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X Mu, S Ahmad, S Hur
The ability to distinguish between self and nonself is the fundamental basis of the immune system in all organisms. The conceptual distinction between self and nonself, however, breaks down when it comes to endogenous retroviruses and other retroelements. While some retroelements retain the virus-like features including the capacity to replicate and reinvade the host genome, most have become inactive through mutations or host epigenetic silencing. And yet, accumulating evidence suggests that endogenous retroelements, both active and inactive, play important roles not only in pathogenesis of immune disorders, but also in proper functioning of the immune system...
2016: Advances in Immunology
Stefanie Luecke, Søren R Paludan
Nucleic acids sensors of the innate immune system recognize various RNA and DNA structures during infection to induce transcription of interferon and pro-inflammatory cytokines and activation of inflammasomes. Cytosolic RNA is recognized by RIG-I and MDA5, while intracellular DNA is sensed among others by cGAS, AIM2, IFI16 and RNA polymerase III. The diversity of nucleic acid species produced during infection in the cytosol and nucleus and the limited chemical differences between self and non-self nucleic acids challenge the host's innate pattern recognition system to ensure reliable sensing while avoiding immune activation by self nucleic acids...
October 14, 2016: Cytokine
Shun Li, Long-Feng Lu, Scott E LaPatra, Dan-Dan Chen, Yong-An Zhang
The aquatic spring viremia of carp virus (SVCV) causes significant mortality in common carp (Cyprinus carpio), and TBK1 plays a crucial role in the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) system by phosphorylating its substrates to induce type I interferons (IFNs) and cellular antiviral responses. In this study, we report that zebrafish STAT6 is induced during SVCV infection and reduces IFNφ1 expression by suppressing TBK1 phosphorylation. A typical IFN stimulatory response element (ISRE) motif was found in the promoter region of zebrafish STAT6, and zebrafish STAT6 transcription was significantly upregulated in the early stages of virus infection...
October 12, 2016: Developmental and Comparative Immunology
Akihiko Komuro, Yuya Homma, Takaharu Negoro, Glen N Barber, Curt M Horvath
LGP2 and MDA5 cooperate to detect viral RNA in the cytoplasm of Picornavirus-infected cells and activate innate immune responses. To further define regulatory components of RNA recognition by LGP2/MDA5, a yeast two-hybrid screen was used to identify LGP2-interacting proteins. The screening has identified the TAR-RNA binding protein (TRBP), which is known to be an essential factor for RNA interference (RNAi). Immuno-precipitation experiments demonstrated that TRBP interacted specifically with LGP2 but not with related RIG-I-like receptors, RIG-I or MDA5...
October 12, 2016: Biochemical and Biophysical Research Communications
Diana M Giraldo, Juan C Hernandez, Silvio Urcuqui-Inchima
Neutrophils are key effector cells of the innate immune system and are involved in the host defense against invading pathogens such as viruses. Recently, it was reported that HIV-1-neutrophil interaction triggers neutrophil activation and promotes expression of Toll-like receptors (TLRs). Here, we assessed the role of single-stranded RNA40 (ssRNA40) derived from HIV-1 in neutrophil activation. We observed functional activation of neutrophils in response to HIV-1-derived ssRNA40 based on the expression of TLR7/8, RIG-I, and MDA5, induction of cytokines (IL-6 and TNF-α), and the production of reactive oxygen species (ROS)...
October 7, 2016: Immunologic Research
Ning Li, Tianqi Hong, Rong Li, Yao Wang, Mengjiao Guo, Zongxi Cao, Yumei Cai, Sidang Liu, Tongjie Chai, Liangmeng Wei
Mitochondrial antiviral-signaling protein (MAVS), an adaptor protein of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)-mediated signal pathway, is involved in innate immunity. In this study, Cherry Valley duck MAVS (duMAVS) was cloned from the spleen and analyzed. duMAVS was determined to have a caspase activation and recruitment domain at N-terminal, followed by a proline-rich domain and a transmembrane domain at C-terminal. Quantitative real-time PCR indicated that duMAVS was expressed in all tissues tested across a broad expression spectrum...
