scholarly journals Transcriptome Analysis of the Cerebellum of Mice Fed a Manganese-Deficient Diet

2020 ◽  
Vol 11 ◽  
Author(s):  
Young Ah Seo ◽  
Eun-Kyung Choi ◽  
Luisa Aring ◽  
Molly Paschall ◽  
Shigeki Iwase
Keyword(s):  
Gene Expression ◽  
Cerebellar Atrophy ◽  
Epidemiological Studies ◽  
Receptor Interaction ◽  
Herpes Simplex Virus 1 ◽  
Deficient Diet ◽  
Mn Deficiency ◽  
Metal Levels ◽  
Simplex Virus ◽  
The Impact

Manganese (Mn), primarily acquired through diet, is required for brain function and development. Epidemiological studies have found an association between both low and high levels of Mn and impaired neurodevelopment in children. Recent genetic studies have revealed that patients with congenital Mn deficiency display severe psychomotor disability and cerebral and cerebellar atrophy. Although the impact of Mn on gene expression is beginning to be appreciated, Mn-dependent gene expression remains to be explored in vertebrate animals. The goal of this study was to use a mouse model to define the impact of a low-Mn diet on brain metal levels and gene expression. We interrogated gene expression changes in the Mn-deficient mouse brain at the genome-wide scale by RNA-seq analysis of the cerebellum of mice fed low or normal Mn diets. A total of 137 genes were differentially expressed in Mn-deficient cerebellums compared with Mn-adequate cerebellums (Padj < 0.05). Mn-deficient mice displayed downregulation of key pathways involved with “focal adhesion,” “neuroactive ligand-receptor interaction,” and “cytokine-cytokine receptor interaction” and upregulation of “herpes simplex virus 1 infection,” “spliceosome,” and “FoxO signaling pathway.” Reactome pathway analysis identified upregulation of the splicing-related pathways and transcription-related pathways, as well as downregulation of “metabolism of carbohydrate,” and “extracellular matrix organization,” and “fatty acid metabolism” reactomes. The recurrent identifications of splicing-related pathways suggest that Mn deficiency leads to upregulation of splicing machineries and downregulation of diverse biological pathways.

scholarly journals Viral DNA Sensors IFI16 and Cyclic GMP-AMP Synthase Possess Distinct Functions in Regulating Viral Gene Expression, Immune Defenses, and Apoptotic Responses during Herpesvirus Infection

mBio ◽  
2016 ◽  
Vol 7 (6) ◽  
Author(s):  
Benjamin A. Diner ◽  
Krystal K. Lum ◽  
Jared E. Toettcher ◽  
Ileana M. Cristea
Keyword(s):  
Gene Expression ◽  
Live Cell Imaging ◽  
Nuclear Periphery ◽  
Viral Gene Expression ◽  
Live Cell ◽  
Viral Gene ◽  
Viral Dna ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTThe human interferon-inducible protein IFI16 is an important antiviral factor that binds nuclear viral DNA and promotes antiviral responses. Here, we define IFI16 dynamics in space and time and its distinct functions from the DNA sensor cyclic dinucleotide GMP-AMP synthase (cGAS). Live-cell imaging reveals a multiphasic IFI16 redistribution, first to viral entry sites at the nuclear periphery and then to nucleoplasmic puncta upon herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV) infections. Optogenetics and live-cell microscopy establish the IFI16 pyrin domain as required for nuclear periphery localization and oligomerization. Furthermore, using proteomics, we define the signature protein interactions of the IFI16 pyrin and HIN200 domains and demonstrate the necessity of pyrin for IFI16 interactions with antiviral proteins PML and cGAS. We probe signaling pathways engaged by IFI16, cGAS, and PML using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated knockouts in primary fibroblasts. While IFI16 induces cytokines, only cGAS activates STING/TBK-1/IRF3 and apoptotic responses upon HSV-1 and HCMV infections. cGAS-dependent apoptosis upon DNA stimulation requires both the enzymatic production of cyclic dinucleotides and STING. We show that IFI16, not cGAS or PML, represses HSV-1 gene expression, reducing virus titers. This indicates that regulation of viral gene expression may function as a greater barrier to viral replication than the induction of antiviral cytokines. Altogether, our findings establish coordinated and distinct antiviral functions for IFI16 and cGAS against herpesviruses.IMPORTANCEHow mammalian cells detect and respond to DNA viruses that replicate in the nucleus is poorly understood. Here, we decipher the distinct functions of two viral DNA sensors, IFI16 and cGAS, during active immune signaling upon infection with two herpesviruses, herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV). We show that IFI16 rapidly oligomerizes at incoming herpesvirus genomes at the nuclear periphery to transcriptionally repress viral gene expression and limit viral replicative capacity. We further demonstrate that IFI16 does not initiate upstream activation of the canonical STING/TBK-1/IRF3 signaling pathway but is required for downstream antiviral cytokine expression. In contrast, we find that, upon DNA sensing during herpesvirus infection, cGAS triggers apoptosis in a STING-dependent manner. Our live-cell imaging, mass spectrometry-based proteomics, CRISPR-based cellular assays, and optogenetics underscore the value of integrative approaches to uncover complex cellular responses against pathogens.

