The Experts below are selected from a list of 2556 Experts worldwide ranked by ideXlab platform
David L Woodland - One of the best experts on this subject based on the ideXlab platform.
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protection from respiratory Virus Infections can be mediated by antigen specific cd4 t cells that persist in the lungs
Journal of Experimental Medicine, 2001Co-Authors: Robert J Hogan, Edward J Usherwood, Weimin Zhong, Alan D Roberts, Tres Cookenham, David L WoodlandAbstract:Although CD4+ T cells have been shown to mediate protective cellular immunity against respiratory Virus Infections, the underlying mechanisms are poorly understood. For example, although phenotypically distinct populations of memory CD4+ T cells have been identified in different secondary lymphoid tissues, it is not known which subpopulations mediate protective cellular immunity. In this report, we demonstrate that Virus-specific CD4+ T cells persist in the lung tissues and airways for several months after Sendai Virus Infection of C57BL/6 mice. A large proportion of these cells possess a highly activated phenotype (CD44hi, CD62Llo, CD43hi, and CD25hi) and express immediate effector function as indicated by the production of interferon γ after a 5-h restimulation in vitro. Furthermore, intratracheal adoptive transfer of lung memory cells into β2m-deficient mice demonstrated that lung-resident Virus-specific CD4+ T cells mediated a substantial degree of protection against secondary Virus Infection. Taken together, these data demonstrate that activated memory CD4+ T cells persisting at mucosal sites play a critical role in mediating protective cellular immunity.
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activated antigen specific cd8 t cells persist in the lungs following recovery from respiratory Virus Infections
Journal of Immunology, 2001Co-Authors: Robert J Hogan, Edward J Usherwood, Weimin Zhong, Alan D Roberts, Richard W Dutton, Allen G Harmsen, David L WoodlandAbstract:The poor correlation between cellular immunity to respiratory Virus Infections and the numbers of memory CD8 + T cells in the secondary lymphoid organs suggests that there may be additional reservoirs of T cell memory to this class of Infection. Here we identify a substantial population of Ag-specific T cells in the lung that persist for several months after recovery from an influenza or Sendai Virus Infection. These cells are present in high numbers in both the airways and lung parenchyma and can be distinguished from memory cell populations in the spleen and peripheral lymph nodes in terms of the relative frequencies among CD8 + T cells, activation status, and kinetics of persistence. In addition, these cells are functional in terms of their ability to proliferate, express cytolytic activity, and secrete cytokines, although they do not express constitutive cytolytic activity. Adoptive transfer experiments demonstrated that the long-term establishment of activated T cells in the lung did not require Infection in the lung by a pathogen carrying the inducing Ag. The kinetics of persistence of Ag-specific CD8 + T cells in the lung suggests that they play a key role in protective cellular immunity to respiratory Virus Infections.
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functionally heterogeneous cd8 t cell memory is induced by Sendai Virus Infection of mice
Journal of Virology, 1999Co-Authors: Edward J Usherwood, Robert J Hogan, David L Woodland, Twala L Hogg, Graham Crowther, Sherri L Surman, John D AltmanAbstract:It has recently been established that memory CD8(+) T cells induced by viral Infection are maintained at unexpectedly high frequencies in the spleen. While it has been established that these memory cells are phenotypically heterogeneous, relatively little is known about the functional status of these cells. Here we investigated the proliferative potential of CD8(+) memory T cells induced by Sendai Virus Infection. High frequencies of CD8(+) T cells specific for both dominant and subdominant Sendai Virus epitopes persisted for many weeks after primary Infection, and these cells were heterogeneous with respect to CD62L expression (approximately 20% CD62L(hi) and 80% CD62L(lo)). Reactivation of these cells with the antigenic peptide in vitro induced strong proliferation of antigen-specific CD8(+) T cells. However, approximately 20% of the cells failed to proliferate in vitro in response to a cognate peptide but nevertheless differentiated into effector cells and acquired full cytotoxic potential. These cells also expressed high levels of CD62L (in marked contrast to the CD62L(lo) status of the proliferating cells in the culture). Direct isolation of CD62L(hi) and CD62L(lo) CD8(+) T cells from memory mice confirmed the correlation of this marker with proliferative potential. Taken together, these data demonstrate that Sendai Virus Infection induces high frequencies of memory CD8(+) T cells that are highly heterogeneous in terms of both their phenotype and their proliferative potential.
