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Kate M Franz, William J Neidermyer, Yee-Joo Tan, Sean P J Whelan, Jonathan C Kagan
In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I-like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP-AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses...
February 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Venkata Krishnan Ramaswamy, Francesco Di Palma, Attilio V Vargiu, Angela Corona, Dario Piano, Paolo Ruggerone, Luca Zinzula, Enzo Tramontano
The multifunctional Ebola virus (EBOV) VP35 protein is a key determinant of virulence. VP35 is essential for EBOV replication, is a component of the viral RNA polymerase and participates in nucleocapsid formation. Furthermore, VP35 contributes to EBOV evasion of the host innate immune response by suppressing RNA silencing and blocking RIG-I like receptors' pathways that lead to type I interferon (IFN) production. VP35 homo-oligomerization has been reported to be critical for its replicative function and to increase its IFN-antagonism properties...
February 7, 2018: Virus Research
Xiaolin Zhang, Wei Yang, Xinlu Wang, Xuyuan Zhang, Huabin Tian, Hongyu Deng, Liguo Zhang, Guangxia Gao
Virus infection induces the production of type I interferons (IFNs). IFNs bind to their heterodimeric receptors to initiate downstream cascade of signaling, leading to the up-regulation of interferon-stimulated genes (ISGs). ISGs play very important roles in innate immunity through a variety of mechanisms. Although hundreds of ISGs have been identified, it is commonly recognized that more ISGs await to be discovered. The aim of this study was to identify new ISGs and to probe their roles in regulating virus-induced type I IFN production...
February 9, 2018: Protein & Cell
Yuena Sun, Jingjing Han, Qing Chu, Xuezhu Liu, Tianjun Xu
microRNAs (miRNAs) are endogenous small non-coding RNAs that participate in the regulation of various biological processes. A series of microRNAs have been shown to be important regulators of both innate and adaptive immune responses, including RIG-I signaling pathway. In this study, we evaluated the regulation role of miR-210 in the RLRs signaling pathway of miiuy croaker. Upon poly(I:C) stimulation, the expression of miR-210 in both miiuy croaker spleen tissues and macrophages were significantly upregulated...
February 3, 2018: Fish & Shellfish Immunology
Wanwan Zhang, Peng Jia, Wei Liu, Yunlong Li, Meisheng Yi, Kuntong Jia
Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a multifunctional regulator implicated in both bacterial defense and antiviral immunity. Here, a TRAF3 gene from the seawater fish sea perch, designated as LjTRAF3, was characterized. The full-length cDNA of LjTRAF3 was 2972 bp including a 5' untranslated region (UTR) of 243 bp, a 3'UTR of 941 bp and a putative open reading frame of 1608 bp encoding a putative protein of 536 amino acid. The deduced LjTRAF3 protein contained a RING finger, two zinc fingers, a coiled-coil, and a meprin and TRAF-C homology domain...
January 30, 2018: Fish & Shellfish Immunology
Anu S Helin, Michelle Wille, Clara Atterby, Josef D Järhult, Jonas Waldenström, Joanne R Chapman
The vertebrate innate immune system provides hosts with a rapid, non-specific response to a wide range of invading pathogens. However, the speed and duration of innate responses will be influenced by the co-evolutionary dynamics of specific host-pathogen combinations. Here, we show that low pathogenic avian influenza virus (LPAI) subtype H1N1 elicits a strong but extremely transient innate immune response in its main wildlife reservoir, the mallard (Anas platyrhynchos). Using a series of experimental and methodological improvements over previous studies, we followed the expression of retinoic acid inducible gene 1 (RIG-I) and myxovirus resistance gene (Mx) in mallards semi-naturally infected with low pathogenic H1N1...
February 2, 2018: Molecular Immunology
Maciej Czerkies, Zbigniew Korwek, Wiktor Prus, Marek Kochańczyk, Joanna Jaruszewicz-Błońska, Karolina Tudelska, Sławomir Błoński, Marek Kimmel, Allan R Brasier, Tomasz Lipniacki
The innate immune system processes pathogen-induced signals into cell fate decisions. How information is turned to decision remains unknown. By combining stochastic mathematical modelling and experimentation, we demonstrate that feedback interactions between the IRF3, NF-κB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast to pulse-like responses to bacterial LPS. Poly(I:C) activates both IRF3 and NF-κB, a requirement for induction of IFNβ expression. Autocrine IFNβ initiates a JAK/STAT-mediated positive-feedback stabilising nuclear IRF3 and NF-κB in first responder cells...