scholarly journals The ATP-Dependent RNA Helicase DDX3X Modulates Herpes Simplex Virus 1 Gene Expression

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Bita Khadivjam ◽  
Camille Stegen ◽  
Marc-Aurèle Hogue-Racine ◽  
Nabil El Bilali ◽  
Katinka Döhner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Herpes Simplex ◽  
Rna Viruses ◽  
Rna Helicase ◽  
Viral Gene ◽  
Herpes Simplex Virus 1 ◽  
Dna Viruses ◽  
Viral Particles ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The human protein DDX3X is a DEAD box ATP-dependent RNA helicase that regulates transcription, mRNA maturation, and mRNA export and translation. DDX3X concomitantly modulates the replication of several RNA viruses and promotes innate immunity. We previously showed that herpes simplex virus 1 (HSV-1), a human DNA virus, incorporates DDX3X into its mature particles and that DDX3X is required for optimal HSV-1 infectivity. Here, we show that viral gene expression, replication, and propagation depend on optimal DDX3X protein levels. Surprisingly, DDX3X from incoming viral particles was not required for the early stages of the HSV-1 infection, but, rather, the protein controlled the assembly of new viral particles. This was independent of the previously reported ability of DDX3X to stimulate interferon type I production. Instead, both the lack and overexpression of DDX3X disturbed viral gene transcription and thus subsequent genome replication. This suggests that in addition to its effect on RNA viruses, DDX3X impacts DNA viruses such as HSV-1 by an interferon-independent pathway. IMPORTANCE Viruses interact with a variety of cellular proteins to complete their life cycle. Among them is DDX3X, an RNA helicase that participates in most aspects of RNA biology, including transcription, splicing, nuclear export, and translation. Several RNA viruses and a limited number of DNA viruses are known to manipulate DDX3X for their own benefit. In contrast, DDX3X is also known to promote interferon production to limit viral propagation. Here, we show that DDX3X, which we previously identified in mature HSV-1 virions, stimulates HSV-1 gene expression and, consequently, virion assembly by a process that is independent of its ability to promote the interferon pathway.

scholarly journals Herpes Simplex Virus 1 and 2 Infections during Differentiation of Human Cortical Neurons

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2072
Author(s):  
Petra Bergström ◽  
Edward Trybala ◽  
Charlotta E. Eriksson ◽  
Maria Johansson ◽  
Tugce Munise Satir ◽  
...  
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Rna Polymerase Ii ◽  
Cortical Neurons ◽  
Fold Increase ◽  
Synaptic Activity ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) and 2 (HSV-2) can infect the central nervous system (CNS) with dire consequences; in children and adults, HSV-1 may cause focal encephalitis, while HSV-2 causes meningitis. In neonates, both viruses can cause severe, disseminated CNS infections with high mortality rates. Here, we differentiated human induced pluripotent stem cells (iPSCs) towards cortical neurons for infection with clinical CNS strains of HSV-1 or HSV-2. Progenies from both viruses were produced at equal quantities in iPSCs, neuroprogenitors and cortical neurons. HSV-1 and HSV-2 decreased viability of neuroprogenitors by 36.0% and 57.6% (p < 0.0001), respectively, 48 h post-infection, while cortical neurons were resilient to infection by both viruses. However, in these functional neurons, both HSV-1 and HSV-2 decreased gene expression of two markers of synaptic activity, CAMK2B and ARC, and affected synaptic activity negatively in multielectrode array experiments. However, unaltered secretion levels of the neurodegeneration markers tau and NfL suggested intact axonal integrity. Viral replication of both viruses was found after six days, coinciding with 6-fold and 22-fold increase in gene expression of cellular RNA polymerase II by HSV-1 and HSV-2, respectively. Our results suggest a resilience of human cortical neurons relative to the replication of HSV-1 and HSV-2.

scholarly journals IM-4 Impact of oHSV activated NOTCH signaling in tumor microenvironment and its impact on anti-tumor immunity

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi7-vi7
Author(s):  
Otani Yoshihiro ◽  
Ji Young Yoo ◽  
Sean E Lawler ◽  
Antonio E Chiocca ◽  
Balveen Kaur
Keyword(s):  
Tumor Microenvironment ◽  
Notch Signaling ◽  
Tumor Immunity ◽  
Myeloid Cell ◽  
Suppressor Cell ◽  
Therapeutic Benefit ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
The Impact ◽  
Recurrent Gbm