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induction of cd8 t cell responses to dominant and subdominant epitopes and protective immunity to Sendai Virus Infection by dna vaccination
Journal of Immunology, 1998Co-Authors: Yongjin Chen, Robert G Webster, David L WoodlandAbstract:While recent studies have demonstrated that DNA vaccination induces potent CD8 + T cell memory in vivo, it is unclear whether this memory is qualitatively and quantitatively comparable with that induced by natural viral Infection. In the current studies, we have investigated the induction of CD8 + memory CTL responses to Sendai Virus nucleoprotein (NP) in C57BL/6 mice following gene gun vaccination. The data demonstrate that this mode of vaccination induces potent long-lived memory CTL precursors (CTLp) specific for both the dominant (NP 324–332 /K b ) and the subdominant (NP 324–332 /D b ) epitopes of NP. The frequencies of T cells specific for each of these epitopes in the spleen is about 1:2000 CD8 + T cells, similar to those induced by intranasal Infection with Sendai Virus. Moreover, the induction of memory CTLp by DNA vaccination is independent of MHC class II molecules or Ab, as is the case for memory CTLp induction by live Sendai Virus Infection. CTLp specific for both epitopes are capable of migrating to the lung following Sendai Virus Infection and express potent cytotoxic activity at the site of Infection. Consistent with this activity, DNA vaccination with Sendai Virus NP induced a substantial degree of Ab-independent protection from a challenge with a lethal dose of Sendai Virus. Taken together, these data demonstrate that for the parameters tested, DNA vaccination is indistinguishable from live Virus Infection in terms of priming functional memory CTLp with broad specificity for both dominant and subdominant T cell epitopes.
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efficient priming of cd8 memory t cells specific for a subdominant epitope following Sendai Virus Infection
Journal of Immunology, 1997Co-Authors: G A Cole, Twala L Hogg, M A Coppola, David L WoodlandAbstract:The relationship between the primary effector CTL response to viral Infection and the subsequent pool of memory CTL precursors (CTLp) is poorly understood. Here, we have analyzed the induction of both effector CTL and memory CTLp to dominant and subdominant epitopes following Sendai Virus Infection of C57BL/6 mice. A single peptide derived from the Sendai Virus nucleoprotein (NP(324-332)) binds to both H-2 Kb and Db MHC class I molecules, generating both immunodominant (NP(324-332)/Kb) and subdominant (NP(324-332)/Db) epitopes. Following intranasal Sendai Virus Infection, NP(324-332)/Kb-specific CTL dominated the primary effector CTL response in the lung and were present at high frequency in the memory CTLp pool. In contrast, NP(324-332)/Db-specific CTL were not a detectable component of the effector response to primary Sendai Virus Infection. However, memory CTLp specific for this subdominant epitope were induced at frequencies approaching those of CTLp specific for the immunodominant epitope. These data indicate that memory CTLp specific for subdominant epitopes can be primed by Sendai Virus Infection in the absence of a detectable effector response. To determine whether CTLp memory to subdominant epitopes is functional in the context of Sendai Virus Infection, memory CTLp specific for a subdominant epitope were selectively primed by vaccination. These cells dominated the subsequent effector CTL response to Sendai Virus Infection, demonstrating that memory CTLp primed against subdominant epitopes can participate in an immune response and effectively compete with T cells specific for immunodominant epitopes. These data have implications for the development of vaccines designed to emphasize cellular immunity.
