Hepatitis B virus (HBV) infection disrupt the innate immunity response, which may play an important role in the chronic mechanism, while retinoic acid-induced gene I (RIG-I) mediated signaling pathway is one of the most important channel in the innate immunity. HBx and HBV polymerase may disrupt RIG-I mediated signaling pathway. The recent advances about HBV and RIG-I are reviewed in this article.
DEAD Box Protein 58 ; DEAD-box RNA Helicases ; metabolism ; Gene Products, pol ; metabolism ; Hepatitis B ; immunology ; Humans ; Immunity, Innate ; immunology ; Signal Transduction ; Trans-Activators ; metabolism

Influenza A virus can create acute respiratory infection in humans and animals throughout the world, and it is still one of the major causes of morbidity and mortality in humans worldwide. Numerous studies have shown that influenza A virus infection induces rapidly host innate immune response. Influenza A virus triggers the activation of signaling pathways that are dependent on host pattern recognition receptors (PRRs) including toll like receptors (TLRs) and RIG-I like receptors (RLRs). Using a variety of regulatory mechanisms, these signaling pathways activate downstream transcript factors that control expression of various interferons and cytokines, such as type I and type III interferons. Thus, these interferons stimulate the transcript of relevant interferon-stimulated genes (ISGs) and expression of the antiviral proteins, which are critical components of host innate immunity. In this review, we will highlight the mechanisms by which influenza A virus infection induces the interferon-mediated host innate immunity.
Cytokines ; immunology ; DEAD Box Protein 58 ; DEAD-box RNA Helicases ; immunology ; Humans ; Immunity, Innate ; Influenza A virus ; Influenza, Human ; immunology ; Interferons ; immunology ; Receptors, Pattern Recognition ; immunology ; Signal Transduction ; Toll-Like Receptors ; immunology

RIG-I-like receptors (RLRs) belong to pattern recognition receptors, which perform significant roles in antiviral responses. RLRs can initiate a cascade of signaling transduction that induces the production of type I interferon and activates the interferon signaling pathway, ultimately resulting in antiviral responses. In the course of evolution, viruses have been constantly counteracting host immune systems to facilitate their own survival and replication, and have developed a set of antagonistic strategies. These mainly comprise elusion, disguise and attack strategies to eliminate the activation of RLRs. In virus-infected cells, RLRs recognize viral RNA and then induce antiviral responses. A better understanding of viral antagonistic strategies against RLRs will provide insights into the development of new antiviral medicines. This mini-review concludes that there are three main antagonistic strategies by which RNA viruses can counteract the activation of the RLRs pathway. It aims to provide references and insights for similar studies on viral antagonism in an array of RNA viruses.
DEAD Box Protein 58 ; DEAD-box RNA Helicases ; genetics ; immunology ; Host-Pathogen Interactions ; Humans ; RNA Viruses ; genetics ; immunology ; physiology ; RNA, Double-Stranded ; genetics ; immunology ; RNA, Viral ; genetics ; immunology ; Virus Diseases ; genetics ; immunology ; virology

The innate immune response is the first line of host defense to eliminate viral infection. Pattern recognition receptors in the cytosol, such as RIG-I-like receptors (RLR) and Nod-like receptors (NLR), and membrane bound Toll like receptors (TLR) detect viral infection and initiate transcription of a cohort of antiviral genes, including interferon (IFN) and interferon stimulated genes (ISGs), which ultimately block viral replication. Another mechanism to reduce viral spread is through RIPA, the RLR-induced IRF3-mediated pathway of apoptosis, which causes infected cells to undergo premature death. The transcription factor IRF3 can mediate cellular antiviral responses by both inducing antiviral genes and triggering apoptosis through the activation of RIPA. The mechanism of IRF3 activation in RIPA is distinct from that of transcriptional activation; it requires linear polyubiquitination of specific lysine residues of IRF3. Using RIPA-active, but transcriptionally inactive, IRF3 mutants, it was shown that RIPA can prevent viral replication and pathogenesis in mice.
Animals ; Apoptosis ; DEAD Box Protein 58 ; genetics ; immunology ; metabolism ; Humans ; Immunity, Innate ; Interferon Regulatory Factor-3 ; genetics ; immunology ; metabolism ; Mice ; Virus Diseases ; genetics ; immunology ; metabolism

