scholarly journals hCMV-Mediated Immune Escape Mechanisms Favor Pathogen Growth and Disturb the Immune Privilege of the Eye

2019 ◽  
Vol 20 (4) ◽  
pp. 858 ◽  
Author(s):  
Katrin Spekker-Bosker ◽  
Christoph-Martin Ufermann ◽  
Marco Maywald ◽  
Albert Zimmermann ◽  
Andreas Domröse ◽  
...  
Keyword(s):  
Defense Mechanisms ◽  
Hcmv Infection ◽  
Immune Escape ◽  
Retinal Pigment ◽  
Posterior Uveitis ◽  
Immune Privilege ◽  
Target Cells ◽  
Immune Escape Mechanisms ◽  
Cell Inhibition

Human retinal pigment epithelial (hRPE) cells are important for the establishment and maintenance of the immune privilege of the eye. They function as target cells for human cytomegalovirus (hCMV), but are able to restrict viral replication. hCMV causes opportunistic posterior uveitis such as retinitis and chorioretinitis. Both mainly occur in severely immunocompromised patients and rarely manifest in immunocompetent individuals. In this study, hRPE cells were infected with hCMV in vitro and activated with proinflammatory cytokines. The enzymatic activities of indoleamine 2,3-dioxygenase-1 (IDO1) and inducible nitric oxide synthase (iNOS) were determined. The antimicrobial capacity of both molecules was analyzed in co-infection experiments using Staphylococcus aureus (S. aureus) and Toxoplasma gondii (T. gondii), causing uveitis in patients. We show that an hCMV infection of hRPE cells blocks IDO1 and iNOS mediated antimicrobial defense mechanisms necessary for the control of S. aureus and T. gondii. hCMV also inhibits immune suppressive effector mechanisms in hRPE. The interferon gamma-induced IDO1 dependent immune regulation was severely blocked, as detected by the loss of T cell inhibition. We conclude that an active hCMV infection in the eye might favor the replication of pathogens causing co-infections in immunosuppressed individuals. An hCMV caused blockade of IDO1 might weaken the eye’s immune privilege and favor the development of post-infectious autoimmune uveitis.

scholarly journals Cell Models to Study Regulation of Cell Transformation in Pathologies of Retinal Pigment Epithelium

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Alla V. Kuznetsova ◽  
Alexander M. Kurinov ◽  
Maria A. Aleksandrova
Keyword(s):  
Retinal Pigment Epithelium ◽  
Molecular Mechanisms ◽  
Cell Transformation ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Specific Treatment ◽  
Target Cells ◽  
Signal Pathways ◽  
Culture Models

The retinal pigment epithelium (RPE) plays a key role in the development of many eye diseases leading to visual impairment and even blindness. Cell culture models of pathological changes in the RPE make it possible to study factors responsible for these changes and signaling pathways coordinating cellular and molecular mechanisms of cell interactions under pathological conditions. Moreover, they give an opportunity to reveal target cells and develop effective specific treatment for degenerative and dystrophic diseases of the retina. In this review, data are presented on RPE cell sources for culture models, approaches to RPE cell culturing, phenotypic changes of RPE cellsin vitro, the role of signal pathways, and possibilities for their regulation in pathological processes.

scholarly journals The role of tumor-derived exosomes in tumor immune escape: A concise review

2020 ◽  
Vol 7 (11) ◽  
pp. 4132-4137
Author(s):  
Nhat Chau Truong ◽  
Thao Nhi Huynh ◽  
Khuong Duy Pham ◽  
Phuc Van Pham
Keyword(s):  
Immune Modulation ◽  
Immune Escape ◽  
Suppressor Cells ◽  
Target Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Immune Escape ◽  
Concise Review ◽  
Viable Cells ◽  
Immune Escape Mechanisms

