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Analysis of Mouse Brain Transcriptome After Experimental Duvenhage Virus Infection Shows Activation of Innate Immune Response and Pyroptotic Cell Death Pathway.

ABSTRACT: Rabies is an important neglected disease, characterized by invariably fatal encephalitis. Several studies focus on understanding the pathogenic mechanisms of the prototype lyssavirus rabies virus (RABV) infection, and little is known about the pathogenesis of rabies caused by other lyssaviruses. We sought to characterize the host response to Duvenhage virus infection and compare it with responses observed during RABV infection by gene expression profiling of brains of mice with the respective infections. We found in both infections differentially expressed genes leading to increased expression of type I interferons (IFNs), chemokines, and proinflammatory cytokines. In addition several genes of the IFN signaling pathway are up-regulated, indicating a strong antiviral response and activation of the negative feedback mechanism to limit type I IFN responses. Furthermore we provide evidence that in the absence of significant neuronal apoptotic death, cell death of neurons is mediated via the pyroptotic pathway in both infections. Taken together, we have identified several genes and/or pathways for both infections that could be used to explore novel approaches for intervention strategies against rabies.

SUBMITTER: Koraka P

PROVIDER: S-EPMC5869263 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Analysis of Mouse Brain Transcriptome After Experimental Duvenhage Virus Infection Shows Activation of Innate Immune Response and Pyroptotic Cell Death Pathway.

Koraka Penelope P Martina Byron E E BEE van den Ham Henk-Jan HJ Zaaraoui-Boutahar Fatiha F van IJcken Wilfred W Roose Jouke J van Amerongen Geert G Andeweg Arno A Osterhaus Albertus D M E ADME

Frontiers in microbiology 20180320

Rabies is an important neglected disease, characterized by invariably fatal encephalitis. Several studies focus on understanding the pathogenic mechanisms of the prototype lyssavirus rabies virus (RABV) infection, and little is known about the pathogenesis of rabies caused by other lyssaviruses. We sought to characterize the host response to Duvenhage virus infection and compare it with responses observed during RABV infection by gene expression profiling of brains of mice with the respective in ...[more]

PMID: 29615985

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Project description:The mechanism of hepatitis B virus (HBV) immune tolerance remains unclear. Our previous studies showed that ATOH8 plays an important role in the liver tumor immune microenvironment; however, the specific immune regulatory mechanism requires further studies. Studies have shown that the hepatitis C virus (HCV) can cause hepatocyte pyroptosis; however, the relationship between HBV and pyroptosis is contested. Therefore, this study aimed to determine whether ATOH8 interfered with HBV activity through pyroptosis to further study the mechanism of ATOH8 on immune regulation and enrich our understanding of HBV‑induced invasion. The expression levels of pyroptosis‑related molecules (GSDMD and Caspase‑1) in liver cancer tissues and peripheral blood mononuclear cells (PBMCs) of patients with HBV were assessed using qPCR and western blotting. HepG2.2.15 and Huh7 cells were used to overexpress ATOH8 using a recombinant lentiviral vector. The HBV DNA expression levels in HepG2.2.15 cells were detected using absolute quantitative (q)PCR, and the hepatitis B surface antigen expression levels in the HepG2.2.15 cell culture supernatant were measured using ELISA. The expression of pyroptosis‑related molecules in Huh7 and HepG2.2.15 cells was detected using western blotting and qPCR. Additionally, the expression levels of inflammatory factors including TNF‑α, INF‑α, IL‑18, and IL‑1β were detected using qPCR and ELISA. The liver cancer tissues and PBMCs of patients with HBV showed higher expressions of pyroptosis‑related molecules than those of normal samples. ATOH8‑overexpressed HepG2.2.15 cells had higher HBV expression levels but lower levels of pyroptosis‑related molecules, such as GSDMD and Caspase‑1, than those in the control group. Similarly, the expression levels of pyroptosis‑related molecules in Huh7 cells overexpressing ATOH8 were lower than that in Huh7‑GFP cells. Further detection of the expression of INF‑α and TNF‑α in HepG2.2.15 cells overexpressing ATOH8 showed that ATOH8 overexpression increased the expression of these inflammatory factors, including those associated with pyroptosis (IL‑18 and IL‑1β). In conclusion, ATOH8 promoted HBV immune escape by inhibiting hepatocyte pyroptosis.

Project description:Lung adenocarcinoma (LUAD) is a prevalent type of thoracic cancer with a poor prognosis and high mortality rate. However, the exact pathogenesis of this cancer is still not fully understood. One potential factor that can contribute to the development of lung adenocarcinoma is DNA methylation, which can cause changes in chromosome structure and potentially lead to the formation of tumors. The baculoviral IAP repeat containing the 5 (BIRC5) gene encodes the Survivin protein, which is a multifunctional gene involved in cell proliferation, migration, and invasion of tumor cells. This gene is elevated in various solid tumors, but its specific role and mechanism in lung adenocarcinoma are not well-known. To identify the potential biomarkers associated with lung adenocarcinoma, we screened the methylation-regulated differentially expressed genes (MeDEGs) of LUAD via bioinformatics analysis. Gene ontology (GO) process and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to investigate the biological function and pathway of MeDEGs. A protein-protein interaction (PPI) network was employed to explore the key module and screen hub genes. We screened out eight hub genes whose products are aberrantly expressed, and whose DNA methylation modification level is significantly changed in lung adenocarcinoma. BIRC5 is a bona fide marker which was remarkably up-regulated in tumor tissues. Flow cytometry analysis, lactate dehydrogenase release (LDH) assay and Micro-PET imaging were performed in A549 cells and a mouse xenograft tumor to explore the function of BIRC5 in cell death of lung adenocarcinoma. We found that BIRC5 was up-regulated and related to a high mortality rate in lung adenocarcinoma patients. Mechanically, the knockdown of BIRC5 inhibited the proliferation of A549 cells and induced pyroptosis via caspase3/GSDME signaling. Our findings have unraveled that BIRC5 holds promise as a novel biomarker and therapeutic target for lung adenocarcinoma. Additionally, we have discovered a novel pathway in which BIRC5 inhibition can induce pyroptosis through the caspase3-GSDME pathway in lung adenocarcinoma cells.

Dataset Information

Analysis of Mouse Brain Transcriptome After Experimental Duvenhage Virus Infection Shows Activation of Innate Immune Response and Pyroptotic Cell Death Pathway.

Publications

Analysis of Mouse Brain Transcriptome After Experimental Duvenhage Virus Infection Shows Activation of Innate Immune Response and Pyroptotic Cell Death Pathway.

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