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mitochondrial DNA antiviral

Takuma Yoshizumi, Hiromi Imamura, Tomohiro Taku, Takahiro Kuroki, Atsushi Kawaguchi, Kaori Ishikawa, Kazuto Nakada, Takumi Koshiba
Mitochondria act as a platform for antiviral innate immunity, and the immune system depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) signaling pathway via an adaptor molecule, mitochondrial antiviral signaling. We report that RLR-mediated antiviral innate immunity requires oxidative phosphorylation (OXPHOS) activity, a prominent physiologic function of mitochondria. Cells lacking mitochondrial DNA or mutant cells with respiratory defects exhibited severely impaired virus-induced induction of interferons and proinflammatory cytokines...
July 14, 2017: Scientific Reports
Bo Sun, Karin B Sundström, Jun Jie Chew, Pradeep Bist, Esther S Gan, Hwee Cheng Tan, Kenneth C Goh, Tanu Chawla, Choon Kit Tang, Eng Eong Ooi
Cyclic GMP-AMP synthetase (cGAS) is a DNA-specific cytosolic sensor, which detects and initiates host defense responses against microbial DNA. It is thus curious that a recent study identified cGAS as playing important roles in inhibiting positive-sense single-stranded RNA (+ssRNA) viral infection, especially since RNA is not known to activate cGAS. Using a dengue virus serotype 2 (DENV-2) vaccine strain (PDK53), we show that infection creates an endogenous source of cytosolic DNA in infected cells through the release of mitochondrial DNA (mtDNA) to drive the production of cGAMP by cGAS...
June 15, 2017: Scientific Reports
Alessandra Zevini, David Olagnier, John Hiscott
Detection of evolutionarily conserved molecules on microbial pathogens by host immune sensors represents the initial trigger of the immune response against infection. Cytosolic receptors sense viral and intracellular bacterial genomes, as well as nucleic acids produced during replication. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Although distinct classes of receptors are responsible for the RNA and DNA sensing, the downstream signaling components are physically and functionally interconnected...
March 2017: Trends in Immunology
E John Tokarsky, Petra C Wallenmeyer, Kenneth K Phi, Zucai Suo
Human PrimPol is a recently discovered bifunctional enzyme that displays DNA template-directed primase and polymerase activities. PrimPol has been implicated in nuclear and mitochondrial DNA replication fork progression and restart as well as DNA lesion bypass. Published evidence suggests that PrimPol is a Mn(2+)-dependent enzyme as it shows significantly improved primase and polymerase activities when binding Mn(2+), rather than Mg(2+), as a divalent metal ion cofactor. Consistently, our fluorescence anisotropy assays determined that PrimPol binds to a primer/template DNA substrate with affinities of 29 and 979nM in the presence of Mn(2+) and Mg(2+), respectively...
January 2017: DNA Repair
Martijn Fenaux, Xiaodong Lin, Fumiaki Yokokawa, Zachary Sweeney, Oliver Saunders, Lili Xie, Siew Pheng Lim, Marianne Uteng, Kyoko Uehara, Robert Warne, Wang Gang, Christopher Jones, Satya Yendluri, Helen Gu, Keith Mansfield, Julie Boisclair, Tycho Heimbach, Alexandre Catoire, Kathryn Bracken, Margaret Weaver, Heinz Moser, Weidong Zhong
Nucleoside or nucleotide inhibitors are a highly successful class of antivirals due to selectivity, potency, broad coverage, and high barrier to resistance. Nucleosides are the backbone of combination treatments for HIV, hepatitis B virus, and, since the FDA approval of sofosbuvir in 2013, also for hepatitis C virus (HCV). However, many promising nucleotide inhibitors have advanced to clinical trials only to be terminated due to unexpected toxicity. Here we describe the in vitro pharmacology of compound 1, a monophosphate prodrug of a 2'-ethynyluridine developed for the treatment of HCV...
December 2016: Antimicrobial Agents and Chemotherapy
Maria C Olianas, Simona Dedoni, Pierluigi Onali
BACKGROUND AND PURPOSE: Although clinically useful for their immunomodulatory, antiproliferative and antiviral properties, type I interferons (IFNs) are involved in the pathogenesis of several neurodegenerative/neuroinflammatory diseases. In the present study, we investigated the ability of cholinergic stimulation to protect from IFN-β-induced neuronal apoptosis. EXPERIMENTAL APPROACH: The effects of the ACh receptor agonist carbachol (CCh) on IFN-β-induced apoptosis of human SH-SY5Y neuroblastoma cells were examined by using western blots, immunofluorescence and cytofluorimetry...
October 2016: British Journal of Pharmacology
Nuruddin Unchwaniwala, Nathan M Sherer, Daniel D Loeb
UNLABELLED: To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria...
