scholarly journals Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes

2021 ◽  
Vol 17 (11) ◽  
pp. e1010100
Author(s):  
Marine J. Petit ◽  
Matthew W. Kenaston ◽  
Oanh H. Pham ◽  
Ariana A. Nagainis ◽  
Adam T. Fishburn ◽  
...  
Keyword(s):  
Immune Response ◽  
Dengue Virus ◽  
Protein Interaction ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Close Association ◽  
Gene Expression Profiles ◽  
Structural Protein ◽  
Immune Response Genes ◽  
Viral Determinants

Dengue virus (DENV) disruption of the innate immune response is critical to establish infection. DENV non-structural protein 5 (NS5) plays a central role in this disruption, such as antagonism of STAT2. We recently found that DENV serotype 2 (DENV2) NS5 interacts with Polymerase associated factor 1 complex (PAF1C). The primary members of PAF1C are PAF1, LEO1, CTR9, and CDC73. This nuclear complex is an emerging player in the immune response. It promotes the expression of many genes, including genes related to the antiviral, antimicrobial and inflammatory responses, through close association with the chromatin of these genes. Our previous work demonstrated that NS5 antagonizes PAF1C recruitment to immune response genes. However, it remains unknown if NS5 antagonism of PAF1C is complementary to its antagonism of STAT2. Here, we show that knockout of PAF1 enhances DENV2 infectious virion production. By comparing gene expression profiles in PAF1 and STAT2 knockout cells, we find that PAF1 is necessary to express immune response genes that are STAT2-independent. Finally, we mapped the viral determinants for the NS5-PAF1C protein interaction. We found that NS5 nuclear localization and the C-terminal region of the methyltransferase domain are required for its interaction with PAF1C. Mutation of these regions rescued the expression of PAF1-dependent immune response genes that are antagonized by NS5. In sum, our results support a role for PAF1C in restricting DENV2 replication that NS5 antagonizes through its protein interaction with PAF1C.

scholarly journals Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes

2021 ◽  
Author(s):  
Marine J Petit ◽  
Matthew W Kenaston ◽  
Ariana A Nagainis ◽  
Priya S Shah
Keyword(s):  
Immune Response ◽  
Dengue Virus ◽  
Protein Interaction ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Close Association ◽  
Gene Expression Profiles ◽  
Structural Protein ◽  
Immune Response Genes ◽  
Viral Determinants

Dengue virus (DENV) disruption of the innate immune response is critical to establish infection. DENV non-structural protein 5 (NS5) plays a central role in this disruption, such as antagonism of STAT2. We recently found that DENV serotype 2 (DENV2) NS5 interacts with Polymerase associated factor 1 complex (PAF1C). The primary members of PAF1C are PAF1, LEO1, CTR9 and CDC73. This nuclear complex is an emerging player in the immune response. It promotes the expression of many genes, including genes related to the antiviral, antimicrobial and inflammatory responses, through close association with the chromatin of these genes. Our previous work demonstrated that NS5 antagonizes PAF1C recruitment to immune response genes. However, it remains unknown if NS5 antagonism of PAF1C is complementary to its antagonism of STAT2. Here, we show that knockout of PAF1 enhances DENV2 infectious virion production. By comparing gene expression profiles in PAF1 and STAT2 knockout cells, we find that PAF1 is necessary to express immune response genes that are STAT2-independent. Finally, we mapped the viral determinants for the NS5-PAF1C protein interaction. We found that NS5 nuclear localization and the C-terminal region of the methyltransferase domain are required for its interaction with PAF1C. Mutation of these regions rescued the expression of PAF1-dependent immune response genes that are antagonized by NS5. In sum, our results support a role for PAF1C in restricting DENV2 replication that NS5 antagonizes through its protein interaction with PAF1C.

scholarly journals Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients

2021 ◽  
Vol 14 (1) ◽  
pp. 41
Author(s):  
Hana Votavova ◽  
Zuzana Urbanova ◽  
David Kundrat ◽  
Michaela Dostalova Merkerova ◽  
Martin Vostry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Blood Cell ◽  
Myelodysplastic Syndrome ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Adaptive Immune Response ◽  
Gene Expression Profiles ◽  
Iron Chelator ◽  
Multiple Cancer

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

Vitamin D regulates the expression of immune and stress response genes in dengue virus-infected macrophages by inducing specific microRNAs

MicroRNA ◽  
2021 ◽  
Vol 11 ◽  
Author(s):  
Geysson Javier Fernandez ◽  
Jorge Andrés Castillo ◽  
Diana Marcela Giraldo ◽  
Silvio Urcuqui-Inchima
Keyword(s):  
Vitamin D ◽  
Immune Response ◽  
Stress Response ◽  
Dengue Virus ◽  
Mirna Expression ◽  
Expression Profiles ◽  
Denv Infection ◽  
High Dose ◽  
Regulatory Pathways ◽  
Stress Response Genes

