scholarly journals Deficiency in Translesion DNA Polymerase ζ Induces an Innate Immune Response

2020 ◽  
Author(s):  
Sara K. Martin ◽  
Junya Tomida ◽  
Richard D. Wood
Keyword(s):  
Immune Response ◽  
Dna Polymerase ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Dna Lesions ◽  
Innate Immune ◽  
Protective Function ◽  
Interferon Stimulated Genes ◽  
Protein Levels ◽  
Genomic Stress

ABSTRACTDNA polymerase pol ζ is regarded as a specialized DNA polymerase for bypass of DNA lesions. In mammalian cells, pol ζ also contributes to genomic stability during normal DNA replication. Disruption of Rev3l (the catalytic subunit of pol ζ) is toxic to cells and mice, with increased constitutive chromosome damage, including micronuclei. As the cellular manifestations of this genomic stress have remained unexplored, we measured genome-wide transcriptional changes by RNA-seq in pol ζ-defective cells. Expression of 1117 transcripts was altered by 4-fold or more in Rev3l knockout mouse embryonic fibroblasts (MEFs), with a pattern showing an induction of an innate immune response. We validated the increased expression of known interferon-stimulated genes (ISG) at the mRNA and protein levels. We found that the cGAS-STING axis, which senses cytosolic DNA, drives ISG expression in Rev3l knockout MEFs. These results reveal a new genome protective function of pol ζ and indicate that inhibition of pol ζ may be therapeutically useful by simultaneously increasing sensitivity to genotoxins and inducing a cytotoxic innate immune response.

scholarly journals Disruption of DNA polymerase ζ engages an innate immune response

Cell Reports ◽  
2021 ◽  
Vol 34 (8) ◽  
pp. 108775
Author(s):  
Sara K. Martin ◽  
Junya Tomida ◽  
Richard D. Wood
Keyword(s):  
Immune Response ◽  
Dna Polymerase ◽  
Innate Immune Response ◽  
Innate Immune

scholarly journals The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance

2018 ◽  
Author(s):  
Leeanna El-Houjeiri ◽  
Elite Possik ◽  
Tarika Vijayaraghavan ◽  
Mathieu Paquette ◽  
José A Martina ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Pathogen Resistance ◽  
Innate Immune ◽  
Negative Regulator ◽  
Energy Status ◽  
Rapid Reduction ◽  
Coupling Energy ◽  
Mtorc1 Signaling

AbstractTFEB and TFE3 are transcriptional regulators of the innate immune response, but the mechanisms regulating their activation upon pathogen infection are poorly elucidated. UsingC. elegansand mammalian models, we report that the master metabolic modulator 5’-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN) act upstream of TFEB/TFE3 in the innate immune response, independently of the mTORC1 signaling pathway. In nematodes, loss of FLCN or overexpression of AMPK conferred pathogen resistanceviaactivation of TFEB/TFE3-dependent antimicrobial genes, while ablation of total AMPK activity abolished this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induced TFEB/TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages was observed upon lipopolysaccharide (LPS) treatment accompanied by an acute AMPK activation and TFEB nuclear localization. These results uncover an ancient, highly conserved and pharmacologically actionable mechanism coupling energy status with innate immunity.

scholarly journals Interferon-Stimulated Genes as Enhancers of Antiviral Innate Immune Signaling

2017 ◽  
Vol 10 (2) ◽  
pp. 85-93 ◽  
Author(s):  
Keaton M. Crosse ◽  
Ebony A. Monson ◽  
Michael R. Beard ◽  
Karla J. Helbig
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Regulatory Factor ◽  
Interferon Stimulated Genes ◽  
Innate Immune Signaling ◽  
Recent Advancement ◽  
Antiviral Function

The ability of a host to curb a viral infection is heavily reliant on the effectiveness of an initial antiviral innate immune response, resulting in the upregulation of interferon (IFN) and, subsequently, IFN-stimulated genes (ISGs). ISGs serve to mount an antiviral state within a host cell, and although the specific antiviral function of a number of ISGs has been characterized, the function of many of these ISGs remains to be determined. Recent research has uncovered a novel role for a handful of ISGs, some of them directly induced by IFN regulatory factor 3 in the absence of IFN itself. These ISGs, most with potent antiviral activity, are also able to augment varying arms of the innate immune response to viral infection, thereby strengthening this response. This new understanding of the role of ISGs may, in turn, help the recent advancement of novel therapeutics aiming to augment innate signaling pathways in an attempt to control viral infection and pathogenesis.

Role of miRNA-146a in the regulation of the innate immune response and cancer

2008 ◽  
Vol 36 (6) ◽  
pp. 1211-1215 ◽  
Author(s):  
Andrew E. Williams ◽  
Mark M. Perry ◽  
Sterghios A. Moschos ◽  
Hanna M. Larner-Svensson ◽  
Mark A. Lindsay
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Mrna Translation ◽  
Nuclear Factor Κb ◽  
Causal Link ◽  
Innate Immune ◽  
Major Function ◽  
Biological Responses

In mammalian cells, miRNAs (microRNAs) are the most abundant family of small non-coding RNAs that regulate mRNA translation through the RNA interference pathway. In general, it appears that the major function of miRNAs is in development, differentiation and homoeostasis, which is indicated by studies showing aberrant miRNA expression during the development of cancer. Interestingly, changes in the expression of miR-146a have been implicated in both the development of multiple cancers and in the negative regulation of inflammation induced via the innate immune response. Furthermore, miR-146a expression is driven by the transcription factor NF-κB (nuclear factor κB), which has been implicated as an important causal link between inflammation and carcinogenesis. In the present article, we review the evidence for a role of miR-146a in innate immunity and cancer and assess whether changes in miR-146a might link these two biological responses.