October 1, 2016: Journal of Virology
Mohsin Khan, Gulam Hussain Syed, Seong-Jun Kim, Aleem Siddiqui
Hepatitis B virus (HBV) suppresses innate immune signaling to establish persistent infection. Although HBV is a DNA virus, its pre-genomic RNA (pgRNA) can be sensed by RIG-I and activates MAVS to mediate interferon (IFN) λ synthesis. Despite of the activation of RIG-I-MAVS axis by pgRNA, the underlying mechanism explaining how HBV infection fails to induce interferon-αβ (IFN) synthesis remained uncharacterized. We demonstrate that HBV induced parkin is able to recruit the linear ubiquitin assembly complex (LUBAC) to mitochondria and abrogates IFN β synthesis...
June 2016: PLoS Pathogens
Baoyu Zhao, Chang Shu, Xinsheng Gao, Banumathi Sankaran, Fenglei Du, Catherine L Shelton, Andrew B Herr, Jun-Yuan Ji, Pingwei Li
Type I IFNs are key cytokines mediating innate antiviral immunity. cGMP-AMP synthase, ritinoic acid-inducible protein 1 (RIG-I)-like receptors, and Toll-like receptors recognize microbial double-stranded (ds)DNA, dsRNA, and LPS to induce the expression of type I IFNs. These signaling pathways converge at the recruitment and activation of the transcription factor IRF-3 (IFN regulatory factor 3). The adaptor proteins STING (stimulator of IFN genes), MAVS (mitochondrial antiviral signaling), and TRIF (TIR domain-containing adaptor inducing IFN-β) mediate the recruitment of IRF-3 through a conserved pLxIS motif...
June 14, 2016: Proceedings of the National Academy of Sciences of the United States of America
Xiao-Bo Yu, Xiao-Hui Chen, Fei Ling, Kai Hao, Gao-Xue Wang, Bin Zhu
Moroxydine hydrochloride (Mor) is known to have multi-antiviral activities against DNA and RNA viruses but very little information exists on its pharmacology. The paper was undertaken to explore the antiviral response and antiapoptotic mechanism of Mor against grass carp reovirus (GCRV) in Ctenopharyngodon idella kidney (CIK) cells. The results showed that exposing GCRV-infected cell to 6.3 μg mL(-1) of Mor for 96 h avoid ca. 50% apoptosis. Meanwhile, Mor had lower cytotoxicity than ribavirin (Rib) as the value of safe concentration was threefold higher than effective concentration and the compound could ensure sufficient into and out of cells within 4 h when tested at the maximal safe concentration...
July 2016: Antiviral Research
Zbigniew Wyżewski, Karolina P Gregorczyk, Justyna Struzik, Marek Niemiałtowski, Lidia Szulc-Dąbrowska
Mitochondrial antiviral signaling protein (MAVS) transmits activation signal of type I interferon (IFN) gene transcription in the molecular intracellular pathway, which depends on the protein encoded by retinoic acid inducible gene I (RIG-I) or melanoma differentiation-associated protein-5 (MDA-5). MAVS, as a signal molecule, performs an essential function in the development of an antiviral immune response. The molecule of MAVS consists of two domains: the N-terminal domain and the C-terminal domain. The N-terminal end of MAVS contains the caspase activation and recruitment domain (CARD)...
January 26, 2016: Postȩpy Higieny i Medycyny Doświadczalnej
Andrea C Mislak, Karen S Anderson
Human PrimPol is a newly identified DNA and RNA primase-polymerase of the archaeo-eukaryotic primase (AEP) superfamily and only the second known polymerase in the mitochondria. Mechanistic studies have shown that interactions of the primary mitochondrial DNA polymerase γ (mtDNA Pol γ) with nucleoside reverse transcriptase inhibitors (NRTIs), key components in treating HIV infection, are a major source of NRTI-associated toxicity. Understanding the interactions of host polymerases with antiviral and anticancer nucleoside analog therapies is critical for preventing life-threatening adverse events, particularly in AIDS patients who undergo lifelong treatment...
November 9, 2015: Antimicrobial Agents and Chemotherapy
Zoltán V Varga, Peter Ferdinandy, Lucas Liaudet, Pál Pacher
Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult...
November 2015: American Journal of Physiology. Heart and Circulatory Physiology
Elisa Franzolin, Cristiano Salata, Vera Bianchi, Chiara Rampazzo
The dNTP triphosphohydrolase SAMHD1 is a nuclear antiviral host restriction factor limiting HIV-1 infection in macrophages and a major regulator of dNTP concentrations in human cells. In normal human fibroblasts its expression increases during quiescence, contributing to the small dNTP pool sizes of these cells. Down-regulation of SAMHD1 by siRNA expands all four dNTP pools, with dGTP undergoing the largest relative increase. The deoxyguanosine released by SAMHD1 from dGTP can be phosphorylated inside mitochondria by deoxyguanosine kinase (dGK) or degraded in the cytosol by purine nucleoside phosphorylase...
