scholarly journals Rotavirus Antagonizes Cellular Antiviral Responses by Inhibiting the Nuclear Accumulation of STAT1, STAT2, and NF-κB

2009 ◽  
Vol 83 (10) ◽  
pp. 4942-4951 ◽  
Author(s):  
Gavan Holloway ◽  
Thanhmai T. Truong ◽  
Barbara S. Coulson
Keyword(s):  
Gene Expression ◽  
Viral Infection ◽  
Rna Virus ◽  
Host Responses ◽  
Nuclear Accumulation ◽  
Type I ◽  
Nonstructural Proteins ◽  
Necrosis Factor Alpha ◽  
Intracellular Expression ◽  
Infected Cells

ABSTRACT A vital arm of the innate immune response to viral infection is the induction and subsequent antiviral effects of interferon (IFN). Rotavirus reduces type I IFN induction in infected cells by the degradation of IFN regulatory factors. Here, we show that the monkey rotavirus RRV and human rotavirus Wa also block gene expression induced by type I and II IFNs through a mechanism allowing signal transducer and activator of transcription 1 (STAT1) and STAT2 activation but preventing their nuclear accumulation. In infected cells, this may allow rotavirus to block the antiviral actions of IFN produced early in infection or by activated immune cells. As the intracellular expression of rotavirus nonstructural proteins NSP1, NSP3, and NSP4 individually did not inhibit IFN-stimulated gene expression, their involvement in this process is unlikely. RRV and Wa rotaviruses also prevented the tumor necrosis factor alpha-stimulated nuclear accumulation of NF-κB and NF-κB-driven gene expression. In addition, NF-κB was activated by rotavirus infection, confirming earlier findings by others. As NF-κB is important for the induction of IFN and other cytokines during viral infection, this suggests that rotavirus prevents cellular transcription as a means to evade host responses. To our knowledge, this is the first report of the use of this strategy by a double-stranded RNA virus.

scholarly journals HSV-1 single-cell analysis reveals the activation of anti-viral and developmental programs in distinct sub-populations

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Nir Drayman ◽  
Parthiv Patel ◽  
Luke Vistain ◽  
Savaş Tay
Keyword(s):  
Gene Expression ◽  
Viral Infection ◽  
Single Cell ◽  
Viral Gene Expression ◽  
Population Level ◽  
Cellular Reprogramming ◽  
Viral Gene ◽  
Type I ◽  
Infected Cells ◽  
Hsv 1

Viral infection is usually studied at the population level by averaging over millions of cells. However, infection at the single-cell level is highly heterogeneous, with most infected cells giving rise to no or few viral progeny while some cells produce thousands. Analysis of Herpes Simplex virus 1 (HSV-1) infection by population-averaged measurements has taught us a lot about the course of viral infection, but has also produced contradictory results, such as the concurrent activation and inhibition of type I interferon signaling during infection. Here, we combine live-cell imaging and single-cell RNA sequencing to characterize viral and host transcriptional heterogeneity during HSV-1 infection of primary human cells. We find extreme variability in the level of viral gene expression among individually infected cells and show that these cells cluster into transcriptionally distinct sub-populations. We find that anti-viral signaling is initiated in a rare group of abortively infected cells, while highly infected cells undergo cellular reprogramming to an embryonic-like transcriptional state. This reprogramming involves the recruitment of β-catenin to the host nucleus and viral replication compartments, and is required for late viral gene expression and progeny production. These findings uncover the transcriptional differences in cells with variable infection outcomes and shed new light on the manipulation of host pathways by HSV-1.

scholarly journals Cell-Cell Sensing of Viral Infection by Plasmacytoid Dendritic Cells

2016 ◽  
Vol 90 (22) ◽  
pp. 10050-10053 ◽  
Author(s):  
Brian Webster ◽  
Sonia Assil ◽  
Marlène Dreux
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Immune Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Host Responses ◽  
Cell Contact ◽  
Type I ◽  
Antiviral Responses ◽  
Infected Cells ◽  
Cell Cell

All cells possess signaling pathways designed to trigger antiviral responses, notably characterized by type I interferon (IFN) production, upon recognition of invading viruses. Especially, host sensors recognize viral nucleic acids. Nonetheless, virtually all viruses have evolved potent strategies that preclude host responses within the infected cells. The plasmacytoid dendritic cell (pDC) is an immune cell type known as a robust type I IFN producer in response to viral infection. Evidence suggests that such functionality of the pDCs participates in viral clearance. Nonetheless, their contribution, which is likely complex and varies depending on the pathogen, is still enigmatic for many viruses. pDCs are not permissive to most viral infections, and consistently, recent examples suggest that pDCs respond to immunostimulatory viral RNA transferred via noninfectious and/or noncanonical viral/cellular carriers. Therefore, the pDC response likely bypasses innate signaling blockages induced by virus within infected cells. Importantly, the requirement for cell-cell contact is increasingly recognized as a hallmark of the pDC-mediated antiviral state, triggered by evolutionarily divergent RNA viruses.

