scholarly journals STAT2-Dependent Immune Responses Ensure Host Survival despite the Presence of a Potent Viral Antagonist

2018 ◽  
Vol 92 (14) ◽  
Author(s):  
Vu Thuy Khanh Le-Trilling ◽  
Kerstin Wohlgemuth ◽  
Meike U. Rückborn ◽  
Andreja Jagnjic ◽  
Fabienne Maaßen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Mutual Influence ◽  
Type I ◽  
Mcmv Infection ◽  
General Importance ◽  
Interferon Antagonism ◽  
Deficient Mice

ABSTRACTA pathogen encounter induces interferons, which signal via Janus kinases and STAT transcription factors to establish an antiviral state. However, the host and pathogens are situated in a continuous arms race which shapes host evolution toward optimized immune responses and the pathogens toward enhanced immune-evasive properties. Mouse cytomegalovirus (MCMV) counteracts interferon responses by pM27-mediated degradation of STAT2, which directly affects the signaling of type I as well as type III interferons. Using MCMV mutants lackingM27and mice lacking STAT2, we studied the opposing relationship between antiviral activities and viral antagonism in a natural host-pathogen pairin vitroandin vivo. In contrast to wild-type (wt) MCMV, ΔM27 mutant MCMV was efficiently cleared from all organs within a few days in BALB/c, C57BL/6, and 129 mice, highlighting the general importance of STAT2 antagonism for MCMV replication. Despite this effective and relevant STAT2 antagonism, wt and STAT2-deficient mice exhibited fundamentally different susceptibilities to MCMV infections. MCMV replication was increased in all assessed organs (e.g., liver, spleen, lungs, and salivary glands) of STAT2-deficient mice, resulting in mortality during the first week after infection. Taken together, the results of our study reveal the importance of cytomegaloviral interferon antagonism for viral replication as well as a pivotal role of the remaining STAT2 activity for host survival. This mutual influence establishes a stable evolutionary standoff situation with fatal consequences when the equilibrium is disturbed.IMPORTANCEThe host limits viral replication by the use of interferons (IFNs), which signal via STAT proteins. Several viruses evolved antagonists targeting STATs to antagonize IFNs (e.g., cytomegaloviruses, Zika virus, dengue virus, and several paramyxoviruses). We analyzed infections caused by MCMV expressing or lacking the STAT2 antagonist pM27 in STAT2-deficient and control mice to evaluate its importance for the host and the virusin vitroandin vivo. The inability to counteract STAT2 directly translates into exaggerated IFN susceptibilityin vitroand pronounced attenuationin vivo. Thus, the antiviral activity mediated by IFNs via STAT2-dependent signaling drove the development of a potent MCMV-encoded STAT2 antagonist which became indispensable for efficient virus replication and spread to organs required for dissemination. Despite this clear impact of viral STAT2 antagonism, the host critically required the remaining STAT2 activity to prevent overt disease and mortality upon MCMV infection. Our findings highlight a remarkably delicate balance between host and virus.

scholarly journals Transcriptional role of p53 in interferon-mediated antiviral immunity

2008 ◽  
Vol 205 (8) ◽  
pp. 1929-1938 ◽  
Author(s):  
César Muñoz-Fontela ◽  
Salvador Macip ◽  
Luis Martínez-Sobrido ◽  
Lauren Brown ◽  
Joseph Ashour ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Viral Replication ◽  
Viral Infections ◽  
Suppressor Gene ◽  
Central Component ◽  
Type I ◽  
Infected Cells

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516–523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.

scholarly journals Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

2008 ◽  
Vol 205 (13) ◽  
pp. 3187-3199 ◽  
Author(s):  
Lee-Hwa Tai ◽  
Marie-Line Goulet ◽  
Simon Belanger ◽  
Noriko Toyama-Sorimachi ◽  
Nassima Fodil-Cornu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Function ◽  
Viral Infections ◽  
Plasmacytoid Dendritic Cell ◽  
Class I ◽  
Type I ◽  
Class I Mhc ◽  
Mhc Molecules

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo.

scholarly journals Type I and Type II Interferons Inhibit the Translation of Murine Norovirus Proteins

2009 ◽  
Vol 83 (11) ◽  
pp. 5683-5692 ◽  
Author(s):  
Harish Changotra ◽  
Yali Jia ◽  
Tara N. Moore ◽  
Guangliang Liu ◽  
Shannon M. Kahan ◽  
...  
Keyword(s):  
Viral Replication ◽  
Small Animal ◽  
Type I ◽  
Type Ii ◽  
Murine Norovirus ◽  
Human Noroviruses ◽  
Interferon Responses ◽  
Replication Intermediates