Curt M Horvath - One of the best experts on this subject based on the ideXlab platform.
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Sendai Virus Infection induces expression of novel rnas in human cells
Scientific Reports, 2018Co-Authors: Roli Mandhana, Curt M HorvathAbstract:Innate antiviral immune responses are driven by Virus-induced changes in host gene expression. While much research on antiviral effectors has focused on Virus-inducible mRNAs, recent genome-wide analyses have identified hundreds of novel target sites for Virus-inducible transcription factors and RNA polymerase. These sites are beyond the known antiviral gene repertoire and their contribution to innate immune responses is largely unknown. In this study, RNA-sequencing of mock-infected and Sendai Virus-infected cells was performed to characterize the Virus-inducible transcriptome and identify novel Virus-inducible RNAs (nviRNAs). Virus-inducible transcription was observed throughout the genome resulting in expression of 1755 previously RefSeq-annotated RNAs and 1545 nviRNAs. The previously-annotated RNAs primarily consist of protein-coding mRNAs, including several well-known antiviral mRNAs that had low sequence conservation but were highly Virus-inducible. The previously-unannotated nviRNAs were mostly noncoding RNAs with poor sequence conservation. Independent analyses of nviRNAs based on Infection with Sendai Virus, influenza Virus, and herpes simplex Virus 1, or direct stimulation with IFNα revealed a range of expression patterns in various human cell lines. These phylogenetic and expression analyses suggest that many of the nviRNAs share the high inducibility and low sequence conservation characteristic of well-known primary antiviral effectors and may represent dynamically evolving antiviral factors.
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microrna profiling of Sendai Virus infected a549 cells identifies mir 203 as an interferon inducible regulator of ifit1 isg56
Journal of Virology, 2013Co-Authors: William A Buggele, Curt M HorvathAbstract:The mammalian type I interferon (IFN) response is a primary barrier for Virus Infection and is essential for complete innate and adaptive immunity. Both IFN production and IFN-mediated antiviral signaling are the result of differential cellular gene expression, a process that is tightly controlled at transcriptional and translational levels. To determine the potential for microRNA (miRNA)-mediated regulation of the antiviral response, small-RNA profiling was used to analyze the miRNA content of human A549 cells at steady state and following Infection with the Cantell strain of Sendai Virus, a potent inducer of IFN and cellular antiviral responses. While the miRNA content of the cells was largely unaltered by Infection, specific changes in miRNA abundance were identified during Sendai Virus Infection. One miRNA, miR-203, was found to accumulate in infected cells and in response to IFN treatment. Results indicate that miR-203 is an IFN-inducible miRNA that can negatively regulate a number of cellular mRNAs, including an IFN-stimulated gene target, IFIT1/ISG56, by destabilizing its mRNA transcript.
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rna and Virus independent inhibition of antiviral signaling by rna helicase lgp2
Journal of Virology, 2006Co-Authors: Akihiko Komuro, Curt M HorvathAbstract:Antiviral innate immune responses can be triggered by accumulation of intracellular nucleic acids resulting from Virus Infections. Double-stranded RNA (dsRNA) can be detected by the cytoplasmic RNA helicase proteins RIG-I and MDA5, two proteins that share sequence similarities within a caspase recruitment domain (CARD) and a DExD/H box RNA helicase domain. These proteins are considered dsRNA sensors and are thought to transmit the signal to the mitochondrial adapter, IPS-1 (also known as MAVS, VISA, or CARDIF) via CARD interactions. IPS-1 coordinates the activity of protein kinases that activate transcription factors needed to induce beta interferon (IFN-β) gene transcription. Another helicase protein, LGP2, lacks the CARD region and does not activate IFN-β gene expression. LGP2 mRNA is induced by interferon, dsRNA treatments, or Sendai Virus Infection and acts as a feedback inhibitor for antiviral signaling. Results indicate that LGP2 can inhibit antiviral signaling independently of dsRNA or Virus Infection intermediates by engaging in a protein complex with IPS-1. Experiments suggest that LGP2 can compete with the kinase IKKi (also known as IKKe) for a common interaction site on IPS-1. These results provide the first demonstration of protein interaction as an element of negative-feedback regulation of intracellular antiviral signaling by LGP2.