scholarly journals The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1062
Author(s):  
Victoria Callahan ◽  
Seth Hawks ◽  
Matthew A. Crawford ◽  
Caitlin W. Lehman ◽  
Holly A. Morrison ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Virus ◽  
Pulmonary Complications ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
Inflammatory Chemokines ◽  
Inflammatory State ◽  
Infected Cells ◽  
Ifn Γ

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.

scholarly journals Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Negatively Regulates Innate Immunity Against RNA Virus by Targeting RIG-I in Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Ziqi Zou ◽  
Mengyao Li ◽  
Yunlian Zhou ◽  
Jiaying Li ◽  
Ting Pan ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Retinoic Acid ◽  
Viral Infection ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Rna Virus ◽  
Type I ◽  
Factor Α ◽  
Necrosis Factor ◽  
Inducible Gene

A systematic and flexible immunoregulatory network is required to ensure the proper outcome of antiviral immune signaling and maintain homeostasis during viral infection. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been extensively studied in inflammatory response, apoptosis, and cancer. However, the function of TIPE2 in antiviral innate immunity is poorly clarified. In this study, we reported that the expression of TIPE2 declined at the early period and then climbed up in macrophages under RNA virus stimulation. Knockout of TIPE2 in the macrophages enhanced the antiviral capacity and facilitated type I interferon (IFN) signaling after RNA viral infection both in vitro and in vivo. Consistently, overexpression of TIPE2 inhibited the production of type I IFNs and pro-inflammatory cytokines, and thus promoted the viral infection. Moreover, TIPE2 restrained the activation of TBK1 and IRF3 in the retinoic acid inducible gene-I (RIG-I)-like receptors (RLR) signaling pathway by directly interacting with retinoic acid inducible gene-I (RIG-I). Taken together, our results suggested that TIPE2 suppresses the type I IFN response induced by RNA virus by targeting RIG-I and blocking the activation of downstream signaling. These findings will provide new insights to reveal the immunological function of TIPE2 and may help to develop new strategies for the clinical treatment of RNA viral infections.

scholarly journals Virus-Specific Responses of Heterosigma akashiwo to Infection

2006 ◽  
Vol 72 (12) ◽  
pp. 7829-7834 ◽  
Author(s):  
Janice E. Lawrence ◽  
Corina P. D. Brussaard ◽  
Curtis A. Suttle
Keyword(s):  
Viral Infection ◽  
Rna Virus ◽  
Geographic Area ◽  
Heterosigma Akashiwo ◽  
Dna Virus ◽  
Cellular Physiology ◽  
Sytox Green ◽  
Double Stranded Dna ◽  
Infected Cells

ABSTRACT We used flow cytometry to examine the process of cell death in the bloom-forming alga Heterosigma akashiwo during infection by a double-stranded DNA virus (OIs1) and a single-stranded RNA virus (H. akashiwo RNA virus [HaRNAV]). These viruses were isolated from the same geographic area and infect the same strain of H. akashiwo. By use of the live/dead stains fluorescein diacetate and SYTOX green as indicators of cellular physiology, cells infected with OIs1 showed signs of infection earlier than HaRNAV-infected cultures (6 to 17 h versus 23 to 29 h). Intracellular esterase activity was lost prior to increased membrane permeability during infection with OIs1, while the opposite was seen with HaRNAV-infected cultures. In addition, OIs1-infected cells accumulated in the cultures while HaRNAV-infected cells rapidly disintegrated. Progeny OIs1 viruses consisted of large and small morphotypes with estimated latent periods of 11 and 17 h, respectively, and about 1,100 and 16,000 viruses produced per cell, respectively. In contrast, HaRNAV produced about 21,000 viruses per cell and had a latent period of 29 h. This study reveals that the characteristics of viral infection in algae are virus dependent and therefore are variable among viruses infecting the same species. This is an important consideration for ecosystem modeling exercises; calculations based on in situ measurements of algal physiology must be sensitive to the diverse responses of algae to viral infection.

scholarly journals Impairment of Interferon-Induced IRF-7 Gene Expression due to Inhibition of ISGF3 Formation by Trichostatin A

