performed in a primary bovine endothelial cell type. Furthermore, by using a primary host cell type, false influences on host cellular cell cycle progression or cell division activities driven by cell immortalization or tumoral origin was avoided (Mondello and Chiodi 2013).…”

Section: Discussionmentioning

confidence: 93%

“…As such, T. gondii and Leishmania spp. induce cell cycle arrest and eventually dampen host cell proliferation (Brunet et al 2008;Costales et al 2009;Kim et al 2016;Kuzmenok et al 2005;Molestina et al 2008;Scanlon et al 2000;Velásquez et al 2019), while Theileria annulata and Theileria parva trigger host cell division and proliferation (von Schubert et al 2010;Wiens et al 2014) and induce segregation of Theileria merozoites to each developing daughter cell. Conversely, L. amazonensis interferes early in cell cycle by G0/G1-phase arrest (Kuzmenok et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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Besnoitia besnoiti–driven endothelial host cell cycle alteration

et al. 2020

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Besnoitia besnoiti is an important obligate intracellular parasite of cattle which primarily infects host endothelial cells of blood vessels during the acute phase of infection. Similar to the closely related parasite Toxoplasma gondii, B. besnoiti has fast proliferating properties leading to rapid host cell lysis within 24-30 h p.i. in vitro. Some apicomplexan parasites were demonstrated to modulate the host cellular cell cycle to successfully perform their intracellular development. As such, we recently demonstrated that T. gondii tachyzoites induce G2/M arrest accompanied by chromosome missegregation, cell spindle alteration, formation of supernumerary centrosomes, and cytokinesis impairment when infecting primary bovine umbilical vein endothelial cells (BUVEC). Here, we follow a comparative approach by using the same host endothelial cell system for B. besnoiti infections. The current data showed that-in terms of host cell cycle modulation-infections of BUVEC by B. besnoiti tachyzoites indeed differ significantly from those by T. gondii. As such, cyclin expression patterns demonstrated a significant upregulation of cyclin E1 in B. besnoiti-infected BUVEC, thereby indicating parasite-driven host cell stasis at G1-to-S phase transition. In line, the mitotic phase of host cell cycle was not influenced since alterations of chromosome segregation, mitotic spindle formation, and cytokinesis were not observed. In contrast to respective T. gondii-related data, we furthermore found a significant upregulation of histone H3 (S10) phosphorylation in B. besnoiti-infected BUVEC, thereby indicating enhanced chromosome condensation to occur in these cells. In line to altered G1/S-transition, we here additionally showed that subcellular abundance of proliferating cell nuclear antigen (PCNA), a marker for G1 and S phase sub-stages, was affected by B. besnoiti since infected cells showed increased nuclear PCNA levels when compared with that of control cells.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Besnoitia besnoiti–driven endothelial host cell cycle alteration

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“…S4C). These findings are consistent with potential induction of cell cycle arrest in U-I cells by injected effectors, as previously reported (38–41).…”

Section: Resultssupporting

confidence: 93%

Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular ParasiteToxoplasma gondii

