Person: Young, Lucy
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Young, Lucy
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Publication The human immune response to Toxoplasma: Autophagy versus cell death(Public Library of Science, 2017) Krishnamurthy, Shruthi; Konstantinou, Eleni K.; Young, Lucy; Gold, Daniel A.; Saeij, Jeroen P. J.Publication Issues with the Specificity of Immunological Reagents for NLRP3: Implications for Age-related Macular Degeneration(Nature Publishing Group UK, 2018) Kosmidou, Cassandra; Efstathiou, Nikolaos; Hoang, Mien; Notomi, Shoji; Konstantinou, Eleni K.; Hirano, Masayuki; Takahashi, Kosuke; Maidana, Daniel; Tsoka, Pavlina; Young, Lucy; Gragoudas, Evangelos; Olsen, Timothy W.; Morizane, Yuki; Miller, Joan; Vavvas, DemetriosContradictory data have been presented regarding the implication of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in age-related macular degeneration (AMD), the leading cause of vision loss in the Western world. Recognizing that antibody specificity may explain this discrepancy and in line with recent National Institutes of Health (NIH) guidelines requiring authentication of key biological resources, the specificity of anti-NLRP3 antibodies was assessed to elucidate whether non-immune RPE cells express NLRP3. Using validated resources, NLRP3 was not detected in human primary or human established RPE cell lines under multiple inflammasome-priming conditions, including purported NLRP3 stimuli in RPE such as DICER1 deletion and Alu RNA transfection. Furthermore, NLRP3 was below detection limits in ex vivo macular RPE from AMD patients, as well as in human induced pluripotent stem cell (hiPSC)-derived RPE from patients with overactive NLRP3 syndrome (Chronic infantile neurologic cutaneous and articulate, CINCA syndrome). Evidence presented in this study provides new data regarding the interpretation of published results reporting NLRP3 expression and upregulation in RPE and addresses the role that this inflammasome plays in AMD pathogenesis.Publication Transcriptional Analysis of Murine Macrophages Infected with Different Toxoplasma Strains Identifies Novel Regulation of Host Signaling Pathways(Public Library of Science, 2013) Melo, Mariane B.; Nguyen, Quynh P.; Cordeiro, Cynthia; Hassan, Musa A.; Yang, Ninghan; McKell, Renée; Rosowski, Emily E.; Julien, Lindsay; Butty, Vincent; Dardé, Marie-Laure; Ajzenberg, Daniel; Fitzgerald, Katherine; Young, Lucy; Saeij, Jeroen P. J.Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.Publication Verteporfin-induced formation of protein cross-linked oligomers and high molecular weight complexes is mediated by light and leads to cell toxicity(Nature Publishing Group, 2017) Konstantinou, Eleni K.; Notomi, Shoji; Kosmidou, Cassandra; Brodowska, Katarzyna; Al-Moujahed, Ahmad; Nicolaou, Fotini; Tsoka, Pavlina; Gragoudas, Evangelos; Miller, Joan; Young, Lucy; Vavvas, DemetriosVerteporfin (VP) was first used in Photodynamic therapy, where a non-thermal laser light (689 nm) in the presence of oxygen activates the drug to produce highly reactive oxygen radicals, resulting in local cell and tissue damage. However, it has also been shown that Verteporfin can have non-photoactivated effects such as interference with the YAP-TEAD complex of the HIPPO pathway, resulting in growth inhibition of several neoplasias. More recently, it was proposed that, another non-light mediated effect of VP is the formation of cross-linked oligomers and high molecular weight protein complexes (HMWC) that are hypothesized to interfere with autophagy and cell growth. Here, in a series of experiments, using human uveal melanoma cells (MEL 270), human embryonic kidney cells (HEK) and breast cancer cells (MCF7) we showed that Verteporfin-induced HMWC require the presence of light. Furthermore, we showed that the mechanism of this cross-linking, which involves both singlet oxygen and radical generation, can occur very efficiently even after lysis of the cells, if the lysate is not protected from ambient light. This work offers a better understanding regarding VP’s mechanisms of action and suggests caution when one studies the non-light mediated actions of this drug.Publication Evidence for Baseline Retinal Pigment Epithelium Pathology in the Trp1-Cre Mouse(Elsevier BV, 2012) Thanos, Aristomenis; Morizane, Yuki; Murakami, Yusuke; Giani, Andrea; Mantopoulos, Dimosthenis; Kayama, Maki; Roh, Mi