2003 ◽  
Vol 77 (12) ◽  
pp. 7113-7119 ◽  
Author(s):  
Pierre Génin ◽  
Pierre Morin ◽  
Ahmet Civas
Keyword(s):  
Gene Expression ◽  
Trichostatin A ◽  
Nuclear Accumulation ◽  
Signal Transducer ◽  
Interferon Stimulated Genes ◽  
Deacetylase Inhibitor ◽  
Dependent Inhibition ◽  
Infected Cells ◽  
And Function ◽  
Amplification Cascade

ABSTRACT Two members of the signal transducer and activator of transcription family, STAT1 and STAT2, form, together with interferon regulatory factor 9 (IRF-9), the ISGF3 complex that activates the expression of the interferon-stimulated genes (ISG). The ISGF3 complex also participates in the virus-induced alpha/beta interferon (IFN-α/β) gene amplification cascade by up-regulating IRF-7 gene expression. Here, we show that treatment of cells with trichostatin A (TSA), a deacetylase inhibitor, inhibits the virus-induced activation of IFN-α/β promoters and dramatically reduces the ability of different ISG promoters to respond to IFN stimulation. Impairment of IFN-α/β and ISG expression by TSA in infected cells is due to the blockage of interferon-stimulated ISGF3 complex formation, which leads to the abolition of IRF-7 gene expression. We also show that the TSA-dependent inhibition of ISGF3 is related to impaired nuclear accumulation of STAT2. Our data suggest that an acetylation/deacetylation mechanism participates in the regulation of cellular distribution and function of STAT2 in IFN-α/β signaling.

scholarly journals Bacterial Internalization, Localization, and Effectors Shape the Epithelial Immune Response during Shigella flexneri Infection

2015 ◽  
Vol 83 (9) ◽  
pp. 3624-3637 ◽  
Author(s):  
Juliane Lippmann ◽  
Frederik Gwinner ◽  
Camille Rey ◽  
Uyanga Tamir ◽  
Helen K. W. Law ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Single Cell Analysis ◽  
Single Cells ◽  
Shigella Flexneri ◽  
Host Responses ◽  
Host Immune System ◽  
Content Type ◽  
Infected Cells ◽  
Gene Expression Studies

Intracellular pathogens are differentially sensed by the compartmentalized host immune system. Nevertheless, gene expression studies of infected cells commonly average the immune responses, neglecting the precise pathogen localization. To overcome this limitation, we dissected the transcriptional immune response toShigella flexneriacross different infection stages in bulk and single cells. This identified six distinct transcriptional profiles characterizing the dynamic, multilayered host response in both bystander and infected cells. These profiles were regulated by external and internal danger signals, as well as whether bacteria were membrane bound or cytosolic. We found that bacterial internalization triggers a complex, effector-independent response in bystander cells, possibly to compensate for the undermined host gene expression in infected cells caused by bacterial effectors, particularly OspF. Single-cell analysis revealed an important bacterial strategy to subvert host responses in infected cells, demonstrating that OspF disrupts concomitant gene expression of proinflammatory, apoptosis, and stress pathways within cells. This study points to novel mechanisms through which bacterial internalization, localization, and injected effectors orchestrate immune response transcriptional signatures.

scholarly journals Rotavirus inhibits IFN-induced STAT nuclear translocation by a mechanism that acts after STAT binding to importin-α

2014 ◽  
Vol 95 (8) ◽  
pp. 1723-1733 ◽  
Author(s):  
Gavan Holloway ◽  
Vi T. Dang ◽  
David A. Jans ◽  
Barbara S. Coulson
Keyword(s):  
Nuclear Export ◽  
Nuclear Translocation ◽  
Strain Analysis ◽  
Nuclear Accumulation ◽  
Type I ◽  
Group A Rotaviruses ◽  
Importin Α ◽  
Group A ◽  
Infected Cells ◽  
Novel Strategy

The importance of innate immunity to rotaviruses is exemplified by the range of strategies evolved by rotaviruses to interfere with the IFN response. We showed previously that rotaviruses block gene expression induced by type I and II IFNs, through a mechanism allowing activation of signal transducer and activator of transcription (STAT) 1 and STAT2 but preventing their nuclear accumulation. This normally occurs through activated STAT1/2 dimerization, enabling an interaction with importin α5 that mediates transport into the nucleus. In rotavirus-infected cells, STAT1/2 inhibition may limit the antiviral actions of IFN produced early in infection. Here we further analysed the block to STAT1/2 nuclear accumulation, showing that activated STAT1 accumulates in the cytoplasm in rotavirus-infected cells. STAT1/2 nuclear accumulation was inhibited by rotavirus even in the presence of the nuclear export inhibitor Leptomycin B, demonstrating that enhanced nuclear export is not involved in STAT1/2 cytoplasmic retention. The ability to inhibit STAT nuclear translocation was completely conserved amongst the group A rotaviruses tested, including a divergent avian strain. Analysis of mutant rotaviruses indicated that residues after amino acid 47 of NSP1 are dispensable for STAT inhibition. Furthermore, expression of any of the 12 Rhesus monkey rotavirus proteins did not inhibit IFN-stimulated STAT1 nuclear translocation. Finally, co-immunoprecipitation experiments from transfected epithelial cells showed that STAT1/2 binds importin α5 normally following rotavirus infection. These findings demonstrate that rotavirus probably employs a novel strategy to inhibit IFN-induced STAT signalling, which acts after STAT activation and binding to the nuclear import machinery.