Cytotoxicity of, and innate immune response to, size-controlled polypyrrole nanoparticles in mammalian cells

Biomaterials ◽  
2011 ◽  
Vol 32 (9) ◽  
pp. 2342-2350 ◽  
Author(s):  
Sojin Kim ◽  
Wan-Kyu Oh ◽  
Yoon Seon Jeong ◽  
Jin-Yong Hong ◽  
Bo-Ram Cho ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Innate Immune ◽  
Polypyrrole Nanoparticles ◽  
Size Controlled

scholarly journals Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

2013 ◽  
Vol 94 (11) ◽  
pp. 2367-2392 ◽  
Author(s):  
Geoffrey L. Smith ◽  
Camilla T. O. Benfield ◽  
Carlos Maluquer de Motes ◽  
Michela Mazzon ◽  
Stuart W. J. Ember ◽  
...  
Keyword(s):  
Immune Response ◽  
Vaccinia Virus ◽  
Innate Immune Response ◽  
Immune Evasion ◽  
Mammalian Cells ◽  
Innate Immune ◽  
Gene Encoding ◽  
Cytokines And Chemokines ◽  
Host Innate Immune Response ◽  
New Hosts

Virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. In response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. Poxviruses, such as vaccinia virus (VACV), have large DNA genomes and encode many proteins that are dedicated to host immune evasion. Some of these proteins are secreted from the infected cell, where they bind and neutralize complement factors, interferons, cytokines and chemokines. Other VACV proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines. In this review, these VACV immunomodulatory proteins are described and the potential to create more immunogenic VACV strains by manipulation of the gene encoding these proteins is discussed.

scholarly journals Transcriptome Profiling of the Virus-Induced Innate Immune Response in Pteropus vampyrus and Its Attenuation by Nipah Virus Interferon Antagonist Functions

2015 ◽  
Vol 89 (15) ◽  
pp. 7550-7566 ◽  
Author(s):  
Nicole B. Glennon ◽  
Omar Jabado ◽  
Michael K. Lo ◽  
Megan L. Shaw
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Nipah Virus ◽  
A549 Cells ◽  
Hendra Virus ◽  
Innate Immune ◽  
Viral Control ◽  
Content Type ◽  
Pteropus Vampyrus

ABSTRACTBats are important reservoirs for several viruses, many of which cause lethal infections in humans but have reduced pathogenicity in bats. As the innate immune response is critical for controlling viruses, the nature of this response in bats and how it may differ from that in other mammals are of great interest. Using next-generation transcriptome sequencing (mRNA-seq), we profiled the transcriptional response ofPteropus vampyrusbat kidney (PVK) cells to Newcastle disease virus (NDV), an avian paramyxovirus known to elicit a strong innate immune response in mammalian cells. ThePteropusgenus is a known reservoir of Nipah virus (NiV) and Hendra virus (HeV). Analysis of the 200 to 300 regulated genes showed that genes for interferon (IFN) and antiviral pathways are highly upregulated in NDV-infected PVK cells, including genes for beta IFN, RIG-I, MDA5, ISG15, and IRF1. NDV-infected cells also upregulated several genes not previously characterized to be antiviral, such as RND1, SERTAD1, CHAC1, and MORC3. In fact, we show that MORC3 is induced by both IFN and NDV infection in PVK cells but is not induced by either stimulus in human A549 cells. In contrast to NDV infection, HeV and NiV infection of PVK cells failed to induce these innate immune response genes. Likewise, an attenuated response was observed in PVK cells infected with recombinant NDVs expressing the NiV IFN antagonist proteins V and W. This study provides the first global profile of a robust virus-induced innate immune response in bats and indicates that henipavirus IFN antagonist mechanisms are likely active in bat cells.IMPORTANCEBats are the reservoir host for many highly pathogenic human viruses, including henipaviruses, lyssaviruses, severe acute respiratory syndrome coronavirus, and filoviruses, and many other viruses have also been isolated from bats. Viral infections are reportedly asymptomatic or heavily attenuated in bat populations. Despite their ecological importance to viral maintenance, research into their immune system and mechanisms for viral control has only recently begun. Nipah virus and Hendra virus are two paramyxoviruses associated with high mortality rates in humans and whose reservoir is thePteropusgenus of bats. Greater knowledge of the innate immune response ofP. vampyrusbats to viral infection may elucidate how bats serve as a reservoir for so many viruses.

scholarly journals A virus-encoded microRNA contributes to evade innate immune response during SARS-CoV-2 infection

2021 ◽  
Author(s):  
Meetali Singh ◽  
Maxime Chazal ◽  
Piergiuseppe Quarato ◽  
Loan Bourdon ◽  
Christophe Malabat ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Small Rnas ◽  
Viral Genome ◽  
Innate Immune ◽  
Micro Rna ◽  
Interferon Response ◽  
Interferon Stimulated Genes ◽  
Argonaute Proteins ◽  
Infected Cells

SARS-CoV-2 infection results in impaired interferon response in severe COVID-19 patients. However, how SARS-CoV-2 interferes with host immune response is incompletely understood. Here, we sequenced small RNAs from SARS-CoV-2-infected human cells and identified a micro-RNA (miRNA) encoded in a recently evolved region of the viral genome. We show that the virus-encoded miRNA produces two miRNA isoforms in infected cells by the enzyme Dicer and they are loaded into Argonaute proteins. Moreover, the predominant miRNA isoform targets the 3’UTR of interferon-stimulated genes and represses their expression in a miRNA-like fashion. Finally, the two viral miRNA isoforms were detected in nasopharyngeal swabs from COVID-19 patients. We propose that SARS-CoV-2 employs a virus-encoded miRNA to hijack the host miRNA machinery and evade the interferon-mediated immune response.

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