Exosomes are small vesicles secreted by viable cells into the microenvironment. These vesicles bring various compositions, including lipids, RNAs and proteins, which carry information from producer cells to target cells. Cancer cells also produce exosomes, termed as tumor-derived exosomes (TDEs), which play important roles in immune modulation, angiogenesis and metastasis of tumors. This review summarizes the roles of TDEs in tumor immune escape mechanisms. TDEs affect all kinds of tumor-associated immune cells, including natural killer (NK) cells, dendritic cells (DCs), T and B lymphocytes, and myeloid-derived suppressor cells (MDSCs). Generally, TDEs suppress the immune system to promote tumor immune escape, thereby significantly contributing to tumorigenesis and metastasis.

scholarly journals Protective responses to sublytic complement in the retinal pigment epithelium

2016 ◽  
Vol 113 (31) ◽  
pp. 8789-8794 ◽  
Author(s):  
Li Xuan Tan ◽  
Kimberly A. Toops ◽  
Aparna Lakkaraju
Keyword(s):  
Retinal Pigment Epithelium ◽  
Cell Surface ◽  
Defense Mechanisms ◽  
Oxidized Ldl ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Acid Sphingomyelinase ◽  
Mitochondrial Injury ◽  
Age Related

The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4−/− Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4−/− mice, indicating that they could be effective therapeutic approaches for macular degenerations.

scholarly journals Immune Privilege: The Microbiome and Uveitis

2021 ◽  
Vol 11 ◽  
Author(s):  
Christine Mölzer ◽  
Jarmila Heissigerova ◽  
Heather M. Wilson ◽  
Lucia Kuffova ◽  
John V. Forrester
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Posterior Uveitis ◽  
Immune Privilege ◽  
Blood Retinal Barrier ◽  
Uveal Tract ◽  
Immune Mediated ◽  
Infectious Uveitis ◽  
Brb Breakdown ◽  
The Brain

Immune privilege (IP), a term introduced to explain the unpredicted acceptance of allogeneic grafts by the eye and the brain, is considered a unique property of these tissues. However, immune responses are modified by the tissue in which they occur, most of which possess IP to some degree. The eye therefore displays a spectrum of IP because it comprises several tissues. IP as originally conceived can only apply to the retina as it contains few tissue-resident bone-marrow derived myeloid cells and is immunologically shielded by a sophisticated barrier – an inner vascular and an outer epithelial barrier at the retinal pigment epithelium. The vascular barrier comprises the vascular endothelium and the glia limitans. Immune cells do not cross the blood-retinal barrier (BRB) despite two-way transport of interstitial fluid, governed by tissue oncotic pressure. The BRB, and the blood-brain barrier (BBB) mature in the neonatal period under signals from the expanding microbiome and by 18 months are fully established. However, the adult eye is susceptible to intraocular inflammation (uveitis; frequency ~200/100,000 population). Uveitis involving the retinal parenchyma (posterior uveitis, PU) breaches IP, while IP is essentially irrelevant in inflammation involving the ocular chambers, uveal tract and ocular coats (anterior/intermediate uveitis/sclerouveitis, AU). Infections cause ~50% cases of AU and PU but infection may also underlie the pathogenesis of immune-mediated “non-infectious” uveitis. Dysbiosis accompanies the commonest form, HLA-B27–associated AU, while latent infections underlie BRB breakdown in PU. This review considers the pathogenesis of uveitis in the context of IP, infection, environment, and the microbiome.

scholarly journals Isolation of Human Small Extracellular Vesicles and Tracking of Their Uptake by Retinal Pigment Epithelial Cells In Vitro

2020 ◽  
Vol 21 (11) ◽  
pp. 3799
Author(s):  
Irene C. Marcu ◽  
Naja Eberhard ◽  
Anaïs Yerly ◽  
Verena Balmer ◽  
Andrew Hemphill ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Fluorescent Protein ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Target Cells ◽  
Rpe Cells ◽  
Membrane Bound ◽  
Green Fluorescent

Small extracellular vesicles (EVs) are among the most frequently investigated EVs and play major roles in intercellular communication by delivering various cargo molecules to target cells. They could potentially represent an alternative delivery strategy to treat ocular toxoplasmosis, a parasitosis affecting the retinal pigment epithelium (RPE). To date, the uptake of human small EVs by RPE cells has never been reported. In this study, we report on the intracellular uptake of fluorescently labelled human urine and fibroblast-derived small EVs by human RPE cells. In summary, both dye-labelled urinary small EVs and small EVs obtained from fibroblasts stably expressing membrane-bound green fluorescent protein were successfully internalized by RPE cells as revealed by immunohistochemistry. In recipient ARPE19 cells, BODIPY-labelled small EVs were found in close vicinity to the parasite Toxoplasma gondii. Additionally, an ultrastructural method was enabled to distinguish between labelled exogenous and endogenous small EVs within target cells.