Background: The pathogenesis associated with Dengue virus (DENV) infection is marked by the impairment of host immune response. Consequently, the modulation of immune response has emerged as an important therapeutic target for the control of DENV infection. Vitamin D has been shown to regulate the immune response in DENV infection, although the molecular mechanism remains poorly understood. Post-transcriptional regulation of mRNA by miRNAs offers an opportunity to gain insight into the immunomodulation mediated by vitamin D Objective: Previously, it has been observed that a high dose of vitamin D (4000 IU) decreased DENV-2 infection and inflammatory response in monocyte-derived macrophages (MDMs). Here, we examine whether high or low doses of vitamin D supplements exert differential effect on miRNA expression in DENV-infected macrophages Methods: We analyzed miRNA expression profiles in MDMs isolated from healthy individuals who were given either 1000 or 4000 IU/day of vitamin D for 10 days. MDMs before or after vitamin D supplementation were challenged with DENV-2, and miRNAs profiles were analyzed by qPCR arrays. Results: DENV-2 infected MDMs supplemented with 4000 IU, showed up-regulation of miR-374a-5p, miR-363-3p, miR-101-3p, miR-9-5p, miR-34a-5p, miR-200a-3p, and the family of miRNAs miR-21-5p, and miR-590-p. The miRNA profile and predicted target mRNAs suggested regulatory pathways in MDMs obtained from healthy donors who received higher doses of vitamin D. These DENV-2 infected MDMs expressed a unique set of miRNAs that target immune and cellular stress response genes. Conclusion: The results suggest vitamin D dose-dependent differential expression of miRNAs target key signaling pathways of the pathogenesis of dengue disease.

scholarly journals n-3 Fatty acids, inflammation and immunity: new mechanisms to explain old actions

2013 ◽  
Vol 72 (3) ◽  
pp. 326-336 ◽  
Author(s):  
Philip C. Calder
Keyword(s):  
Fatty Acids ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Mechanisms Of Action ◽  
Lipid Mediators ◽  
Functional Responses ◽  
New Family ◽  
Epa And Dha ◽  
Novel Interactions

Numerous effects of n-3 fatty acids EPA and DHA on functional responses of cells involved in inflammation and immunity have been described. Fatty acid-induced modifications in membrane order and in the availability of substrates for eicosanoid synthesis are long-standing mechanisms that are considered important in explaining the effects observed. More recently, effects on signal transduction pathways and on gene expression profiles have been identified. Over the last 10 years or so, significant advances in understanding the mechanisms of action of n-3 fatty acids have been made. These include the identification of new actions of lipid mediators that were already described and of novel interactions among those mediators and the description of an entirely new family of lipid mediators, resolvins and protectins that have anti-inflammatory actions and are critical to the resolution of inflammation. It is also recognised that EPA and DHA can inhibit activation of the prototypical inflammatory transcription factor NF-κB. Recent studies suggest three alternative mechanisms by which n-3 fatty acids might have this effect. Within T-cells, as well as other cells of relevance to immune and inflammatory responses, EPA and DHA act to disrupt very early events involving formation of the structures termed lipid rafts which bring together various proteins to form an effective signalling platform. In summary, recent research has identified a number of new mechanisms of action that help to explain previously identified effects of n-3 fatty acids on inflammation and immunity.

Whole blood genome-wide gene expression profile in males after prolonged wakefulness and sleep recovery

2012 ◽  
Vol 44 (21) ◽  
pp. 1003-1012 ◽  
Author(s):  
R. Pellegrino ◽  
D. Y. Sunaga ◽  
C. Guindalini ◽  
R. C. S. Martins ◽  
D. R. Mazzotti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Killer Cell ◽  
Gene Expression Profiles ◽  
Sleep Loss ◽  
The Body ◽  
Dna Damage And Repair ◽  
Peripheral Tissues

Although the specific functions of sleep have not been completely elucidated, the literature has suggested that sleep is essential for proper homeostasis. Sleep loss is associated with changes in behavioral, neurochemical, cellular, and metabolic function as well as impaired immune response. Using high-resolution microarrays we evaluated the gene expression profiles of healthy male volunteers who underwent 60 h of prolonged wakefulness (PW) followed by 12 h of sleep recovery (SR). Peripheral whole blood was collected at 8 am in the morning before the initiation of PW (Baseline), after the second night of PW, and one night after SR. We identified over 500 genes that were differentially expressed. Notably, these genes were related to DNA damage and repair and stress response, as well as diverse immune system responses, such as natural killer pathways including killer cell lectin-like receptors family, as well as granzymes and T-cell receptors, which play important roles in host defense. These results support the idea that sleep loss can lead to alterations in molecular processes that result in perturbation of cellular immunity, induction of inflammatory responses, and homeostatic imbalance. Moreover, expression of multiple genes was downregulated following PW and upregulated after SR compared with PW, suggesting an attempt of the body to re-establish internal homeostasis. In silico validation of alterations in the expression of CETN3, DNAJC, and CEACAM genes confirmed previous findings related to the molecular effects of sleep deprivation. Thus, the present findings confirm that the effects of sleep loss are not restricted to the brain and can occur intensely in peripheral tissues.

scholarly journals Molecular Profiling and Clinical Outcome of High-Grade Serous Ovarian Cancer Presenting with Low- versus High-Volume Ascites

