scholarly journals Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

2015 ◽  
Vol 89 (13) ◽  
pp. 6805-6816 ◽  
Author(s):  
Yu Xiang ◽  
Jing-Jie Tang ◽  
Wanyin Tao ◽  
Xuezhi Cao ◽  
Bao-Liang Song ◽  
...  
Keyword(s):  
Immune Response ◽  
Lipid Metabolism ◽  
Hepatitis C ◽  
Immune Responses ◽  
Host Response ◽  
Innate Immune ◽  
Hcv Infection ◽  
Innate Response ◽  
Viral Pathogens ◽  
Host Innate Immune Response

ABSTRACTHepatitis C virus (HCV), a single-stranded positive-sense RNA virus of theFlaviviridaefamily, causes chronic liver diseases, including hepatitis, cirrhosis, and cancer. HCV infection is critically dependent on host lipid metabolism, which contributes to all stages of the viral life cycle, including virus entry, replication, assembly, and release. 25-Hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses, and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I·C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in humans but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics.IMPORTANCERecent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here, we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated upon poly(I·C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice showing thatch25his an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy.

scholarly journals Hepatitis C virus evades IFN signaling by suppressing long non-coding RNA Linc-Pint involving c/EBP-β

2021 ◽  
Author(s):  
Mousumi Khatun ◽  
Jinsong Zhang ◽  
Ranjit Ray ◽  
Ratna B. Ray
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Immune System ◽  
Hepatitis C ◽  
Immune Responses ◽  
Promoter Activity ◽  
Innate Immune ◽  
Hcv Infection ◽  
Positive Regulator

Hepatitis C virus (HCV) regulates many cellular genes in modulating host immune system for benefit of viral replication and long-term persistence in a host for chronic infection. Long non-coding RNAs (lncRNAs) play an important role in the regulation of many important cellular processes, including immune responses. We recently reported that HCV infection downregulates lncRNA Linc-Pint expression, although the mechanism of repression and functional consequence are not well understood. In this study, we demonstrated that HCV infection of hepatocytes transcriptionally reduces Linc-Pint expression through CCAAT/enhancer binding protein-β (C/EBP-β). Subsequently, we observed that overexpression of Linc-Pint significantly upregulates IFN-α and IFN-β expression in HCV replicating hepatocytes. Using unbiased proteomics, we identified Linc-Pint associates with DDX24, which enables RIP1 to interact with IRF7 of IFN signaling pathway. We further observed that IFN-α-14 promoter activity was enhanced in the presence of Linc-Pint. Together, these results demonstrated that Linc-Pint acts as a positive regulator of host innate immune responses, specially IFN signaling. HCV mediated downregulation of Linc-Pint expression appeared as one of the mechanisms by which HCV may evade innate immunity for long-term persistence and chronicity. IMPORTANCE The mechanism by which lncRNA regulates host immune response during HCV infection is poorly understood. We observed that Linc-Pint was transcriptionally downregulated by HCV. Using ChIP assay, we showed inhibition of transcription factor C/EBP-β binding to the Linc-pint promoter in the presence of HCV infection. We further identified that Linc-Pint associates with DDX24 for immune modulatory function. Overexpression of Linc-Pint reduces DDX24 expression which in turn results in disruption of DDX24-RIP1 complex formation and activation of IRF7. An induction of IFN-α14 promoter activity in the presence of Linc-Pint further confirms our observation. Together, our results suggest that Linc-Pint acts as a positive regulator of host innate immune response. Downregulation of Linc-Pint expression by HCV helps in escaping innate immune system for development of chronicity.

scholarly journals Hepatitis C Virus Induces Toll-Like Receptor 4 Expression, Leading to Enhanced Production of Beta Interferon and Interleukin-6

2006 ◽  
Vol 80 (2) ◽  
pp. 866-874 ◽  
Author(s):  
Keigo Machida ◽  
Kevin T. H. Cheng ◽  
Vicky M.-H. Sung ◽  
Alexandra M. Levine ◽  
Steven Foung ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cells ◽  
Immune Responses ◽  
Interleukin 6 ◽  
Innate Immune ◽  
Hcv Infection ◽  
Innate Immune Responses ◽  
Altered Expression ◽  
Beta Interferon