Retinoic acid-inducible gene-I (RIG-I) functions as an intracellular pattern recognition receptor (PRR) that recognizes the 5'-triphosphate moiety of single-stranded RNA viruses to initiate the innate immune response. Previous studies have shown that Lys63-linked ubiquitylation is required for RIG-I activation and the downstream anti-viral type I interferon (IFN-I) induction. Herein we reported that, RIG-I was also modified by small ubiquitin-like modifier-1 (SUMO-1). Functional analysis showed that RIG-I SUMOylation enhanced IFN-I production through increased ubiquitylation and the interaction with its downstream adaptor molecule Cardif. Our results therefore suggested that SUMOylation might serve as an additional regulatory tier for RIG-I activation and IFN-I signaling.
Adaptor Proteins, Signal Transducing ; physiology ; Base Sequence ; Binding Sites ; DEAD Box Protein 58 ; DEAD-box RNA Helicases ; chemistry ; genetics ; immunology ; physiology ; DNA Primers ; genetics ; Gene Knockdown Techniques ; HEK293 Cells ; HeLa Cells ; Humans ; Immunity, Innate ; Interferon Type I ; immunology ; physiology ; RNA Interference ; SUMO-1 Protein ; physiology ; Sendai virus ; immunology ; Signal Transduction ; Sumoylation ; Ubiquitin-Conjugating Enzymes ; antagonists & inhibitors ; genetics ; physiology

Tripartite motif (TRIM) family proteins are important effectors of innate immunity against viral infections. Here we identified TRIM35 as a regulator of TRAF3 activation. Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon (IFN) in response to viral infection. Trim35-deficient mice were more susceptible to influenza A virus (IAV) infection than were wild-type mice. TRIM35 promoted the RIG-I-mediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1. IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3. TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2, thereby antagonizing its suppression of TRAF3 activation. Our in vitro and in vivo findings thus reveal novel roles of TRIM35, through catalyzing Lys63- or Lys48-linked polyubiquitination, in RIG-I antiviral immunity and mechanism of defense against IAV infection.
A549 Cells ; Animals ; Apoptosis Regulatory Proteins/immunology* ; DEAD Box Protein 58/immunology* ; Dogs ; HEK293 Cells ; Humans ; Influenza A Virus, H1N1 Subtype/immunology* ; Madin Darby Canine Kidney Cells ; Mice ; Mice, Knockout ; Orthomyxoviridae Infections/pathology* ; Proteolysis ; RAW 264.7 Cells ; Signal Transduction/immunology* ; THP-1 Cells ; TNF Receptor-Associated Factor 3/immunology* ; Ubiquitination/immunology* ; Viral Proteins/immunology*

Hepatitis B virus (HBV) is regarded as a stealth virus, invading and replicating efficiently in human liver undetected by host innate antiviral immunity. Here, we show that type I interferon (IFN) induction but not its downstream signaling is blocked by HBV replication in HepG2.2.15 cells. This effect may be partially due to HBV X protein (HBx), which impairs IFNβ promoter activation by both Sendai virus (SeV) and components implicated in signaling by viral sensors. As a deubiquitinating enzyme (DUB), HBx cleaves Lys63-linked polyubiquitin chains from many proteins except TANK-binding kinase 1 (TBK1). It binds and deconjugates retinoic acid-inducible gene I (RIG I) and TNF receptor-associated factor 3 (TRAF3), causing their dissociation from the downstream adaptor CARDIF or TBK1 kinase. In addition to RIG I and TRAF3, HBx also interacts with CARDIF, TRIF, NEMO, TBK1, inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon (IKKi) and interferon regulatory factor 3 (IRF3). Our data indicate that multiple points of signaling pathways can be targeted by HBx to negatively regulate production of type I IFN.
Animals ; B-Lymphocytes ; immunology ; metabolism ; Cell Line ; DEAD Box Protein 58 ; DEAD-box RNA Helicases ; antagonists & inhibitors ; immunology ; metabolism ; Hep G2 Cells ; Hepatitis B virus ; immunology ; metabolism ; Humans ; I-kappa B Kinase ; antagonists & inhibitors ; immunology ; metabolism ; Immune Evasion ; Immunity, Innate ; Interferon Regulatory Factor-3 ; antagonists & inhibitors ; immunology ; metabolism ; Interferon Type I ; antagonists & inhibitors ; immunology ; metabolism ; Mice ; Molecular Targeted Therapy ; Polyubiquitin ; antagonists & inhibitors ; metabolism ; Protein Binding ; immunology ; Sendai virus ; immunology ; metabolism ; Signal Transduction ; immunology ; TNF Receptor-Associated Factor 3 ; antagonists & inhibitors ; immunology ; metabolism ; Trans-Activators ; immunology ; metabolism