Molecular basis of transcriptional repression of anti-CRISPR by anti-CRISPR-associated 2

2022 ◽  
Vol 78 (1) ◽  
Author(s):  
So Yeon Lee ◽  
Gi Eob Kim ◽  
Hyun Ho Park
Keyword(s):  
Host Defense ◽  
Transcriptional Repression ◽  
Defense Mechanisms ◽  
Transcriptional Control ◽  
Immune Escape ◽  
Working Mechanism ◽  
Upstream Promoter ◽  
Fine Regulation ◽  
Immune Escape Mechanisms

CRISPR–Cas systems are well known host defense mechanisms that are conserved in bacteria and archaea. To counteract CRISPR–Cas systems, phages and viruses have evolved to possess multiple anti-CRISPR (Acr) proteins that can inhibit the host CRISPR–Cas system via different strategies. The expression of acr genes is controlled by anti-CRISPR-associated (Aca) proteins that bind to an upstream promoter and regulate the expression of acr genes during transcription. Although the role of Aca as a transcriptional repressor has been demonstrated, the mechanism of action of Aca has not been determined. Here, the molecular mechanism underlying the Aca2-mediated transcriptional control of acr genes was elucidated by determining the crystal structure of Aca2 from Oceanimonas smirnovii at a high resolution of 1.92 Å. Aca2 forms a dimer in solution, and dimerization of Aca2 is critical for specific promoter binding. The promoter-binding strategy of dimeric Aca2 was also revealed by performing mutagenesis studies. The atomic structure of the Aca family shown in this study provides insights into the fine regulation of host defense and immune-escape mechanisms and also demonstrates the conserved working mechanism of the Aca family.

scholarly journals Research Advances on the Interactions between Rabies Virus Structural Proteins and Host Target Cells: Accrued Knowledge from the Application of Reverse Genetics Systems

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2288
Author(s):  
Juanbin Yin ◽  
Xiangwei Wang ◽  
Ruoqing Mao ◽  
Zhixiong Zhang ◽  
Xin Gao ◽  
...  
Keyword(s):  
Rabies Virus ◽  
Reverse Genetics ◽  
Immune Escape ◽  
Clinical Symptoms ◽  
Genetic Manipulation ◽  
Structural Proteins ◽  
Target Cells ◽  
Therapeutic Drugs ◽  
Applied Development ◽  
Immune Escape Mechanisms

Rabies is a lethal zoonotic disease caused by lyssaviruses, such as rabies virus (RABV), that results in nearly 100% mortality once clinical symptoms appear. There are no curable drugs available yet. RABV contains five structural proteins that play an important role in viral replication, transcription, infection, and immune escape mechanisms. In the past decade, progress has been made in research on the pathogenicity of RABV, which plays an important role in the creation of new recombinant RABV vaccines by reverse genetic manipulation. Here, we review the latest advances on the interaction between RABV proteins in the infected host and the applied development of rabies vaccines by using a fully operational RABV reverse genetics system. This article provides a background for more in-depth research on the pathogenic mechanism of RABV and the development of therapeutic drugs and new biologics.

scholarly journals Cell membrane coating integrity affects the internalization mechanism of biomimetic nanoparticles

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lizhi Liu ◽  
Xuan Bai ◽  
Maria-Viola Martikainen ◽  
Anna Kårlund ◽  
Marjut Roponen ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Immune Escape ◽  
Target Cells ◽  
Coated Nanoparticles ◽  
Internalization Mechanism ◽  
Cancer Nanomedicine ◽  
Biomimetic Nanoparticles ◽  
Membrane Coating ◽  
Time Specific