Takashi Agui - One of the best experts on this subject based on the ideXlab platform.
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the response of adipose tissues to mycoplasma pulmonis and Sendai Virus Infection in c57bl 6 and dba 2 mice
Journal of Veterinary Medical Science, 2021Co-Authors: Tussapon Boonyarattanasoonthorn, Masami Morimatsu, Keisuke Sato, Yuko Okamatsuogura, Takashi AguiAbstract:Adipose tissues in mammals are categorized into white and brown adipose tissues in which cellular morphology, cell functions, and tissue distribution are different. White adipose tissue (WAT) plays a major role in energy reservation, while brown adipose tissue (BAT) mainly relates to the thermoregulation of the body. One interesting function of adipose tissue is the response to the Infection, especially the pathogens that cause pneumonia. We have previously reported that DBA/2 (D2) mice are susceptible to pathogens causing pneumonia, Mycoplasma (M.) pulmonis and Sendai Virus (SeV), whereas C57BL/6 (B6) mice are resistant to them. Furthermore, morphological alteration of mediastinal fat tissue (MFT) was seen after Infection of M. pulmonis in D2 mice but not in B6 mice. In this study, we aimed to exhibit the difference in adipose tissue response in other areas, including interscapular brown adipose tissue (iBAT), inguinal white adipose tissue (ingWAT), and perigonadal WAT (perigoWAT) between resistant strain, B6 and susceptible strain, D2 after challenging them with M. pulmonis and SeV. Compared with B6 mice, D2 mice showed an increase in fat-associated lymphoid cluster in MFT, an increase in BAT in both iBAT and ingWAT after M. pulmonis and SeV Infection. The results of this study indicate that pneumonia caused by M. pulmonis and SeV Infection induces browning of adipocyte, suggesting that BAT plays a role in pathogen Infection and inflammation.
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verification of genetic loci responsible for the resistance susceptibility to the Sendai Virus Infection using congenic mice
Infection Genetics and Evolution, 2018Co-Authors: Raghda Mohamed Fathi Abbas, Nobuya Sasaki, Daisuke Torigoe, Yayoi Kameda, Hassan T Tageldinhassan, Masami Morimatsu, Takashi AguiAbstract:Sendai Virus (SeV) is one of the most important pathogens in the specific-pathogen free rodents. It is known that there are some inbred mouse strains susceptible or resistant to SeV Infection. The C57BL/6 (B6) and DBA/2 (D2) mice are representative of the resistant and susceptible strains, respectively. Previous study with the quantitative trait locus (QTL) analysis identified three QTLs responsible for resistance or susceptibility to SeV Infection on different chromosomes and indicated that resistance or susceptibility to SeV Infection was almost predicted by genotypes of these three QTLs. In this paper, to verify the above hypothesis, congenic lines were generated as follows; B6-congenic lines carrying one of the D2 alleles of three QTLs and combination of these three QTLs, and D2-congenic lines carrying single or combination of B6 alleles of three QTLs. All these congenic lines were then challenged with SeV Infection. D2 congenic lines introgressed single or combination of B6 alleles of QTLs changed to resistance to SeV Infection. Especially, a D2 triple-congenic line became resistant as similar level to B6-parental strain. However, B6-congenic lines introgressed single or combination of D2 alleles of QTLs all remained to be resistant to SeV Infection. Both IL-6 and TNF-α in broncho-alveolar lavage fluid of D2 triple-congenic line were decreased to the similar level of B6 mice, suggesting that this is a part of factors that D2 triple-congenic line became resistant to the similar level of B6 mice. Data obtained from these congenic mice verified that three QTLs identified previously were indeed responsible for the resistance/susceptibility to SeV Infection in B6 and D2 mice.