In; Michaud, Norman; Pawlyk, Basil; Sandberg, Michael; Young, Lucy; Miller, Joan; Vavvas, DemetriosThe increasing popularity of the Cre/loxP recombination system has led to the generation of numerous transgenic mouse lines in which Cre recombinase is expressed under the control of organ- or cell-specific promoters. Alterations in retinal pigment epithelium (RPE), a multifunctional cell monolayer that separates the retinal photoreceptors from the choroid, are prevalent in the pathogenesis of a number of ocular disorders, including age-related macular degeneration. To date, six transgenic mouse lines have been developed that target Cre to the RPE under the control of various gene promoters. However, multiple lines of evidence indicate that high levels of Cre expression can be toxic to mammalian cells. In this study, we report that in the Trp1-Cre mouse, a commonly used transgenic Cre strain for RPE gene function studies, Cre recombinase expression alone leads to RPE dysfunction and concomitant disorganization of RPE layer morphology, large areas of RPE atrophy, retinal photoreceptor dysfunction, and microglial cell activation in the affected areas. The phenotype described herein is similar to previously published reports of conditional gene knockouts that used the Trp1-Cre mouse, suggesting that Cre toxicity alone could account for some of the reported phenotypes and highlighting the importance of the inclusion of Cre-expressing mice as controls in conditional gene targeting studies.Publication Choroidal Neovascular Membrane Formation and Retinochoroidopathy in a Patient with Systemic Langerhans Cell Histiocytosis: A Case Report and Review of the Literature(S. Karger AG, 2012) Thanos, Aristomenis; Vavvas, Demetrios; Young, Lucy; Foster, CharlesWe report a case of bilateral atrophic retinochoroidopathy with choroidal neovascular membrane (CNVM) formation in a patient with systemic Langerhans cell histiocytosis (LCH). A 35-year-old female, diagnosed with LCH at the age of 3, experienced an episode of acute vision loss in her right eye. Visual acuity was counting fingers. Dilated fundus exam and fluorescein angiography revealed the presence of CNVM along with bilateral widespread areas of chorioretinal atrophy. The patient underwent removal of CNVM with excellent postoperative visual acuity (20/25); however, indolent progression of her disease led to gradual deterioration of visual acuity (20/80 in the right eye and 20/320 in the left). This case shows that in contrast to previous reports, intraocular involvement of LCH does not need to be dramatic and clinically evident but it can acquire a chronic degenerative form. This report aims to raise awareness among ophthalmologists concerning the potential intraocular sequelae of LCH.Publication AICAR suppresses TNF-α-induced complement factor B in RPE cells(Nature Publishing Group UK, 2017) Chung, Eun Jee; Efstathiou, Nikolaos; Konstantinou, Eleni K.; Maidana, Daniel; Miller, Joan; Young, Lucy; Vavvas, DemetriosAge related macular degeneration is the leading cause of blindness in the developed world. Although its precise cause remains elusive, dysfunction of the retinal pigment epithelium (RPE) and dysregulation of complement have been implicated in its pathogenesis. The goal of this study was to evaluate the role of an AMP-dependent kinase (AMPK) activator, 5-aminoimidazole-4-carboxamide riboside (AICAR), on tumor necrosis factor alpha (TNF-α) induction of complement factor B (CFB) in RPE cells. We found that AICAR inhibited TNF-α-induced CFB expression in ARPE-19 and human primary RPE cells in a dose-dependent fashion. Treatment of cells with dipyridamole, which blocks AICAR cellular uptake abolished these effects. In contrast, the adenosine kinase inhibitor, 5-iodotubericidin, which inhibits the conversion of AICAR to the direct activator of AMPK, ZMP, did not reverse the effects on TNF-α-induced CFB expression, suggesting AMPK-independent effects. Indeed, knockout of AMPK in RPE cells using Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 did not abolish the inhibitory effects of AICAR on RPE CFB expression. Collectively, our results suggest that AICAR can suppress TNF-α-induced CFB expression in RPE cells in an AMPK-independent mechanism, and could be used as a therapeutic target in certain complement over-activation scenarios.