Cytosolic retinoic acid-inducible gene I (RIG-I) is an important innate immune RNA sensor and can induce antiviral cytokines, e.g., interferon-β (IFN-β). Innate immune response to hepatitis B virus (HBV) plays a pivotal role in viral clearance and persistence. However, knowledge of the role that RIG-I plays in HBV infection is limited. The woodchuck is a valuable model for studying HBV infection. To characterize the molecular basis of woodchuck RIG-I (wRIG-I), we analyzed the complete coding sequences (CDSs) of wRIG-I, containing 2778 base pairs that encode 925 amino acids. The deduced wRIG-I protein was 106.847 kD with a theoretical isoelectric point (pI) of 6.07, and contained three important functional structures [caspase activation and recruitment domains (CARDs), DExD/H-box helicases, and a repressor domain (RD)]. In woodchuck fibroblastoma cell line (WH12/6), wRIG-I-targeted small interfering RNA (siRNA) down-regulated RIG-I and its downstrean effector-IFN-β transcripts under RIG-I' ligand, 5'-ppp double stranded RNA (dsRNA) stimulation. We also measured mRNA levels of wRIG-I in different tissues from healthy woodchucks and in the livers from woodchuck hepatitis virus (WHV)-infected woodchucks. The basal expression levels of wRIG-I were abundant in the kidney and liver. Importantly, wRIG-I was significantly up-regulated in acutely infected woodchuck livers, suggesting that RIG-I might be involved in WHV infection. These results may characterize RIG-I in the woodchuck model, providing a strong basis for further study on RIG-I-mediated innate immunity in HBV infection.
Animals ; Cell Line, Tumor ; Cloning, Molecular ; DEAD Box Protein 58 ; antagonists & inhibitors ; genetics ; immunology ; Fibroblasts ; immunology ; pathology ; Gene Expression ; Hepatitis B ; genetics ; immunology ; pathology ; veterinary ; Hepatitis B Virus, Woodchuck ; Immunity, Innate ; Interferon-beta ; genetics ; immunology ; Isoelectric Point ; Kidney ; immunology ; pathology ; virology ; Liver ; immunology ; pathology ; virology ; Marmota ; genetics ; immunology ; virology ; Open Reading Frames ; Protein Domains ; RNA, Double-Stranded ; RNA, Small Interfering ; genetics ; metabolism ; Rodent Diseases ; genetics ; immunology ; pathology ; virology

OBJECTIVETo observe the anti-virus effects of andrographolide (AD) on the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) signaling pathway when immunological cells were infected with H1N1.

METHODSLeukomonocyte was obtained from umbilical cord blood by Ficoll density gradient centrifugation, and immunological cells were harvested after cytokines stimulation. Virus infected cell model was established by H1N1 co-cultured with normal human bronchial epithelial cell line (16HBE). The optimal concentration of AD was defined by methyl-thiazolyl-tetrazolium (MTT) assay. After the virus infected cell model was established, AD was added into the medium as a treatment intervention. After 24-h co-culture, cell supernatant was collected for interferon gamma (IFN-γ) and interleukin-4 (IL-4) enzyme-linked immunosorbent assay (ELISA) detection while immunological cells for real-time polymerase chain reaction (RT-PCR).

RESULTSThe optimal concentration of AD for anti-virus effect was 250 μg/mL. IL-4 and IFN-γ in the supernatant and mRNA levels in RLRs pathway increased when cells was infected by virus, RIG-I, IFN-β promoter stimulator-1 (IPS-1), interferon regulatory factor (IRF)-7, IRF-3 and nuclear transcription factor κB (NF-κB) mRNA levels increased significantly (P<0.05). When AD was added into co-culture medium, the levels of IL-4 and IFN-γ were lower than those in the non-interference groups and the mRNA expression levels decreased, RIG-I, IPS-1, IRF-7, IRF-3 and NF-κB decreased significantly in each group with significant statistic differences (P<0.05).

CONCLUSIONSThe RLRs mediated viral recognition provided a potential molecular target for acute viral infections and andrographolide could ameliorate H1N1 virus-induced cell mortality. And the antiviral effects might be related to its inhibition of viral-induced activation of the RLRs signaling pathway.

Adaptor Proteins, Signal Transducing ; genetics ; metabolism ; Antiviral Agents ; pharmacology ; Cells, Cultured ; Coculture Techniques ; DEAD Box Protein 58 ; DEAD-box RNA Helicases ; genetics ; metabolism ; Dendritic Cells ; drug effects ; immunology ; virology ; Diterpenes ; pharmacology ; Fetal Blood ; cytology ; Humans ; Influenza A Virus, H1N1 Subtype ; drug effects ; immunology ; Influenza, Human ; drug therapy ; immunology ; virology ; Interferon-beta ; genetics ; metabolism ; Interferon-gamma ; metabolism ; Interleukin-4 ; metabolism ; Leukocytes, Mononuclear ; drug effects ; immunology ; virology ; Macrophages ; drug effects ; virology ; NF-kappa B ; genetics ; metabolism ; Promoter Regions, Genetic ; drug effects ; immunology ; RNA, Messenger ; metabolism ; Signal Transduction ; drug effects ; genetics ; immunology