Disruption of outer blood-retinal barrier by Toxoplasma gondii-infected monocytes is mediated by paracrinely activated FAK signaling

Song, Hyun Beom; Jun, Hyoung Oh; Kim, Jin Hyoung; Lee, Young Ha; Choi, Min Ho; Kim, Jeong Hun

doi:10.1371/journal.pone.0175159

Cited by 17 publications

(22 citation statements)

References 36 publications

(44 reference statements)

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“…Ocular toxoplasmosis is a common, vision-threatening eye disease that is characterized clinically and histopathologically by disruption of the retinal pigment epithelium (4). Multiple studies have described specific molecular interactions between the human retinal pigment epithelial cell and the rapidly proliferating tachyzoite form of the parasite (14–18). We present a transcriptomic view of the epithelial cell response to infection with T. gondii .…”

Section: Discussionmentioning

confidence: 99%

“…This epithelial monolayer contributes to the blood-retinal barrier, and performs multiple diverse functions, including: light absorption, production of growth factors and signaling molecules, control of subretinal ion homeostasis, all-trans retinal re-isomerization during the visual cycle, phagocytosis of photoreceptor debris, and maintenance of immune privilege in the posterior eye (13). Over several decades, multiple research groups have described individual molecular responses of human retinal pigment epithelial cells to infection with T. gondii (14–18). The transcriptome of the infected retinal pigment epithelium has not been reported, however.…”

Section: Introductionmentioning

confidence: 99%

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Immunological Molecular Responses of Human Retinal Pigment Epithelial Cells to Infection With Toxoplasma gondii

et al. 2019

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Ocular toxoplasmosis is the commonest clinical manifestation of infection with obligate intracellular parasite, Toxoplasma gondii . Active ocular toxoplasmosis is characterized by replication of T. gondii tachyzoites in the retina, with reactive inflammation. The multifunctional retinal pigment epithelium is a key target cell population for T. gondii . Since the global gene expression profile is germane to understanding molecular involvements of retinal pigment epithelial cells in ocular toxoplasmosis, we performed RNA-Sequencing (RNA-Seq) of human cells following infection with T. gondii tachyzoites. Primary cell isolates from eyes of cadaveric donors ( n = 3), and the ARPE-19 human retinal pigment epithelial cell line, were infected for 24 h with GT-1 strain T. gondii tachyzoites (multiplicity of infection = 5) or incubated uninfected as control. Total and small RNA were extracted from cells and sequenced on the Illumina NextSeq 500 platform; results were aligned to the human hg19 reference sequence. Multidimensional scaling showed good separation between transcriptomes of infected and uninfected primary cell isolates, which were compared in edgeR software. This differential expression analysis revealed a sizeable response in the total RNA transcriptome—with significantly differentially expressed genes totaling 7,234 (28.9% of assigned transcripts)—but very limited changes in the small RNA transcriptome—totaling 30 (0.35% of assigned transcripts) and including 8 microRNA. Gene ontology and pathway enrichment analyses of differentially expressed total RNA in CAMERA software, identified a strong immunologic transcriptomic signature. We conducted RT-qPCR for 26 immune response-related protein-coding and long non-coding transcripts in epithelial cell isolates from different cadaveric donors ( n = 3), extracted by a different isolation protocol but similarly infected with T. gondii , to confirm immunological activity of infected cells. For microRNA, increases in miR-146b and miR-212 were detected by RT-qPCR in 2 and 3 of these independent cell isolates. Biological network analysis in the InnateDB platform, including 735 annotated differentially expressed genes plus 2,046 first-order interactors, identified 10 contextural hubs and 5 subnetworks in the transcriptomic immune response of cells to T. gondii . Our observations provide a solid base for future studies of molecular and cellular interactions between T. gondii and the human retinal pigment epithelium to illuminate mechanisms of ocular toxoplasmosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunological Molecular Responses of Human Retinal Pigment Epithelial Cells to Infection With Toxoplasma gondii

et al. 2019

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“…This can be a further mechanism that enhances the incidence of miscarriage after primary infection with Toxoplasma gondii during early pregnancy. The ability of Toxoplasma to precipitate mal‐angiogenesis in the infected tissues has confirmed by Song et al . They discovered that the Toxoplasma ‐infected monocytes are able to disrupt the outer blood‐retinal barrier through signalling the paracrinely activated focal adhesion kinase (FAK).…”

Section: Discussionmentioning

confidence: 92%

Human placental PPAR‐γ and SOX‐2 expression in serologically proved toxoplasmosis

Saad

El‐Anwar

Lotfy

et al. 2018

Parasite Immunology

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To explore PPAR-γ and SOX-2 transcription factors expression in placenta according to maternal anti-Toxoplasma gondii serological profile during pregnancy and pregnancy outcome. The study included 240 placentas, grouped according to IgM and IgG serostatus and then subgrouped according to pregnancy outcome that varied between miscarriages, premature labour, stillbirth and giving birth to CNS anomaly or apparently healthy neonates. Samples were H&E stained and histopathologically scored blindly. PPAR-γ expression was measured by ELISA, while SOX-2-positive nuclei were stained immunohistochemically to be calculated by ImageJ. The mean pathological score was significantly higher in IgM+ve and IgG rising than IgG-ve and persistent low groups. Former groups showed significantly higher PPAR-γ (mean = 258.63, 227.11). However, PPAR-γ was higher in apparently healthy neonate subgroups. SOX-2 was significantly lower in IgM+ve and IgG rising groups (mean = 12.87, 43.13) and associated with obvious fibrosis. SOX-2 lowest count was in CNS anomaly subgroup. PPAR-γ and SOX-2 changes may give clues of how Toxoplasma induces pathogenesis during vertical transmission. Triggering PPAR-γ expression may be a tool to downregulate the inflammatory response and establish a metabolically permissive cellular environment for Toxoplasma persistence. Low SOX-2 is suspected to disturb placental mesenchymal stem cells pluripotency and neuroectoderm development.

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“…Although not completely clear, it is thought that T. gondii reaches the retinal tissue using a Trojan horse mechanism, being transported by an infected inflammatory cell through the Blood-Retinal Barrier, similarly to described in brain invasion (Kijlstra and Petersen, 2014;Lachenmaier et al, 2014). In experimental models, T. gondii-infected THP-1 monocytes have been reported as transmigrating monolayers of human retinal pigmented epithelial cells (ARPE-19) (Song et al, 2017), whereas direct infection of ARPE-19 cells affects their junctional properties, including decreases in Transepithelial (/endothelial) Electrical Resistance (TEER) (Nogueira et al, 2016). Regarding the Blood-Retinal Barrier, Furtado and colleagues have indicated that T. gondii can cross through retinal endothelial cells without disturbing the integrity of the monolayer (Furtado et al, 2012), thus penetrating the retinal layers and infecting neuronal and glial cells (Furtado et al, 2013).…”

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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Disruption of outer blood-retinal barrier by Toxoplasma gondii-infected monocytes is mediated by paracrinely activated FAK signaling

Cited by 17 publications

References 36 publications

Immunological Molecular Responses of Human Retinal Pigment Epithelial Cells to Infection With Toxoplasma gondii

Immunological Molecular Responses of Human Retinal Pigment Epithelial Cells to Infection With Toxoplasma gondii

Human placental PPAR‐γ and SOX‐2 expression in serologically proved toxoplasmosis

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

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