ABSTRACT Hepatitis C virus (HCV) induces inflammatory signals, leading to hepatitis, hepatocellular carcinomas, and lymphomas. The mechanism of HCV involvement in the host's innate immune responses has not been well characterized. In this study, we analyzed expression and regulation of the entire panel of toll-like receptors (TLRs) in human B cells following HCV infection in vitro. Among all of the TLRs (TLRs 1 to 10) examined, only TLR4 showed an altered expression (a three- to sevenfold up-regulation) after HCV infection. Peripheral blood mononuclear cells from HCV-infected individuals also showed a higher expression level of TLR4 compared with those of healthy individuals. HCV infection significantly increased beta interferon (IFN-β) and interleukin-6 (IL-6) secretion from B cells, particularly after lipopolysaccharide stimulation. The increased IFN-β and IL-6 production was mediated by TLR4 induction, since the introduction of the small interfering RNA against TLR4 specifically inhibited the HCV-induced cytokine production. Among all of the viral proteins, only NS5A caused TLR4 induction in hepatocytes and B cells. NS5A specifically activated the promoter of the TLR4 gene in both hepatocytes and B cells. In conclusion, HCV infection directly induces TLR4 expression and thereby activates B cells, which may contribute to the host's innate immune responses.

scholarly journals Nidovirus papain-like proteases antagonize the host innate immune response

2014 ◽  
Vol 70 (a1) ◽  
pp. C1598-C1598
Author(s):  
Ben Bailey-Elkin ◽  
Puck van Kasteren ◽  
Eric Snijder ◽  
Marjolein Kikkert ◽  
Brian Mark
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Cellular Proteins ◽  
Common Mechanism ◽  
Innate Immune Responses ◽  
Protein Ubiquitination ◽  
Binding Interface ◽  
Host Innate Immune Response

Protein ubiquitination regulates important innate immune responses. Ubiquitin (Ub) can be attached to lysine residues on cellular proteins to promote, among other activities, the innate immune responses of the cell. These pathways can in turn be downregulated by the removal of Ub from cellular proteins by deubiquitinases (DUBs). Viruses of the order Nidovirales have positive-sense, single stranded RNA genomes. Within this order are the families Coronaviridae and Arteriviridae, which include viruses known to cause severe disease in humans and animals, respectively. Members of the families Coronaviridae and Arteriviridae share a common mechanism of gene expression, whereby the viral nonstructural proteins (nsps) are initially expressed as a single polyprotein, which is then cleaved into functional units by papain-like protease (PLP) domains encoded within. Interestingly, while also being necessary for viral replication, a number of Nidovirus PLPs have been shown to remove Ub from host proteins, in order to down-regulate the host innate immune response. Here we present the crystal structure of a Nidovirus PLP in complex with Ub. The structure allowed for the characterization of a Ub-binding interface, and identification of specific residues involved in Ub recognition that are distant from the enzyme active site.  The selective inactivation of DUB activity of viral PLP enzymes verses their polyprotein cleavage activity by site directed mutagenesis is allowing us to understand the role of DUB activity in evading innate immune responses of the host, and opens the door for the development of improved live attenuated vaccines against Nidoviruses and other viruses encoding similar dual specificity proteases.

scholarly journals Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

2016 ◽  
Vol 90 (20) ◽  
pp. 9153-9162 ◽  
Author(s):  
Cordelia Manickam ◽  
Premeela Rajakumar ◽  
Lynn Wachtman ◽  
Joshua A. Kramer ◽  
Amanda J. Martinot ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Hepatitis C ◽  
Immune Responses ◽  
Nk Cells ◽  
Nk Cell ◽  
Acute Infection ◽  
Innate Immune ◽  
Hcv Infection ◽  
Common Marmosets ◽  
Viral Loads

ABSTRACTDespite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R= 0.698;P= 0.015) and liver (R= 0.567;P= 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-γ) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection.IMPORTANCEHepatitis C virus (HCV) infection has created a global health crisis, and despite new effective antivirals, it is still a leading cause of liver disease and death worldwide. Recent evidence suggests that innate immunity may be a potential therapeutic target for HCV, but it may also be a correlate of increased disease. Due to a lack of access to human tissues with acute HCV infection, in this study we evaluated the role of innate immunity in resolving infection with a hepacivirus, GBV-B, in common marmosets. Collectively, our data suggest that NK cell and DC mobilization in acute hepacivirus infection can dampen virus replication but also regulate acute and chronic liver damage. How these two opposing effects on the host may be modulated in future therapeutic and vaccine approaches warrants further study.

scholarly journals EFTUD2 Is a Novel Innate Immune Regulator Restricting Hepatitis C Virus Infection through the RIG-I/MDA5 Pathway