AbstractCell membrane coated nanoparticles (NPs) have recently been recognized as attractive nanomedical tools because of their unique properties such as immune escape, long blood circulation time, specific molecular recognition and cell targeting. However, the integrity of the cell membrane coating on NPs, a key metrics related to the quality of these biomimetic-systems and their resulting biomedical function, has remained largely unexplored. Here, we report a fluorescence quenching assay to probe the integrity of cell membrane coating. In contradiction to the common assumption of perfect coating, we uncover that up to 90% of the biomimetic NPs are only partially coated. Using in vitro homologous targeting studies, we demonstrate that partially coated NPs could still be internalized by the target cells. By combining molecular simulations with experimental analysis, we further identify an endocytic entry mechanism for these NPs. We unravel that NPs with a high coating degree (≥50%) enter the cells individually, whereas the NPs with a low coating degree (<50%) need to aggregate together before internalization. This quantitative method and the fundamental understanding of how cell membrane coated NPs enter the cells will enhance the rational designing of biomimetic nanosystems and pave the way for more effective cancer nanomedicine.

Ultrastructural Changes in Tumor Cells During Human Peripheral Blood Monocyte-Mediated Cytotoxicity

1981 ◽  
Vol 39 ◽  
pp. 452-453
Author(s):  
K. E. Muse ◽  
D. G. Fischer ◽  
H. S. Koren
Keyword(s):  
Target Cell ◽  
Human Peripheral Blood ◽  
Mononuclear Phagocytes ◽  
Ultrastructural Changes ◽  
Target Cells ◽  
Limited Information ◽  
Blood Monocytes ◽  
Tumoricidal Activity ◽  
Activated State

Mononuclear phagocytes, a pluripotential cell line, manifest an array of basic extracellular functions. Among these physiological regulatory functions is the expression of spontaneous cytolytic potential against tumor cell targets.The limited observations on human cells, almost exclusively blood monocytes, initially reported limited or a lack of tumoricidal activity in the absence of antibody. More recently, freshly obtained monocytes have been reported to spontaneously impair the biability of tumor target cells in vitro (Harowitz et al., 1979; Montavani et al., 1979; Hammerstrom, 1979). Although the mechanism by which effector cells express cytotoxicity is poorly understood, discrete steps can be distinguished in the process of cell mediated cytotoxicity: recognition and binding of effector to target cells,a lethal-hit stage, and subsequent lysis of the target cell. Other important parameters in monocyte-mediated cytotoxicity include, activated state of the monocyte, effector cell concentrations, and target cell suseptibility. However, limited information is available with regard to the ultrastructural changes accompanying monocyte-mediated cytotoxicity.

STEROID HORMONE METABOLISM IN RESPONSIVE TISSUES IN VITRO

1971 ◽  
Vol 68 (1_Suppl) ◽  
pp. S279-S294 ◽  
Author(s):  
Paul Robel
Keyword(s):  
Steroid Hormone ◽  
Physiological Activity ◽  
Physiological State ◽  
Target Cells ◽  
Target Tissue ◽  
Hormone Metabolism ◽  
Metabolizing Enzymes ◽  
Relationship Of

ABSTRACT Of the information available on steroid hormone metabolism in responsive tissues, only that relating hormone metabolism to physiological activity is reviewed, i. e. metabolite activity in isolated in vitro systems, binding of metabolites to target tissue receptors, specific steroid hormone metabolizing enzymes and relationship of hormone metabolism to target organ physiological state. Further, evidence is presented in the androgen field, demonstrating 5α-reduced metabolites, formed inside the target cells, as active compounds. This has led to a consideration of testosterone as a »prehormone«. The possibility that similar events take place in tissues responding to progesterone is discussed. Finally, the role of hormone metabolism in the regulation of hormone availability and/or renewal in target cells is discussed. In this context, reference is made to the potential role of plasma binding proteins and cytosol receptors.

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