Rastogi

Xue

Quake

et al. 2020

Preprint

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words 16Importance: 36 words ABSTRACT 30The intracellular parasite Toxoplasma gondii employs a vast array of effector 31 proteins from the rhoptry and dense granule organelles to modulate host cell biology; 32 these effectors are known as ROPs and GRAs, respectively. To examine the individual 33 impacts of ROPs and GRAs on host gene expression, we developed a robust, novel 34 protocol to enrich for ultra-pure populations of a naturally occurring and reproducible 35 population of host cells called uninfected-injected (U-I) cells, which Toxoplasma injects 36with ROPs but subsequently fails to invade. We then performed single cell 37 transcriptomic analysis at 1-3 hours post-infection on U-I cells (as well as on uninfected 38 and infected controls) arising from infection with either wild type parasites or parasites 39 lacking the MYR1 protein, which is required for soluble GRAs to cross the 40 parasitophorous vacuole membrane (PVM) and reach the host cell cytosol. Based on 41 comparisons of infected and U-I cells, the host's earliest response to infection appears 42 to be driven primarily by the injected ROPs, which appear to induce immune and 43 cellular stress pathways. These ROP-dependent pro-inflammatory signatures appear to 44 be counteracted by at least some of the MYR1-dependent GRAs and may be enhanced 45 by the MYR-independent GRAs, (which are found embedded within the PVM). Finally, 46 signatures detected in uninfected bystander cells from the infected monolayers 47 suggests that MYR1-dependent paracrine effects also counteract inflammatory ROP-48 dependent processes. 49 50 IMPORTANCE 51 This work performs the first transcriptomic analysis of U-I cells, captures the 52 earliest stage of a host cell's interaction with Toxoplasma gondii, and dissects the 53 effects of individual classes of parasite effectors on host cell biology. 54 55 MAIN TEXT 56 Introduction 57The obligate intracellular parasite Toxoplasma gondii parasitizes a wide range of 58 avian and mammalian organisms, including humans (1). During the acute phase of 59 infection, this unicellular eukaryote rapidly expands within host tissues by penetrating 60 host cells, establishing and replicating within an intracellular parasitophorous vacuole 61 (PV), and simultaneously avoiding clearance by the host immune system (reviewed in 62(2)). To orchestrate these events (Fig. 1A), Toxoplasma employs a vast repertoire of 63 effector proteins housed primarily in two secretory organelles, the rhoptries and dense 64 granules. The rhoptry organelle effectors (ROPs) are secreted by the parasite into the 65 host cytosol during or immediately prior to invasion by an as yet undefined mechanism 66 (reviewed in (3)). The handful of ROPs that have been characterized to date include 67 virulence factors that disrupt immune clearance mechanisms (4-7), remodel the host's 68 cortical actin cytoskeleton at the point of parasite penetration (8, 9), and co-opt the 69 STAT3 and STAT6 pathways (10-12). In contrast, the dense granule effectors (GRAs) 70 are thought to be secr...

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“…Using RPE and Müller cells, isolated from Lewis rats, Delair et al (2009) indicated that TNF-α and IFN-γ differentially restrict in vitro T. gondii infection, thus indicating that RMC are more susceptible to infection than RPE. Finally, it was recently described that T. gondii disrupts correct cytokinesis patterns and the formation of the mitotic spindle in bovine endothelial cells (Velásquez et al, 2019). It is known that changes in spindle structure, with or without cell cycle protein alterations, can lead to abnormal retinal and brain cortex development (Uzquiano et al, 2018), which could also explain how CT affects these processes.…”

Section: Congenital Toxoplasmosismentioning

confidence: 99%

Implications of TORCH Diseases in Retinal Development—Special Focus on Congenital Toxoplasmosis

Campos

Calaza

Adesse

2020

Front. Cell. Infect. Microbiol.

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There are certain critical periods during pregnancy when the fetus is at high risk for exposure to teratogens. Some microorganisms, including Toxoplasma gondii, are known to exhibit teratogenic effects, interfering with fetal development and causing irreversible disturbances. T. gondii is an obligate intracellular parasite and the etiological agent of Toxoplasmosis, a zoonosis that affects one third of the world's population. Although congenital infection can cause severe fetal damage, the injury extension depends on the gestational period of infection, among other factors, like parasite genotype and host immunity. This parasite invades the Central Nervous System (CNS), forming tissue cysts, and can interfere with neurodevelopment, leading to frequent neurological abnormalities associated with T. gondii infection. Therefore, T. gondii is included in the TORCH complex of infectious diseases that may lead to neurological malformations (Toxoplasmosis, Others, Rubella, Cytomegalovirus, and Herpes). The retina is part of CNS, as it is derived from the diencephalon. Except for astrocytes and microglia, retinal cells originate from multipotent neural progenitors. After cell cycle exit, cells migrate to specific layers, undergo morphological and neurochemical differentiation, form synapses and establish their circuits. The retina is organized in nuclear layers intercalated by plexus, responsible for translating and preprocessing light stimuli and for sending this information to the brain visual nuclei for image perception. Ocular toxoplasmosis (OT) is a very debilitating condition and may present high severity in areas in which virulent strains are found. However, little is known about the effect of congenital infection on the biology of retinal progenitors/ immature cells and how this infection may affect the development of this tissue. In this context, this study reviews the effects that congenital infections may cause to the developing retina and the cellular and molecular aspects of these diseases, with special focus on congenital OT.

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Toxoplasma gondii-induced host cellular cell cycle dysregulation is linked to chromosome missegregation and cytokinesis failure in primary endothelial host cells

Cited by 28 publications

References 52 publications

Besnoitia besnoiti–driven endothelial host cell cycle alteration

Besnoitia besnoiti–driven endothelial host cell cycle alteration

Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular ParasiteToxoplasma gondii

Implications of TORCH Diseases in Retinal Development—Special Focus on Congenital Toxoplasmosis

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