2015 ◽  
Vol 89 (13) ◽  
pp. 6608-6618 ◽  
Author(s):  
Chuanlong Zhu ◽  
Fei Xiao ◽  
Jian Hong ◽  
Kun Wang ◽  
Xiao Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Innate Immune Response ◽  
Liver Tissue ◽  
Antiviral Effect ◽  
Innate Immune ◽  
Hcv Infection ◽  
Gene Splicing ◽  
Huh7 Cells

ABSTRACTThe elongation factor Tu GTP binding domain-containing protein 2 (EFTUD2) was identified as an anti-hepatitis C virus (HCV) host factor in our recent genome-wide small interfering RNA (siRNA) screen. In this study, we sought to further determine EFTUD2's role in HCV infection and investigate the interaction between EFTUD2 and other regulators involved in HCV innate immune (RIG-I, MDA5, TBK1, and IRF3) and JAK-STAT1 pathways. We found that HCV infection decreased the expression of EFTUD2 and the viral RNA sensors RIG-I and MDA5 in HCV-infected Huh7 and Huh7.5.1 cells and in liver tissue from in HCV-infected patients, suggesting that HCV infection downregulated EFTUD2 expression to circumvent the innate immune response. EFTUD2 inhibited HCV infection by inducing expression of the interferon (IFN)-stimulated genes (ISGs) in Huh7 cells. However, its impact on HCV infection was absent in both RIG-I knockdown Huh7 cells and RIG-I-defective Huh7.5.1 cells, indicating that the antiviral effect of EFTUD2 is dependent on RIG-I. Furthermore, EFTUD2 upregulated the expression of the RIG-I-like receptors (RLRs) RIG-I and MDA5 to enhance the innate immune response by gene splicing. Functional experiments revealed that EFTUD2-induced expression of ISGs was mediated through interaction of the EFTUD2 downstream regulators RIG-I, MDA5, TBK1, and IRF3. Interestingly, the EFTUD2-induced antiviral effect was independent of the classical IFN-induced JAK-STAT pathway. Our data demonstrate that EFTUD2 restricts HCV infection mainly through an RIG-I/MDA5-mediated, JAK-STAT-independent pathway, thereby revealing the participation of EFTUD2 as a novel innate immune regulator and suggesting a potentially targetable antiviral pathway.IMPORTANCEInnate immunity is the first line defense against HCV and determines the outcome of HCV infection. Based on a recent high-throughput whole-genome siRNA library screen revealing a network of host factors mediating antiviral effects against HCV, we identified EFTUD2 as a novel innate immune regulator against HCV in the infectious HCV cell culture model and confirmed that its expression in HCV-infected liver tissue is inversely related to HCV infection. Furthermore, we determined that EFTUD2 exerts its antiviral activity mainly through governing its downstream regulators RIG-I and MDA5 by gene splicing to activate IRF3 and induce classical ISG expression independent of the JAT-STAT signaling pathway. This study broadens our understanding of the HCV innate immune response and provides a possible new antiviral strategy targeting this novel regulator of the innate response.

scholarly journals Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

2016 ◽  
Vol 90 (23) ◽  
pp. 10928-10935 ◽  
Author(s):  
Stephanie T. Chan ◽  
Jiyoung Lee ◽  
Mansi Narula ◽  
J.-H. James Ou
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Innate Immune Response ◽  
Proinflammatory Cytokines ◽  
Host Immunity ◽  
Innate Immune ◽  
Bafilomycin A1 ◽  
Host Innate Immune Response ◽  
Autophagic Degradation

ABSTRACT Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor molecule that mediates the TNFR family and interleukin-1 (IL-1)/Toll-like receptor (TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a posttranslational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes. As bafilomycin A1 is a vacuolar ATPase inhibitor that inhibits autophagic protein degradation, these results suggested that HCV depleted TRAF6 via autophagy. The degradation of TRAF6 was apparently mediated by the p62 sequestosome protein, which is a factor important for selective autophagy, as it could bind to TRAF6 and its silencing stabilized TRAF6. The depletion of TRAF6 suppressed activation of NF-κB and induction of proinflammatory cytokines and enhanced HCV replication. In contrast, the overexpression of TRAF6 suppressed HCV replication. These results revealed a novel mechanism that was used by HCV to disrupt the host innate immune responses for viral replication and persistence. IMPORTANCE HCV can cause severe liver diseases and is one of the most important human pathogens. It establishes chronic infections in the great majority of patients that it infects, indicating that it has evolved sophisticated mechanisms to evade host immunity. TRAF6 is an important signaling molecule that mediates activation of NF-κB and expression of proinflammatory cytokines and interferons. In this study, we found that HCV infection suppressed the host innate immune response through the induction of autophagic degradation of TRAF6. This finding provided important information for further understanding how HCV evades host immunity to establish persistence.