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Tomer Feigenberg ◽  
Blaise Clarke ◽  
Carl Virtanen ◽  
Anna Plotkin ◽  
Michelle Letarte ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Clinical Outcome ◽  
Expression Profiles ◽  
High Volume ◽  
High Grade ◽  
Advanced Stage ◽  
Serous Ovarian Cancer ◽  
Immune Response Genes ◽  
Low Volume

Epithelial ovarian cancer consists of multiple histotypes differing in etiology and clinical course. The most prevalent histotype is high-grade serous ovarian cancer (HGSOC), which often presents at an advanced stage frequently accompanied with high-volume ascites. While some studies suggest that ascites is associated with poor clinical outcome, most reports have not differentiated between histological subtypes or tumor grade. We compared genome-wide gene expression profiles from a discovery cohort of ten patients diagnosed with stages III-IV HGSOC with high-volume ascites and nine patients with low-volume ascites. An upregulation of immune response genes was detected in tumors from patients presenting with low-volume ascites relative to those with high-volume ascites. Immunohistochemical studies performed on tissue microarrays confirmed higher expression of proteins encoded by immune response genes and increased tumorinfiltrating cells in tumors associated with low-volume ascites. Comparison of 149 advanced-stage HGSOC cases with differential ascites volume at time of primary surgery indicated low-volume ascites correlated with better surgical outcome and longer overall survival. These findings suggest that advanced stage HGSOC presenting with low-volume ascites reflects a unique subgroup of HGSOC, which is associated with upregulation of immune related genes, more abundant tumor infiltrating cells and better clinical outcomes.

scholarly journals Identification of Lung-Cancer-Related Genes with the Shortest Path Approach in a Protein-Protein Interaction Network

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Bi-Qing Li ◽  
Jin You ◽  
Lei Chen ◽  
Jian Zhang ◽  
Ning Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Shortest Path ◽  
Protein Interaction ◽  
Expression Profiles ◽  
Shortest Paths ◽  
Gene Expression Profiles ◽  
Cancer Genes ◽  
Ppi Network ◽  
Protein Protein Interaction

Lung cancer is one of the leading causes of cancer mortality worldwide. The main types of lung cancer are small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). In this work, a computational method was proposed for identifying lung-cancer-related genes with a shortest path approach in a protein-protein interaction (PPI) network. Based on the PPI data from STRING, a weighted PPI network was constructed. 54 NSCLC- and 84 SCLC-related genes were retrieved from associated KEGG pathways. Then the shortest paths between each pair of these 54 NSCLC genes and 84 SCLC genes were obtained with Dijkstra’s algorithm. Finally, all the genes on the shortest paths were extracted, and 25 and 38 shortest genes with a permutationPvalue less than 0.05 for NSCLC and SCLC were selected for further analysis. Some of the shortest path genes have been reported to be related to lung cancer. Intriguingly, the candidate genes we identified from the PPI network contained more cancer genes than those identified from the gene expression profiles. Furthermore, these genes possessed more functional similarity with the known cancer genes than those identified from the gene expression profiles. This study proved the efficiency of the proposed method and showed promising results.

Distinct gene expression profiles provoked by polyacrylamide beads (Biogel) during chronic and acute inflammation in mice selected for maximal and minimal inflammatory responses

2016 ◽  
Vol 65 (4) ◽  
pp. 313-323 ◽  
Author(s):  
Jussara Gonçalves Fernandes ◽  
Tatiane Canhamero ◽  
Andrea Borrego ◽  
José Ricardo Jensen ◽  
Wafa Hanna Cabrera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Inflammation ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Distinct Gene

GENE FUNCTION PREDICTION BY A COMBINED ANALYSIS OF GENE EXPRESSION DATA AND PROTEIN-PROTEIN INTERACTION DATA

2005 ◽  
Vol 03 (06) ◽  
pp. 1371-1389 ◽  
Author(s):  
GUANGHUA XIAO ◽  
WEI PAN
Keyword(s):  
Gene Expression ◽  
Protein Interaction ◽  
Gene Function ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Function Prediction ◽  
Protein Interaction Data ◽  
Interaction Data ◽  
Gene Function Prediction ◽  
Protein Protein Interaction

Prediction of biological functions of genes is an important issue in basic biology research and has applications in drug discoveries and gene therapies. Previous studies have shown either gene expression data or protein-protein interaction data alone can be used for predicting gene functions. In particular, clustering gene expression profiles has been widely used for gene function prediction. In this paper, we first propose a new method for gene function prediction using protein-protein interaction data, which will facilitate combining prediction results based on clustering gene expression profiles. We then propose a new method to combine the prediction results based on either source of data by weighting on the evidence provided by each. Using protein-protein interaction data downloaded from the GRID database, published gene expression profiles from 300 microarray experiments for the yeast S. cerevisiae, we show that this new combined analysis provides improved predictive performance over that of using either data source alone in a cross-validated analysis of the MIPS gene annotations. Finally, we propose a logistic regression method that is flexible enough to combine information from any number of data sources while maintaining computational feasibility.

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