Strategies Developed by Toxoplasma gondii to Survive in the Host

Zhu, Wen; Li, Jingyang; Pappoe, Faustina; Shen, Ji‐Long; Yu, Li

doi:10.3389/fmicb.2019.00899

Cited by 40 publications

(44 citation statements)

References 129 publications

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“…Consistent with the previous finding reported in T. gondii-infected mouse liver (He et al, 2016a), many IRGs and GBPs-related genes were upregulated. Although increased expression of IDO in the brain as antitoxoplasma mechanism to control the parasite replication has been reported in previous studies (Nagineni et al, 1996;Zhu et al, 2019), the expression level of IDO did not change in response to T. gondii infection in this study.…”

Section: Discussioncontrasting

confidence: 72%

Transcriptomic Profiling of Mouse Brain During Acute and Chronic Infections by Toxoplasma gondii Oocysts

Elsheikha

et al. 2020

Front. Microbiol.

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Infection by the protozoan Toxoplasma gondii can have a devastating impact on the structure and function of the brain of the infected individuals, particularly immunocompromised patients. A systems biology view of the brain transcriptome can identify key molecular targets and pathways that mediate the neuropathogenesis of cerebral toxoplasmosis. Here, we performed transcriptomic analysis of the brain of mice infected by T. gondii Pru strain oocysts at 11 and 33 days post-infection (dpi) compared to uninfected (control) mice using RNA sequencing (RNA-seq). T. gondii altered the expression of 936 and 2,081 transcripts at 11 and 33 dpi, respectively, and most of these were upregulated in the infected brains. Gene Ontology (GO) enrichment and pathway analysis showed that immune response, such as interferon-gamma (IFN-γ) responsive genes were strongly affected at 11dpi. Likewise, differentially expressed transcripts (DETs) related to T cell activation, cytokine production and immune cell proliferation were significantly altered at 33 dpi. Host-parasite interactome analysis showed that some DETs were involved in immune signaling, metabolism, biosynthesis-related processes and interspecies interaction. These findings should increase knowledge of the mouse brain transcriptome and the changes in transcriptional regulation and downstream signaling pathways during acute and chronic T. gondii infections.

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Section: Discussioncontrasting

confidence: 72%

Transcriptomic Profiling of Mouse Brain During Acute and Chronic Infections by Toxoplasma gondii Oocysts

Elsheikha

et al. 2020

Front. Microbiol.

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“…Previous studies demonstrated that autophagy contributes to host immune defenses against T. gondii infection [8,18]; however, the role of 4-HBA in autophagy activation has not been characterized. To determine whether 4-HBA treatment We next attempted to investigate the role of autophagy in 4-HBA-mediated anti-toxoplasma activity.…”

Section: -Hba-induced Autophagy Played An Essential Role In the Actimentioning

confidence: 98%

4-Hydroxybenzaldehyde Restricts the Intracellular Growth of Toxoplasma gondii by Inducing SIRT1-Mediated Autophagy in Macrophages

et al. 2020

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Toxoplasma gondii is an intracellular protozoan parasite that infects approximately one third of the human popu- lation worldwide. Considering the toxicity and side effects of anti-toxoplasma medications, it is important to develop effec- tive drug alternatives with fewer and less severe off-target effects. In this study, we found that 4-hydroxybenzaldehyde (4- HBA) induced autophagy and the expression of NAD-dependent protein deacetylase sirtuin-1 (SIRT1) in primary murine bone marrow-derived macrophages (BMDMs). Interestingly, treatment of BMDMs with 4-HBA significantly reduced the number of macrophages infected with T. gondii and the proliferation of T. gondii in infected cells. This effect was impaired by pretreating the macrophages with 3-methyladenine or wortmannin (selective autophagy inhibitors) or with sirtinol or EX527 (SIRT1 inhibitors). Moreover, we found that pharmacological inhibition of SIRT1 prevented 4-HBA-mediated expres- sion of LC3-phosphatidylethanolamine conjugate (LC3-II) and the colocalization of T. gondii parasitophorous vacuoles with autophagosomes in BMDMs. These data suggest that 4-HBA promotes antiparasitic host responses by activating SIRT1- mediated autophagy, and 4-HBA might be a promising therapeutic alternative for the treatment of toxoplasmosis.