February 5, 2018: Nature Communications
Hideki Mori, Masamoto Murakami, Teruko Tsuda, Kenji Kameda, Ryo Utsunomiya, Kana Masuda, Ken Shiraishi, Xiuju Dai, Mikiko Tohyama, Hiroki Nakaoka, Koji Sayama
BACKGROUND: High mobility group box 1 (HMGB1) is a nuclear protein that stabilizes DNA and facilitates gene transcription. Additionally, cell stress or death induces the release of HMGB1 outside the cell membrane, where HMGB1 functions as an alarmin, causing an inflammatory response in combination with other cytokines, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs). OBJECTIVE: To evaluate the effect of reduced-HMGB1 (previously termed chemoattractive-HMGB1) on polyinosine-polycytidylic acid [poly(I:C)]-induced inflammation in normal human keratinocytes (NHKs)...
January 29, 2018: Journal of Dermatological Science
Jie Liu, Ling-Yun Tang, Yan-Gui Wang, Shun-Yuan Lu, En-Ning Zhang, Zhu-Gang Wang, Hong-Xin Zhang
Evidence indicated that inflammatory response and some pattern-recognition receptors play important roles in the occurrence and progression of osteoarthritis. This study is conducted to evaluate the role of RIG-I and its adaptor protein MAVS in the pathogenesis of osteoarthritis. Four SNPs in RIG-I gene and four in MAVS gene were genotyped in 1056 Chinese Han population. We also overexpressed MAVS in murine chondrogenic ATDC5 cells and analyzed the cell viability and apoptosis. Rs11795343 (P-allele: 0.063394) in RIG-I, rs17857295 (P-allele: 0...
February 2018: Aging and Disease
Natalia Zamorano Cuervo, Quentin Osseman, Nathalie Grandvaux
The mitochondrial antiviral signaling (MAVS) adaptor protein is a central signaling hub required for cells to mount an antiviral response following virus sensing by retinoic acid-inducible gene I (RIG-I)-like receptors. MAVS localizes in the membrane of mitochondria and peroxisomes and in mitochondrial-associated endoplasmic reticulum membranes. Structural and functional studies have revealed that MAVS activity relies on the formation of functional high molecular weight prion-like aggregates. The formation of protein aggregates typically relies on a dynamic transition between oligomerization and aggregation states...
January 30, 2018: Viruses
Julius C Fischer, Hendrik Poeck
No abstract text is available yet for this article.
December 29, 2017: Oncotarget
Hongjie Xia, Huanle Luo, Chao Shan, Antonio E Muruato, Bruno T D Nunes, Daniele B A Medeiros, Jing Zou, Xuping Xie, Maria Isabel Giraldo, Pedro F C Vasconcelos, Scott C Weaver, Tian Wang, Ricardo Rajsbaum, Pei-Yong Shi
Virus-host interactions determine an infection outcome. The Asian lineage of Zika virus (ZIKV), responsible for the recent epidemics, has fixed a mutation in the NS1 gene after 2012 that enhances mosquito infection. Here we report that the same mutation confers NS1 to inhibit interferon-β induction. This mutation enables NS1 binding to TBK1 and reduces TBK1 phosphorylation. Engineering the mutation into a pre-epidemic ZIKV strain debilitates the virus for interferon-β induction; reversing the mutation in an epidemic ZIKV strain invigorates the virus for interferon-β induction; these mutational effects are lost in IRF3-knockout cells...
January 29, 2018: Nature Communications
Janghyun Lee, Eun-Byeol Park, Jiyoun Min, Si-Eun Sung, Yejin Jang, Jin Soo Shin, Dongmin Chun, Ki-Hun Kim, Jihyun Hwang, Mi-Kyung Lee, Yun Young Go, Dohyeong Kwon, Meehyein Kim, Suk-Jo Kang, Byong-Seok Choi
Retinoic acid-inducible gene I (RIG-I) recognizes double-stranded viral RNAs (dsRNAs) containing two or three 5' phosphates. A few reports of 5'-PPP-independent RIG-I agonists have emerged, but little is known about the molecular principles underlying their recognition. We recently found that the bent duplex RNA from the influenza A panhandle promoter activates RIG-I even in the absence of a 5'-triphosphate moiety. Here, we report that non-canonical synthetic RNA oligonucleotides containing G-U wobble base pairs that form a bent helix can exert RIG-I-mediated antiviral and anti-tumor effects in a sequence- and site-dependent manner...