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epitope mapping of the nucleocapsid protein of Sendai Virus and application of antigenic epitopes for the elisa based diagnosis of Sendai Virus Infection
Journal of Veterinary Medical Science, 2013Co-Authors: Nobuya Sasaki, Daisuke Torigoe, Atsushi Asano, Takashi AguiAbstract:Sendai Virus (SeV) is one of the most prevalent viral pathogens infecting laboratory mice and rats. To date, mature SeV virions have been used as antigens for serological diagnosis. To develop antigens that are more specific and easier to prepare for diagnosis, we examined the antigenic sites in the nucleocapsid protein (NP) of SeV with antisera from experimentally SeV-infected mice and a peptide array membrane containing overlapping 10-mer peptides covering the entire NP. We found antigenic linear sequences in two regions, amino acids 120-160 and 420-500, of the SeV-NP. From these antigenic sequences, we applied two synthesized peptides, IVKTRDMEYERTTEWL and FVTLHGAERLEEETNDE, which correspond to positions 119-134 and 458-474 of the SeV-NP, respectively, as antigens in an enzyme-linked immunosorbent assay (ELISA). Evaluation of the ELISAs using these peptides revealed that they were specific to anti-SeV antisera. Furthermore, the ELISAs using these peptides were able to distinguish between SeV-positive and SeV-negative mouse sera to the same extent as a commercial ELISA kit. These results indicate that these peptides are useful for the serological diagnosis of SeV Infection.
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distinctive and critical roles for cellular immunity and immune inflammatory response in the immunopathology of Sendai Virus Infection in mice
Microbes and Infection, 2011Co-Authors: Ayo Yila Simon, Nobuya Sasaki, Osamu Ichii, Kiichi Kajino, Yasuhiro Kon, Takashi AguiAbstract:Respiratory viral Infections result in severe pulmonary injury, to which host immune response may be a significant contributor. At present, it is not entirely clear the extent to which lung injury is a necessary consequence of host defense. In this report, we use functional genomics approach to characterize the key roles of cellular immunity and immune-inflammatory response in the immunopathology of Sendai Virus Infection in resistant C57BL/6J and susceptible DBA/2J mice. Infected mice manifested an immune-inflammatory response characterized by the pulmonary influx of neutrophils and mononuclear cells. DBA/2J mice mounted a vigorous immune response, with significant up-regulation of cytokine/chemokine genes in two successive waves through the course of Infection. Whereas, C57BL/6J mice displayed an efficient immune response with less severe pathology and clusters of immune-inflammatory responsive genes were exclusively up-regulated on day 4 in this strain. Overall, DBA/2J mice exhibited a dysregulated hyper-inflammatory cytokine/chemokine cascades that does not limit viral spread resulting in a predisposition to severe lung pathology. This response is similar to severe human respiratory paramyxoVirus Infections, which will serve as a model for the elucidation of hyper-immune inflammatory response that result to severe immunopathology in respiratory viral Infections.
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multigenic control of resistance to Sendai Virus Infection in mice
Infection Genetics and Evolution, 2009Co-Authors: Ayo Yila Simon, Nobuya Sasaki, Kanako Moritoh, Daisuke Torigoe, Atsushi Asano, Takashi AguiAbstract:Abstract Experimental Infection of mice with Sendai Virus (SeV) is frequently used as a model of viral pathogenesis of human respiratory disease. To understand the differences in host response to SeV among mice strains, we carried out genetic mapping studies in DBA/2 (D2) (susceptible) and C57BL/6 (B6) (resistant) mice. F 1 , F 2 , and N 2 backcrossed mice were generated and examined for their disease resistance and susceptibility. For the determination of virulence, percentage body weight loss and survival time were used as phenotypes. We, then, carried out a genome wide scan on 108 backcrossed mice for linkage with percentage body weight loss as phenotype. A major quantitative trait locus (QTL) showing significant linkage was mapped to the distal portion of Chr 4 ( SeV1 ). In addition, two other QTLs showing suggestive statistical linkage were also detected on Chr 8 and 14. We, further, performed genome scan for interactions with least squares analysis of variance of all pairs of informative makers in backcrossed progenies. We identified a highly significant epistatic interaction between D3Mit182 and D14Mit10 , then denoted as SeV2 and SeV3 , respectively, and the latter was the same locus showing a suggestive level on Chr 14 in QTL analysis. Considered genotypes of these three loci, we could account for more than 90% of genetic effect on the differential response to SeV Infection between B6 and D2 mice. These findings revealed a novel gene interactions controlling SeV resistance in mice and will enable the identification of resistance genes encoded within these loci.