October 23, 2015: Journal of Biological Chemistry
Christopher A Koczor, Zhe Jiao, Earl Fields, Rodney Russ, Tomika Ludaway, William Lewis
Mitochondrial dysfunction causes oxidative stress and cardiomyopathy. Oxidative stress also is a side effect of dideoxynucleoside antiretrovirals (NRTI) and is observed in NRTI-induced cardiomyopathy. We show here that treatment with the NRTI AZT {1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione} modulates cardiac gene expression epigenetically through production of mitochondrially derived reactive oxygen species. Transgenic mice with ubiquitous expression of mitochondrially targeted catalase (MCAT) and C57Bl/6 wild-type mice littermates (WT) were administered AZT (0...
October 2015: Physiological Genomics
Li Zhou, Xiaoyu Liu, Feng Ren, Yu Chen, Sujun Zheng, Yuanping Han, Caiyan Zhao, Zhongping Duan
BACKGROUND: This study aimed to assess whether long-term entecavir monotherapy induces mitochondrial toxicity in patients with chronic hepatitis B (CHB). MATERIAL AND METHODS: This was a prospective study in 34 antiviral treatment-naïve patients with CHB who received entecavir monotherapy and were followed up for 4 years. Blood samples were collected after 0, 2, 3, and 4 years of entecavir (ETC) monotherapy (ETC0, ETC2, ETC3, and ETC4, respectively). Mitochondrial DNA (mtDNA) contents were determined using real-time quantitative polymerase chain reaction (qRT-PCR) and mtDNA4977 depletions were detected using nested PCR...
2015: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Michal R Szymanski, Vladmir B Kuznetsov, Christie Shumate, Qingchao Meng, Young-Sam Lee, Gayatri Patel, Smita Patel, Y Whitney Yin
The human DNA polymerase gamma (Pol γ) is responsible for DNA replication in mitochondria. Pol γ is particularly susceptible to inhibition by dideoxynucleoside-based inhibitors designed to fight viral infection. Here, we report crystal structures of the replicating Pol γ-DNA complex bound to either substrate or zalcitabine, an inhibitor used for HIV reverse transcriptase. The structures reveal that zalcitabine binds to the Pol γ active site almost identically to the substrate dCTP, providing a structural basis for Pol γ-mediated drug toxicity...
July 14, 2015: EMBO Journal
Garth D Tylden, Hans H Hirsch, Christine Hanssen Rinaldo
BK polyomavirus (BKPyV)-associated hemorrhagic cystitis (PyVHC) complicates 5 to 15% of allogeneic hematopoietic stem cell transplantations. Targeted antivirals are still unavailable. Brincidofovir (BCV; previously CMX001) has shown inhibitory activity against diverse viruses, including BKPyV in a primary human renal tubule cell culture model of polyomavirus-associated nephropathy. We investigated the effects of BCV in BKPyV-infected and uninfected primary human urothelial cells (HUCs), the target cells of BKPyV in PyVHC...
2015: Antimicrobial Agents and Chemotherapy
Troels K H Scheel, Amit Kapoor, Eiko Nishiuchi, Kenny V Brock, Yingpu Yu, Linda Andrus, Meigang Gu, Randall W Renshaw, Edward J Dubovi, Sean P McDonough, Gerlinde R Van de Walle, W Ian Lipkin, Thomas J Divers, Bud C Tennant, Charles M Rice
Nonprimate hepacivirus (NPHV) is the closest known relative of hepatitis C virus (HCV) and its study could enrich our understanding of HCV evolution, immunity, and pathogenesis. High seropositivity is found in horses worldwide with ∼ 3% viremic. NPHV natural history and molecular virology remain largely unexplored, however. Here, we show that NPHV, like HCV, can cause persistent infection for over a decade, with high titers and negative strand RNA in the liver. NPHV is a near-universal contaminant of commercial horse sera for cell culture...
February 17, 2015: Proceedings of the National Academy of Sciences of the United States of America
A Phillip West, William Khoury-Hanold, Matthew Staron, Michal C Tal, Cristiana M Pineda, Sabine M Lang, Megan Bestwick, Brett A Duguay, Nuno Raimundo, Donna A MacDuff, Susan M Kaech, James R Smiley, Robert E Means, Akiko Iwasaki, Gerald S Shadel
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined...
April 23, 2015: Nature
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