ABSTRACT Human noroviruses are responsible for more than 95% of nonbacterial epidemic gastroenteritis worldwide. Both onset and resolution of disease symptoms are rapid, suggesting that components of the innate immune response are critical in norovirus control. While the study of the human noroviruses has been hampered by the lack of small animal and tissue culture systems, our recent discovery of a murine norovirus (MNV) and its in vitro propagation have allowed us to begin addressing norovirus replication strategies and immune responses to norovirus infection. We have previously demonstrated that interferon responses are critical to control MNV-1 infection in vivo and to directly inhibit viral replication in vitro. We now extend these studies to define the molecular basis for interferon-mediated inhibition. Viral replication intermediates were not detected in permissive cells pretreated with type I interferon after either infection or transfection of virion-associated RNA, demonstrating a very early block to virion production that is after virus entry and uncoating. A similar absence of viral replication intermediates was observed in infected primary macrophages and dendritic cells pretreated with type I IFN. This was not due to degradation of incoming genomes in interferon-pretreated cells since similar levels of genomes were present in untreated and pretreated cells through 6 h of infection, and these genomes retained their integrity. Surprisingly, this block to the translation of viral proteins was not dependent on the well-characterized interferon-induced antiviral molecule PKR. Similar results were observed in cells pretreated with type II interferon, except that the inhibition of viral translation was dependent on PKR. Thus, both type I and type II interferon signaling inhibit norovirus translation in permissive myeloid cells, but they display distinct dependence on PKR for this inhibition.

scholarly journals Role of Type I Interferons on Filovirus Pathogenesis

Vaccines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 22 ◽  
Author(s):  
Beatriz Escudero-Pérez ◽  
César Muñoz-Fontela
Keyword(s):  
Animal Models ◽  
Immune Responses ◽  
Marburg Virus ◽  
Type I Interferons ◽  
Type I ◽  
Adaptive Immune ◽  
Antigen Presenting

Filoviruses, such as Ebola and Marburg virus, encode viral proteins with the ability to counteract the type I interferon (IFN-I) response. These IFN-I antagonist proteins are crucial to ensure virus replication, prevent an antiviral state in infected and bystander cells, and impair the ability of antigen-presenting cells to initiate adaptive immune responses. However, in recent years, a number of studies have underscored the conflicting data between in vitro studies and in vivo data obtained in animal models and clinical studies during outbreaks. This review aims to summarize these data and to discuss the relative contributions of IFN-α and IFN-β to filovirus pathogenesis in animal models and humans. Finally, we evaluate the putative utilization of IFN-I in post-exposure therapy and its implications as a biomarker of vaccine efficacy.

scholarly journals TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2

2020 ◽  
Vol 11 (12) ◽  
pp. 894-914
Author(s):  
Nan Sun ◽  
Li Jiang ◽  
Miaomiao Ye ◽  
Yihan Wang ◽  
Guangwen Wang ◽  
...  
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Influenza Infection ◽  
Type I ◽  
Subsequent Formation ◽  
Antiviral Immune Response ◽  
Signaling Complex ◽  
Deficient Mice

AbstractTripartite 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.

AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Keitaro Fukuda ◽  
Ken Okamura ◽  
Rebecca L. Riding ◽  
Xueli Fan ◽  
Khashayar Afshari ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Adoptive T Cell Therapy ◽  
Type I ◽  
T Cell Therapy ◽  
New Treatment ◽  
Dependent Type

The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti–PD-1 immunotherapy for “cold tumors,” which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1β and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.

scholarly journals Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response

2020 ◽  
Author(s):  
EA Monson ◽  
KM Crosse ◽  
M Duan ◽  
W Chen ◽  
RD O’Shea ◽  
...  
Keyword(s):  
Viral Replication ◽  
Viral Infection ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Interferon Response ◽  
Type I ◽  
Antiviral Immune Response ◽  
Alternate Mechanism

SummaryLipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, transient protein sequestration and inter-organelle interactions. However, the role LDs play in antiviral innate immune pathways remains unknown. Here we demonstrate that induction of LDs occurs as early as 2 hours post viral infection, is transient, and returns to basal levels by 72 hours. This phenomenon occurred following viral infections, both in vitro and in vivo. Virally driven LD induction was type-I interferon (IFN) independent, however, was dependent on EGFR engagement, offering an alternate mechanism of LD induction in comparison to our traditional understanding of their biogenesis. Additionally, LD induction corresponded with enhanced cellular type-I and -III IFN production in infected cells, with enhanced LD accumulation decreasing viral replication of both HSV-1 and Zika virus (ZIKV). Here, we demonstrate for the first time, that LDs play vital roles in facilitating the magnitude of the early antiviral immune response specifically through the enhanced modulation of IFN following viral infection, and control of viral replication. By identifying LDs as a critical signalling organelle, this data represents a paradigm shift in our understanding of the molecular mechanisms which coordinate an effective antiviral response.

scholarly journals Cell-Penetrating Mx1 Enhances Anti-Viral Resistance against Mucosal Influenza Viral Infection

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 109 ◽  
Author(s):  
Hi Jung ◽  
Ji Oh ◽  
Heung Lee
Keyword(s):  
Viral Replication ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Cell Penetrating Peptides ◽  
Viral Rna ◽  
Type I ◽  
Cell Penetrating ◽  
Influenza Viral Infection

Dynamin-like GTPase myxovirus resistance protein 1 (Mx1) is an intracellular anti-viral protein following the activation of type I and type III interferon signaling. Mx1 inhibits viral replication by blocking the transcription of viral RNA, and a deficiency in this protein enhances susceptibility to influenza infection. Thus, Mx1 could be another efficient target of anti-influenza therapy. To test our hypothesis, we fused poly-arginine cell-penetrating peptides to the C terminus of Mx1 (Mx1-9R) and examined the anti-viral activity of Mx1-9R in vitro and in vivo. Madin-Darby Canine Kidney epithelial cells internalized the Mx1-9R within 12 h. Pre-exposure Mx1-9R treatment inhibited viral replication and viral RNA expression in infected cells. Further, intranasal administration of Mx1-9R improved the survival of mice infected with the PR8 influenza viral strain. These data support the consideration of Mx1-9R as a novel therapeutic agent against mucosal influenza virus infection.

scholarly journals Viral adaptation to immune selection pressure by HLA class I–restricted CTL responses targeting epitopes in HIV frameshift sequences

2010 ◽  
Vol 207 (1) ◽  
pp. 61-75 ◽  
Author(s):  
Christoph T. Berger ◽  
Jonathan M. Carlson ◽  
Chanson J. Brumme ◽  
Kari L. Hartman ◽  
Zabrina L. Brumme ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Ex Vivo ◽  
Natural Infection ◽  
Human Leukocyte ◽  
Population Level ◽  
Sequence Information ◽  
Viral Control

CD8+ cytotoxic T lymphocyte (CTL)–mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q < 0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03–restricted +2 frame–encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level.

scholarly journals Signalling Alterations in Bones of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Gene Deficient Mice

2018 ◽  
Vol 19 (9) ◽  
pp. 2538 ◽  
Author(s):  
Gergő Józsa ◽  
Vince Szegeczki ◽  
Andrea Pálfi ◽  
Tamás Kiss ◽  
Zsuzsanna Helyes ◽  
...  
Keyword(s):  
Bone Formation ◽  
Adenylate Cyclase ◽  
Morphological Changes ◽  
Bone Matrix ◽  
Transverse Diameter ◽  
Type I ◽  
Pituitary Adenylate Cyclase ◽  
Deficient Mice

: Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with diverse developmental roles, including differentiation of skeletal elements. It is a positive regulatory factor of chondrogenesis and osteogenic differentiation in vitro, but little is known about its in vivo role in bone formation. In our experiments, diaphyses of long bones from hind limbs of PACAP gene-deficient mice showed changes in thickness and increased staining intensity. Our main goal was to perform a detailed morphological and molecular biological analysis of femurs from PACAP knockout (KO) and wild type (WT) mice. Transverse diameter and anterior cortical bone thickness of KO femurs showed significant alterations with disturbed Ca2+ accumulation and collagen type I expression. Higher expression and activity of alkaline phosphatase were also observed, accompanied by increased fragility PACAP KO femurs. Increased expression of the elements of bone morphogenic protein (BMP) and hedgehog signalling was also observed, and are possibly responsible for the compensation mechanism accounting for the slight morphological changes. In summary, our results show that lack of PACAP influences molecular and biomechanical properties of bone matrix, activating various signalling cascade changes in a compensatory fashion. The increased fragility of PACAP KO femur further supports the role of endogenous PACAP in in vivo bone formation.

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