2016: Frontiers in Immunology
Zixiang Zhu, Guoqing Wang, Fan Yang, Weijun Cao, Ruoqing Mao, Xiaoli Du, Xiangle Zhang, Chuntian Li, Dan Li, Keshan Zhang, Hongbing Shu, Xiangtao Liu, Haixue Zheng
: The role of retinoic acid-inducible gene I (RIG-I) in foot-and-mouth disease virus (FMDV)-infected cells remains unknown. Herein, we showed that RIG-I inhibits FMDV replication in host cells. FMDV infection increased the transcription of RIG-I, while it decreased RIG-I protein expression. A detailed analysis revealed that FMDV leader proteinase (L(pro)), as well as 3C proteinase (3C(pro)) and 2B protein, decreased RIG-I protein expression. L(pro) and 3C(pro) are viral proteinases that can cleave various host proteins and are responsible for several of the viral polyprotein cleavages...
October 5, 2016: Journal of Virology
Claire L Donald, Benjamin Brennan, Stephanie L Cumberworth, Veronica V Rezelj, Jordan J Clark, Marli T Cordeiro, Rafael Freitas de Oliveira França, Lindomar J Pena, Gavin S Wilkie, Ana Da Silva Filipe, Christopher Davis, Joseph Hughes, Margus Varjak, Martin Selinger, Luíza Zuvanov, Ania M Owsianka, Arvind H Patel, John McLauchlan, Brett D Lindenbach, Gamou Fall, Amadou A Sall, Roman Biek, Jan Rehwinkel, Esther Schnettler, Alain Kohl
BACKGROUND: The outbreak of Zika virus (ZIKV) in the Americas has transformed a previously obscure mosquito-transmitted arbovirus of the Flaviviridae family into a major public health concern. Little is currently known about the evolution and biology of ZIKV and the factors that contribute to the associated pathogenesis. Determining genomic sequences of clinical viral isolates and characterization of elements within these are an important prerequisite to advance our understanding of viral replicative processes and virus-host interactions...
October 2016: PLoS Neglected Tropical Diseases
Wanwan Huai, Hui Song, Zhongxia Yu, Wenwen Wang, Lihui Han, Takeharu Sakamoto, Motoharu Seiki, Lining Zhang, Qunye Zhang, Wei Zhao
Type I IFNs (IFN-α/β) play crucial roles in the elimination of invading viruses. Multiple immune cells including macrophages recognize viral infection through a variety of pattern recognition receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors, and initiate type I IFN secretion and subsequent antiviral immune responses. However, the mechanisms by which host immune cells can produce adequate amounts of type I IFNs and then eliminate viruses effectively remain to be further elucidated...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Naomi I Maria, Eline C Steenwijk, Arne S IJpma, Cornelia G van Helden-Meeuwsen, Petra Vogelsang, Wouter Beumer, Zana Brkic, Paul L A van Daele, P Martin van Hagen, Peter J van der Spek, Hemmo A Drexhage, Marjan A Versnel
OBJECTIVE: The interferon (IFN) type I signature is present in over half of patients with primary Sjögren's syndrome (pSS) and associated with higher disease-activity and autoantibody presence. Plasmacytoid dendritic cells (pDCs) are considered as the main source of enhanced IFN type I expression. The objective of this study was to unravel the molecular pathways underlying IFN type I bioactivity in pDCs of patients with pSS. METHODS: Blood samples from 42 healthy controls (HC) and 115 patients with pSS were stratified according to their IFN type I signature...