January 24, 2018: Nucleic Acids Research
Tadashi Maemura, Satoshi Fukuyama, Yukihiko Sugita, Tiago J S Lopes, Tomomi Nakao, Takeshi Noda, Yoshihiro Kawaoka
Exosomes regulate cell-cell communication by transferring functional proteins and RNAs between cells. Here, to clarify the function of exosomes during influenza virus infection, we characterized lung-derived exosomal microRNAs (miRNAs). Among the detected miRNAs, miR-483-3p was present at high levels in bronchoalveolar lavage fluid (BALF) exosomes during infection of mice with various strains of influenza virus, and miR-483-3p transfection potentiated gene expression of type I interferon and proinflammatory cytokine upon viral infection of MLE-12 cells...
January 24, 2018: Journal of Infectious Diseases
Hiroyasu Konno, Shota Yamauchi, Anders Berglund, Ryan M Putney, James J Mulé, Glen N Barber
The production of cytokines in response to DNA-damage events may be an important host defense response to help prevent the escape of pre-cancerous cells. The innate immune pathways involved in these events are known to be regulated by cellular molecules such as stimulator of interferon genes (STING), which controls type I interferon and pro-inflammatory cytokine production in response to the presence of microbial DNA or cytosolic DNA that has escaped from the nucleus. STING signaling has been shown to be defective in a variety of cancers, such as colon cancer and melanoma, actions that may enable damaged cells to escape the immunosurveillance system...
January 25, 2018: Oncogene
Yingying Cao, Ruiyuan Cao, Yaowei Huang, Hongxia Zhou, Yuanhua Liu, Xuan Li, Wu Zhong, Pei Hao
BACKGROUND: RNA editing is an important mechanism that expands the diversity and complexity of genetic codes. The conversions of adenosine (A) to inosine (I) and cytosine (C) to uridine (U) are two prominent types of RNA editing in animals. The roles of RNA editing events have been implicated in important biological pathways. Cellular RNA editing activity in response to influenza A virus infection has not been fully characterized in human and avian hosts. This study was designed as a big data analysis to investigate the role and response of RNA editing in epithelial cells during the course of infection with various subtypes of influenza A viruses...
January 19, 2018: BMC Genomics
Soham Gupta, Päivi Ylä-Anttila, Simone Callegari, Ming-Han Tsai, Henri-Jacques Delecluse, Maria G Masucci
The N-terminal domains of the herpesvirus large tegument proteins encode a conserved cysteine protease with ubiquitin- and NEDD8-specific deconjugase activity. The proteins are expressed during the productive virus cycle and are incorporated into infectious virus particles, being delivered to the target cells upon primary infection. Members of this viral enzyme family were shown to regulate different aspects of the virus life cycle and the innate anti-viral response. However, only few substrates have been identified and the mechanisms of these effects remain largely unknown...
January 22, 2018: PLoS Pathogens
Berengere Villeret, Alexandra Dieu, Marjolene Straube, Brigitte Solhonne, Pika Miklavc, Sena Hamadi, Rémi Le Borgne, Arnaud Mailleux, Xavier Norel, Joel Aerts, Devy Diallo, Francois Rouzet, Paul Dietl, Jean-Michel Sallenave, Ignacio Garcia-Verdugo
Silver nanoparticles (AgNPs) are microbicidal agents which could be potentially used as alternative to antivirals to treat human infectious diseases, especially Influenza virus infection where antivirals have generally proven unsuccessful. However, concerns about the use of AgNPs on humans arise from their potential toxicity, although mechanisms are not well-understood. We show here, in the context of Influenza virus infection of lung epithelial cells, that AgNPs down-regulated Influenza induced-CCL-5 and -IFN-β release (two cytokines important in anti-viral immunity) through RIG-I inhibition, while enhancing IL-8 production, a cytokine important for mobilizing host antibacterial responses...
January 22, 2018: ACS Nano
Annemarthe G van der Veen, Pierre V Maillard, Jan Marten Schmidt, Sonia A Lee, Safia Deddouche-Grass, Annabel Borg, Svend Kjær, Ambrosius P Snijders, Caetano Reis E Sousa
In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG-I-like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon-stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG-I, MDA5 and, the least-studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi)...
January 19, 2018: EMBO Journal
Christian R Palmer, Max E Jacobson, Olga Fedorova, Anna M Pyle, John T Wilson
Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern recognition receptor (PRR) that potently activates antiviral innate immunity upon recognition of 5' triphosphorylated double-stranded RNA (pppRNA). Accordingly, RNA ligands of the RIG-I pathway have recently emerged as promising antiviral agents, vaccine adjuvants, and cancer immunotherapeutics. However, RIG-I is expressed constitutively in virtually all cell types, and therefore administration of RIG-I agonists causes risk for systemic inflammation and possible dose-limiting toxicities...
January 19, 2018: Bioconjugate Chemistry
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