Inhibition of Human T-Lymphotropic Virus Type I Gene Expression by the Streptomyces-Derived Substance EM2487

2002 ◽  
Vol 13 (3) ◽  
pp. 177-183 ◽  
Author(s):  
X Wang ◽  
M Okamoto ◽  
M Kawamura ◽  
S Izumo ◽  
M Baba
Keyword(s):  
Gene Expression ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Spastic Paraparesis ◽  
Selective Inhibition ◽  
Pcr Analysis ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
T Lymphotropic Virus ◽  
Infected Cells

EM2487, a Streptomyces-derived substance, has previously been shown to inhibit HIV-1 replication in both acutely and chronically infected cells. In this study, we found that EM2487 was also a selective inhibitor of human T-lymphotropic virus type I (HTLV-I) replication in persistently infected cells. Its 50% effective concentrations for HTLV-I p19 antigen production were 3.6 and 1.2 μM in MT-2 and MT-4 cells, respectively. However, the compound did not reduce cell proliferation and viability at these concentrations. The 50% cytotoxic concentrations of EM2487 were 30.6 and 5.7 μM in MT-2 and MT-4 cells, respectively. The compound also displayed selective inhibition of HTLV-I production in peripheral blood mononuclear cells obtained from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Quantitative reverse transcription PCR analysis revealed that EM2487 selectively suppressed HTLV-I mRNA synthesis in MT-2 cells in a dose-dependent fashion. However, the compound did not inhibit endogenous Tax-induced HTLV-I long terminal repeat-driven reporter gene expression. Furthermore, intracellular Tax accumulation was not suppressed in MT-2 cells exposed to EM2487. These results suggest that the inhibition occurred at the viral transcription level, but it cannot be attributed to the inhibition of the Tax function.

scholarly journals Patterns of cytokine gene expression in infectious mononucleosis

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 707-712 ◽  
Author(s):  
HD Foss ◽  
H Herbst ◽  
M Hummel ◽  
I Araujo ◽  
U Latza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Infectious Mononucleosis ◽  
Clinical Presentation ◽  
Gene Expression Pattern ◽  
Cytokine Gene Expression ◽  
Tnf Alpha ◽  
High Signal ◽  
Cytokine Gene ◽  
Necrosis Factor Alpha ◽  
Infected Cells

Abstract Primary infection with Epstein-Barr virus (EBV) may arise as infectious mononucleosis (IM) in adolescents and young adults. Morphologically, IM- affected lymphoid tissue is characterized by expanded interfollicular areas with formation of atypical lymphoid blasts. It is assumed that morphology and clinical presentation of IM are related to characteristic patterns of cytokine production by EBV-infected and reactive cells. We studied IM tonsils of eight patients and six normal tonsils with a double in situ hybridization procedure using [35S]- labeled RNA probes specific for various cytokines and digoxigenin- labeled probes for the detection of the nuclear EBV encoded RNA transcripts, EBER 1 and 2. All of the IM cases displayed the same distinct cytokine gene expression pattern. When compared with interfollicular areas of normal tonsils, expression of lymphotoxin (LT), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta, but not IL-8 or IL-1 alpha was strongly enhanced in interfollicular areas in IM tonsils. LT was expressed predominantly by EBV-infected cells. TNF-alpha transcripts were also present in EBV- infected cells, although in smaller proportions. IL-6 specific signals were only found in few EBV-infected cells. IL-1 alpha-, IL-1 beta-, and IL-8-specific signals were not observed in EBV-infected cells, but were present at high signal intensity in many cells within and around foci of EBV-infected cells (IL-1 beta), next to areas of necrosis (IL-8, IL- 1 beta), or in epithelial cells (IL-1 alpha). These data suggest that EBV infection in form of IM results in induction of specific sets of cytokine genes in EBV-infected and in neighboring EBV-negative cells contributing to the characteristic morphology and cellular arrangement of the lesion as well as the clinical presentation.

Sign in / Sign up

Export Citation Format

Share Document