September 26, 2016: Annals of the Rheumatic Diseases
Ryo Hayakari, Tomoh Matsumiya, Fei Xing, Hidemi Yoshida, Makoto Hayakari, Tadaatsu Imaizumi
The cytoplasmic viral sensor retinoic acid-inducible gene-I (RIG-I), which is also known as an IFN-stimulated gene (ISG), senses viral RNA to activate antiviral signaling. It is therefore thought that RIG-I is regulated in a STAT1-dependent manner. Although RIG-I-mediated antiviral signaling is indispensable for the induction of an appropriate adaptive immune response, the mechanism underlying the regulation of RIG-I expression remains elusive. Here, we examined the direct regulation of RIG-I expression by interferon regulatory factor 3 (IRF-3), which is an essential molecule for antiviral innate immunity...
2016: PloS One
Magdalena Zurawek, Marta Fichna, Marta Kazimierska, Piotr Fichna, Agnieszka Dzikiewicz-Krawczyk, Grzegorz Przybylski, Marek Ruchala, Jerzy Nowak
Mitochondrial antiviral signaling (MAVS) protein is an intracellular adaptor molecule, downstream of viral sensors, retinoid acid-inducible gene I (RIG-I)-like receptors (RLRs). Impaired antiviral cell signaling might contribute to autoimmunity. Studies have recently shown variations in genes encoding RLRs as risk factors for autoimmune diseases. We investigated whether MAVS coding polymorphisms are associated with Addison's disease (AD) and type 1 diabetes (T1D) in Polish population. We genotyped 140 AD, 532 T1D patients and 600 healthy controls for MAVS rs17857295, rs7262903, rs45437096 and rs7269320...
September 20, 2016: Archivum Immunologiae et Therapiae Experimentalis
Ann Fiegen Durbin, Chen Wang, Joseph Marcotrigiano, Lee Gehrke
UNLABELLED: Invading pathogen nucleic acids are recognized and bound by cytoplasmic (retinoic acid-inducible gene I [RIG-I]-like) and membrane-bound (Toll-like) pattern recognition receptors to activate innate immune signaling. Modified nucleotides, when present in RNA molecules, diminish the magnitude of these signaling responses. However, mechanisms explaining the blunted signaling have not been elucidated. In this study, we used several independent biological assays, including inhibition of virus replication, RIG-I:RNA binding assays, and limited trypsin digestion of RIG-I:RNA complexes, to begin to understand how RNAs containing modified nucleotides avoid or suppress innate immune signaling...
2016: MBio
Tadaatsu Imaizumi, Chikashi Yano, Akiko Numata, Koji Tsugawa, Ryo Hayakari, Tomoh Matsumiya, Hidemi Yoshida, Shojiro Watanabe, Kazushi Tsuruga, Shogo Kawaguchi, Manabu Murakami, Hiroshi Tanaka
BACKGROUND/AIMS: Activation of Toll-like receptor 3 (TLR3) signaling followed by type I interferon (IFN) expression is crucial in antiviral and "pseudoviral" immune reactions in renal mesangial cells (MCs). These reactions are probably involved in the pathogenesis of chronic kidney disease (CKD). However, the role of IFN-induced 35-kDa protein 35 (IFI35), a type I IFN-dependent transcript, in glomerular inflammation is unclear. Here, we aimed to investigate the expression and the role of IFI35 in IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5 and IFN-β/melanoma differentiation-associated gene 5 (MDA5)/CXCL10 axes in MCs...
September 17, 2016: Kidney & Blood Pressure Research
Jingjing Han, Yanjin Wang, Qing Chu, Tianjun Xu
The laboratory of genetics and physiology 2 (LGP2) is a member of retinoic acid-inducible gene I (RIG-I)-like receptors (RLR receptors), which may participate in the immune regulation process. The role of LGP2 on modulating signaling was ambiguous, some researchers suggested that the regulation mechanism of LGP2 to melanoma differentiation-associated gene 5 (MDA5) and retinoic acid inducible gene-I (RIG-I) were different. In this study, the bioinformatics and functions of LGP2 from miiuy croaker (mmLGP2) were characterized...