Abstract Oncolytic herpes simplex virus-1 (oHSV) is novel FDA-approved immunotherapy for advanced melanoma patients in US. Also, oHSV is recently approved for the treatment of recurrent GBM in Japan. We have shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells via HSV-1 microRNA-H16 (Otani Y and Yoo JY, Clin Cancer Res, 2020), however, the consequences of NOTCH on immunotherapy in GBM is unknow. Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment (TME). Analysis of TCGA GBM data and experimental murine models revealed NOTCH induced immunosuppressive myeloid cell recruitment and limited anti-tumor immunity. In oHSV treated tissue, viral infection educated tumor associated macrophages to secrete CCL2 which recruited monocytic myeloid derived suppressor cell (MDSC) that attenuated anti-tumor immunity. Consistent with this, CCL2 induction was also observed in serum of recurrent GBM patients treated with oHSV (NCT03152318). Importantly, blockade of NOTCH signaling reduced the oHSV induced immunosuppressive environment and activated a CD8 dependent anti-tumor memory response. These findings present the opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity in GBM.

scholarly journals Efficacy and Tolerance of Thymus Vulgaris Extract in Patients with Covid-19

2021 ◽  
pp. 1-5
Author(s):  
Yiagnigni Mfopou E ◽  
Keyword(s):  
Hot Water ◽  
Thymus Vulgaris ◽  
Herpes Simplex Virus 1 ◽  
Virus Elimination ◽  
Good Tolerance ◽  
Negative Results ◽  
Simplex Virus ◽  
The Impact ◽  
Blood Urea Level ◽  
Positive Effect

The coronavirus disease 19 (COVID-19) has been a pandemic since February 2020. So far, no effective treatment has been found. WHO has recommended research on medicinal plants as an alternative treatment course. Several studies conducted on Thymus vulgaris have established its antioxidant, antiviral and immunomodulatory properties that induce the elimination of viruses such as Herpes simplex Virus 1 and 2. Following this, we initiated a study entitled Efficacy and tolerance of Thymus vulgaris extract in patients with coronavirus 2019. Material and method: Thymus vulgaris powder was used in this study. A consent letter and a questionnaire about the patients’ symptoms were prepared to be used by a research investigator. According to the statistical calculations of this cohort study, 161 patients testing positive for COVID-19 PCR were consecutively recruited, of which 75 patients were not exposed to Thymus vulgaris and 86 patients were exposed. Information from the questionnaire was gathered from the patients before the initiation of conventional treatment (vitamin C 1000 1 tablet/day, Zinc 20 mg 1tablet/day, Azithromycin 500 1cp day and amoxicillin/clavulamic acid 1g/125 1 tablet per 12 hours for six days in both cohorts) and by combining Thymus vulgaris (1 teaspoon, i.e. 5g, in 100 ml of hot water to be taken every 8 hours) by the patients in the exposed cohort. After three days of this treatment, the evaluative part of the questionnaire was completed to assess the impact of taking or not taking Thymus vulgaris on early symptoms and tolerance; on the 10th day after the start of treatment, the PCR control test was carried out. Thereafter, the various statistical analyses were performed. Results: Statistical evaluation after three days of treatment shows that taking Thymus vulgaris has a statistically significant positive effect on cough (p <0.01), dyspnoea (p <0.001), dizziness (p <0.029), fatigue (p <0.001), anorexia (p <0.001), chest pain (p <0.001), fever (p <0.024), agueusia (p <0.029) and anosmia (p <0.001). There was a significant decrease in neutrophils (p <0.01); in addition, the lymphocyte count increased significantly (p <0.001) as did the serum calcium level (p <0.03). Blood urea level decreased significantly (p <0.01). Significant negative results of the COVID-19 PCR were obtained at Day 10 in the exposed group (p <0.001). In addition, there was no significant change in other biological parameters such as creatinine, blood glucose, aspartate amino transferase. Conclusion: Results of this study show that the use of the powder of Thymus vulgaris, a medicinal plant, with antioxidant, immunomodulatory and antiviral properties, was very effective on coronavirus-induced symptoms and virus elimination. Moreover, there was good tolerance after taking Thymus vulgaris.

scholarly journals Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

2020 ◽  
Author(s):  
David Olagnier ◽  
Ensieh Farahani ◽  
Jacob Thyrsted ◽  
Julia B. Cadanet ◽  
Angela Herengt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Dimethyl Fumarate ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Independent Mechanism ◽  
Pathogenic Viruses ◽  
Anti Oxidant ◽  
Simplex Virus

AbstractAntiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here we demonstrate that the NRF2 anti-oxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, induction of NRF2 by 4-OI and DMF limited host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.One Sentence SummaryNRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

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