scholarly journals NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Yuwen Qin ◽  
Binbin Xue ◽  
Chunyan Liu ◽  
Xiaohong Wang ◽  
Renyun Tian ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Signaling Pathway ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Hcv Infection ◽  
Negative Regulator ◽  
Immune Mediated

ABSTRACT Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. However, attenuation or termination of signaling is also necessary for preventing immune-mediated tissue damage and spontaneous autoimmunity. Here, we identify nucleotide binding oligomerization domain (NOD)-like receptor X1 (NLRX1) as a negative regulator of the mitochondrial antiviral signaling protein (MAVS)-mediated signaling pathway during hepatitis C virus (HCV) infection. The depletion of NLRX1 enhances the HCV-triggered activation of interferon (IFN) signaling and causes the suppression of HCV propagation in hepatocytes. NLRX1, a HCV-inducible protein, interacts with MAVS and mediates the K48-linked polyubiquitination and subsequent degradation of MAVS via the proteasomal pathway. Moreover, poly(rC) binding protein 2 (PCBP2) interacts with NLRX1 to participate in the NLRX1-induced degradation of MAVS and the inhibition of antiviral responses during HCV infection. Mutagenic analyses further revealed that the NOD of NLRX1 is essential for NLRX1 to interact with PCBP2 and subsequently induce MAVS degradation. Our study unlocks a key mechanism of the fine-tuning of innate immunity by which NLRX1 restrains the retinoic acid-inducible gene I-like receptor (RLR)-MAVS signaling cascade by recruiting PCBP2 to MAVS for inducing MAVS degradation through the proteasomal pathway. NLRX1, a negative regulator of innate immunity, is a pivotal host factor for HCV to establish persistent infection. IMPORTANCE Innate immunity needs to be tightly regulated to maximize the antiviral response and minimize immune-mediated pathology, but the underlying mechanisms are poorly understood. In this study, we report that NLRX1 is a proviral host factor for HCV infection and functions as a negative regulator of the HCV-triggered innate immune response. NLRX1 recruits PCBP2 to MAVS and induces the K48-linked polyubiquitination and degradation of MAVS, leading to the negative regulation of the IFN signaling pathway and promoting HCV infection. Overall, this study provides intriguing insights into how innate immunity is regulated during viral infection.

scholarly journals Aging associated altered response to intracellular bacterial infections and its implication on the host

2020 ◽  
Author(s):  
Sheryl E. Fernandes ◽  
Alakesh Singh ◽  
R.S. Rajmani ◽  
Siddharth Jhunjhunwala ◽  
Deepak K. Saini
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Host Response ◽  
Bacterial Infections ◽  
The Elderly ◽  
Innate Immune ◽  
Negative Regulator ◽  
Cellular Models ◽  
Old Mice

Abstract The effects of senescence and aging on geriatric diseases has been well explored but how these influence infections in the elderly have been scarcely addressed. Here, we show that several innate immune responses are elevated in senescent cells and old mice, allowing them to promptly respond to bacterial infections. We have identified higher levels of iNOS as a crucial host response and show that p38 MAPK in senescent cells acts as a negative regulator of iNOS transcription. In old mice, however the ability to impede bacterial proliferation does not correlate with increased survival as elevated immune responses persist unabated eventually affecting the host. The use of anti-inflammatory drugs that could consequently be recommended also decreases iNOS disarming the host of a critical innate immune response. Overall, our study highlights that infection associated mortality in the elderly is not merely an outcome of pathogen load but is also influenced by the host’s ability to resolve inflammation induced damage. Summary statement Using cellular models and old mice we demonstrate the effect of aging on host response to bacterial infections. Aged systems mount a more effective anti-bacterial innate immune response but its persistence results in mortality of the host.

Oral Immune Activation by Disgust and Disease-Related Pictures

2015 ◽  
Vol 29 (3) ◽  
pp. 119-129 ◽  
Author(s):  
Richard J. Stevenson ◽  
Deborah Hodgson ◽  
Megan J. Oaten ◽  
Luba Sominsky ◽  
Mehmet Mahmut ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Negative Control ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Markers ◽  
Before And After ◽  
Secondary Analyses ◽  
Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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