September 13, 2016: Fish & Shellfish Immunology
Mohammad Diab, Alon Vitenshtein, Yaron Drori, Rachel Yamin, Oded Danziger, Rachel Zamostiano, Michal Mandelboim, Eran Bacharach, Ofer Mandelboim
The innate sensing system is equipped with PRRs specialized in recognizing molecular structures (PAMPs) of various pathogens. This leads to the induction of anti-viral genes and inhibition of virus growth. Human Metapneumovirus (HMPV) is a major respiratory virus that causes an upper and lower respiratory tract infection in children. In this study we show that upon HMPV infection, the innate sensing system detects the viral RNA through the RIG-I sensor leading to induction of CEACAM1 expression. We further show that CEACAM1 is induced via binding of IRF3 to the CEACAM1 promoter...
September 12, 2016: Oncotarget
Ning Chen, Xingzhi Li, Pengfei Li, Ziye Pan, Yun Ding, Dehua Zou, Liang Zheng, Yating Zhang, Liyang Li, Lijie Xiao, Baifen Song, Yudong Cui, Hongwei Cao, Hua Zhang
Enterovirus 71 (EV71) is a human pathogen that induces hand, foot, and mouth disease (HFMD) and fatal neurological diseases in young children and infants. Pathogenicity of EV71 is likely related to its ability to evade host innate immunity through inhibiting cellular type I interferon signaling. However, it is less well understood the molecular events governing this process. In this study, we found that EV71 infection suppressed the induction of antiviral immunity by inhibiting the expression levels of IFN-β and IFN-stimulated genes (ISGs), such as ISG54 and ISG56, at the late stage of viral infection...
September 12, 2016: Microbial Pathogenesis
Zhongying Cao, Zhangchuan Xia, Yaqin Zhou, Xiaodan Yang, Hua Hao, Nanfang Peng, Shi Liu, Ying Zhu
RNA virus infections are detected by the RIG-I family of receptors, which signal through the adaptor molecule mitochondrial antiviral signaling (MAVS). MAVS then recruits the adaptor's tumor necrosis factor receptor-associated factor (TRAF) 3 and TRAF6, which in turn activate IRF3 and NF-κB, respectively, to induce interferons (IFNs) and inflammatory responses. Here we show that the biotin-containing enzyme methylcrotonoyl-CoA carboxylase 1 (MCCC1) enhances virus-induced, MAVS-mediated IFN and inflammatory cytokine expression through the NF-κB signaling pathway...
2016: Scientific Reports
Megan E Fitzgerald, David C Rawling, Olga Potapova, Xiaoming Ren, Andrew Kohlway, Anna Marie Pyle
RIG-I is an innate immune receptor that detects and responds to infection by deadly RNA viruses such as influenza, and Hepatitis C. In the cytoplasm, RIG-I is faced with a difficult challenge: it must sensitively detect viral RNA while ignoring the abundance of host RNA. It has been suggested that RIG-I has a 'proof-reading' mechanism for rejecting host RNA targets, and that disruptions of this selectivity filter give rise to autoimmune diseases. Here, we directly monitor RNA proof-reading by RIG-I and we show that it is controlled by a set of conserved amino acids that couple RNA and ATP binding to the protein (Motif III)...
September 12, 2016: Nucleic Acids Research
Ling Xu, Dandan Yu, Yu Fan, Li Peng, Yong Wu, Yong-Gang Yao
The function of the RIG-I-like receptors (RLRs; including RIG-I, MDA5, and LGP2) as key cytoplasmic sensors of viral pathogen-associated molecular patterns (PAMPs) has been subjected to numerous pathogenic challenges and has undergone a dynamic evolution. We found evolutionary evidence that RIG-I was lost in the Chinese tree shrew lineage. Along with the loss of RIG-I, both MDA5 (tMDA5) and LGP2 (tLGP2) have undergone strong positive selection in the tree shrew. tMDA5 or tMDA5/tLGP2 could sense Sendai virus (an RNA virus posed as a RIG-I agonist) for inducing type I IFN, although conventional RIG-I and MDA5 were thought to recognize distinct RNA structures and viruses...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
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