Ganes C Sen - One of the best experts on this subject based on the ideXlab platform.
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irf 3 activation by Sendai Virus Infection is required for cellular apoptosis and avoidance of persistence
Journal of Virology, 2008Co-Authors: Kristi L Peters, Saurabh Chattopadhyay, Ganes C SenAbstract:Here, we report that specific manipulations of the cellular response to Virus Infection can cause prevention of apoptosis and consequent establishment of persistent Infection. Infection of several human cell lines with Sendai Virus (SeV) or human parainfluenza Virus 3, two prototypic paramyxoViruses, caused slow apoptosis, which was markedly accelerated upon blocking the action of phosphatidylinositol 3-kinases (PI3 kinases) in the infected cells. The observed apoptosis required viral gene expression and the action of the caspase 8 pathway. Although Virus Infection activated PI3 kinase, as indicated by AKT activation, its blockage did not inhibit JNK activation or IRF-3 activation. The action of neither the Jak-STAT pathway nor the NF-κB pathway was required for apoptosis. In contrast, IRF-3 activation was essential, although induction of the proapototic protein TRAIL by IRF-3 was not required. When IRF-3 was absent or its activation by the RIG-I pathway was blocked, SeV established persistent Infection, as documented by viral protein production and infectious Virus production. Introduction of IRF-3 in the persistently infected cells restored the cells' ability to undergo apoptosis. These results demonstrated that in our model system, IRF-3 controlled the fate of the SeV-infected cells by promoting apoptosis and preventing persistence.
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distinct induction patterns and functions of two closely related interferon inducible human genes isg54 and isg56
Journal of Biological Chemistry, 2006Co-Authors: Fulvia Terenzi, Daniel J Hui, William C Merrick, Ganes C SenAbstract:Human P54 and P56 proteins are tetratricopeptide proteins that are encoded by two closely related genes, ISG54 and ISG56. These genes are induced strongly but transiently when cells are treated with interferons or double-stranded RNA or infected with a variety of Viruses. We observed that, although double-stranded RNA or Sendai Virus Infection induced the two genes with similar kinetics, their induction kinetics in response to interferon-beta were quite different. The induction kinetics by Virus Infection were also different between two cell lines. Functionally the two proteins were similar. Like P56, P54 bound to the translation initiation factor eIF3 and inhibited translation. However, unlike P56, P54 bound to both the "e" and the "c" subunits of eIF3. Consequently, P54 inhibited two functions of eIF3. Like P56, it inhibited the ability of eIF3 to stabilize the eIF2 x GTP x Met-tRNA(i) ternary complex. But in addition, it also inhibited the formation of the 48 S pre-initiation complex between the 40 S ribosomal subunit and the 20 S complex composed of eIF3, ternary complex, eIF4F, and mRNA. Thus, although similar in structure, the human P54 and P56 proteins are induced differently and function differently.
Nam Hyuk Cho - One of the best experts on this subject based on the ideXlab platform.