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“…T. gondii can actively invade and replicate in all nucleated cells, particularly in the brain and retina. 17 It has developed several strategies, such as resistance to oxidative stress and modulation of host cell survival and death to obtain lifelong parasite survival, to avoid destruction by internal and external stimuli. 17,18 Several studies have shown that cells infected with T. gondii are resistant to multiple inducers of apoptosis, including Fas-dependent and Fas-independent CTL-mediated cytotoxicity, IL-2 deprivation, irradiation, UV irradiation, the calcium ionophore beauvericin, and actinomycin D, staurosporine, exogenous cytochrome c and dATP.…”

Section: Introductionmentioning

confidence: 99%

“…17 It has developed several strategies, such as resistance to oxidative stress and modulation of host cell survival and death to obtain lifelong parasite survival, to avoid destruction by internal and external stimuli. 17,18 Several studies have shown that cells infected with T. gondii are resistant to multiple inducers of apoptosis, including Fas-dependent and Fas-independent CTL-mediated cytotoxicity, IL-2 deprivation, irradiation, UV irradiation, the calcium ionophore beauvericin, and actinomycin D, staurosporine, exogenous cytochrome c and dATP. [19][20][21][22][23] T. gondii inhibits staurosporine-or exogenous cytochrome c/dATPinduced mitochondrial apoptosis by preventing the release of cytochrome c and phosphorylation of the pro-apoptotic Bad protein and inducing overproduction of the anti-apoptotic protein Bcl-2.…”

Section: Introductionmentioning

confidence: 99%

“…With the growing use of nanotechnology in the field of ophthalmology, RPE can receive various external and internal stimuli; however, no information regarding the nanotoxicity of human RPE cells has yet been reported. T. gondii has the ability to inhibit apoptosis in several murine and human host cells against a broad spectrum of proapoptotic stimuli; [17][18][19][20][21][22][23] however, the anti-apoptotic activity against NPs has not yet been investigated. Thus, to investigate the nanotoxicity of AgNPs and its mechanisms in human RPE ARPE-19 cells, as well as modulatory effect of T. gondii in AgNP-treated RPE, ARPE-19 cells were treated with AgNPs alone or in combination with T. gondii, and then, the cellular toxicity, apoptosis, cell cycle analysis, autophagy, ROS generation, NOX4 expression, and mitogen-activated protein kinase (MAPK) and mTOR signaling pathways were investigated.…”

Section: Introductionmentioning

confidence: 99%

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Silver Nanoparticle-Induced Apoptosis in ARPE-19 Cells Is Inhibited by Toxoplasma gondii Pre-Infection Through Suppression of NOX4-Dependent ROS Generation

Quan

Gao

Ismail

et al. 2020

IJN

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External and internal stimuli easily affect the retina. Studies have shown that cells infected with Toxoplasma gondii are resistant to multiple inducers of apoptosis. Nanoparticles (NPs) have been widely used in biomedical fields; however, little is known about cytotoxicity caused by NPs in the retina and the modulators that inhibit nanotoxicity. Materials and Methods: ARPE-19 cells from human retinal pigment epithelium were treated with silver nanoparticles (AgNPs) alone or in combination with T. gondii. Then, the cellular toxicity, apoptosis, cell cycle analysis, autophagy, ROS generation, NOX4 expression, and MAPK/mTOR signaling pathways were investigated. To confirm the AgNP-induced cytotoxicity in ARPE-19 cells and its modulatory effects caused by T. gondii infection, the major experiments carried out in ARPE-19 cells were performed again using human foreskin fibroblast (HFF) cells and bone marrow-derived macrophages (BMDMs) from NOX4 −/− mice. Results: AgNPs dose-dependently induced cytotoxicity and cell death in ARPE-19 cells. Apoptosis, sub-G1 phase cell accumulation, autophagy, JNK phosphorylation, and mitochondrial apoptotic features, such as caspase-3 and PARP cleavages, mitochondrial membrane potential depolarization, and cytochrome c release into the cytosol were observed in AgNP-treated cells. AgNP treatment also increased the Bax, Bik, and Bim protein levels as well as NOX4-dependent ROS generation. However, T. gondii-infected ARPE-19 cells inhibited AgNP-induced apoptosis, JNK phosphorylation, sub-G1 phase cell accumulation, autophagy, NOX4-mediated ROS production, and mitochondrial apoptosis. Furthermore, mitochondrial apoptosis was found in AgNP-treated HFF cells and BMDMs, and AgNP-induced mitochondrial apoptosis inhibition via NOX4dependent ROS suppression in T. gondii pre-infected HFF cells and BMDMs was also confirmed. Conclusion: AgNPs induced mitochondrial apoptosis in human RPE cells combined with cell cycle dysregulation and autophagy; however, these effects were significantly inhibited by T. gondii pre-infection by suppression of NOX4-mediated ROS production, suggesting that T. gondii is a strong inhibitory modulator of nanotoxicity in in vitro models.

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Strategies Developed by Toxoplasma gondii to Survive in the Host

Cited by 40 publications

References 129 publications

Transcriptomic Profiling of Mouse Brain During Acute and Chronic Infections by Toxoplasma gondii Oocysts

Transcriptomic Profiling of Mouse Brain During Acute and Chronic Infections by Toxoplasma gondii Oocysts

4-Hydroxybenzaldehyde Restricts the Intracellular Growth of Toxoplasma gondii by Inducing SIRT1-Mediated Autophagy in Macrophages

<p>Silver Nanoparticle-Induced Apoptosis in ARPE-19 Cells Is Inhibited by <em>Toxoplasma gondii</em> Pre-Infection Through Suppression of NOX4-Dependent ROS Generation</p>

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