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activation of rig i mediated antiviral signaling triggers autophagy through the mavs traf6 beclin 1 signaling axis
Frontiers in Immunology, 2018Co-Authors: Na Rae Lee, Junsu Ban, Noh Jin Lee, Jiyoon Choi, Hyunbin Kim, Jong Kil Lee, Jihye Seong, Nam Hyuk ChoAbstract:Autophagy has been implicated in innate immune responses against various intracellular pathogens. Recent studies have reported that autophagy can be triggered by pathogen recognizing sensors, including Toll-like receptors and cyclic guanosine monophosphate-adenosine monophosphate synthase, to participate in innate immunity. In the present study, we examined whether the RIG-I signaling pathway, which detects viral Infections by recognizing viral RNA, triggers the autophagic process. The introduction of polyI:C into the cytoplasm, or Sendai Virus Infection, significantly induced autophagy in normal cells but not in RIG-I-deficient cells. PolyI:C transfection or Sendai Virus Infection induced autophagy in the cells lacking type-I interferon signaling. This demonstrated that the effect was not due to interferon signaling. RIG-I-mediated autophagy diminished by the deficiency of mitochondrial antiviral signaling protein (MAVS) or tumor necrosis factor receptor-associated factor (TRAF)6, showing that the RIG-I-MAVS-TRAF6 signaling axis was critical for RIG-I-mediated autophagy. We also found that Beclin-1 was translocated to the mitochondria, and it interacted with TRAF6 upon RIG-I activation. Furthermore, Beclin-1 underwent K63-polyubiquitination upon RIG-I activation, and the ubiquitination decreased in TRAF6-deficient cells. This suggests that the RIG-I-MAVS-TRAF6 axis induced K63-linked polyubiquitination of Beclin-1, which has been implicated in triggering autophagy. As deficient autophagy increases the type-I interferon response, the induction of autophagy by the RIG-I pathway might also contribute to preventing an excessive interferon response as a negative-feedback mechanism.
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activation of rig i mediated antiviral signaling triggers autophagy through the mavs traf6 beclin 1 signaling axis
bioRxiv, 2018Co-Authors: Kyung Soo Inn, Na Rae Lee, Junsu Ban, Noh Jin Lee, Jiyoon Choi, Hyunbin Kim, Jong Kil Lee, Jihye Seong, Nam Hyuk Cho, Jae U JungAbstract:Autophagy has been implicated in innate immune responses against various intracellular pathogens. Recent studies have reported that autophagy can be triggered by pathogen recognizing sensors, including Toll-like receptors and cyclic guanosine monophosphate-adenosine monophosphate synthase, to participate in innate immunity. In the present study, we examined whether the RIG-I signaling pathway, which detects viral Infections by recognizing viral RNA, triggers the autophagic process. The introduction of polyI:C into the cytoplasm, or Sendai Virus Infection, significantly induced autophagy in normal cells but not in RIG-I-deficient cells. PolyI:C transfection or Sendai Virus Infection induced autophagy in the cells lacking type-I interferon signaling. This demonstrated that the effect was not due to interferon signaling. RIG-I-mediated autophagy diminished by the deficiency of mitochondrial antiviral signaling protein (MAVS) or tumor necrosis factor receptor-associated factor (TRAF)6, showing that the RIG-I-MAVS-TRAF6 signaling axis was critical for RIG-I-mediated autophagy. We also found that Beclin-1 was translocated to the mitochondria, and it interacted with TRAF6 upon RIG-I activation. Furthermore, Beclin-1 underwent K63-polyubiquitination upon RIG-I activation, and the ubiquitination decreased in TRAF6-deficient cells. This suggests that the RIG-I-MAVS-TRAF6 axis induced K63-linked polyubiquitination of Beclin-1, which has been implicated in triggering autophagy. Collectively, the results of this study show that the recognition of viral Infection by RIG-I is capable of inducing autophagy to control viral replication. As deficient autophagy increases the type-I interferon response, the induction of autophagy by the RIG-I pathway might also contribute to preventing an excessive interferon response as a negative-feedback mechanism.
