scholarly journals Interferon-Stimulated Genes—Mediators of the Innate Immune Response during Canine Distemper Virus Infection

2019 ◽  
Vol 20 (7) ◽  
pp. 1620 ◽  
Author(s):  
Daniela Klotz ◽  
Ingo Gerhauser
Keyword(s):  
Canine Distemper Virus ◽  
Effector Proteins ◽  
Type I ◽  
Canine Distemper ◽  
Oligoadenylate Synthetase ◽  
Protein Kinase R ◽  
Interferon Stimulated Genes ◽  
Cellular Origin ◽  
Mx Protein ◽  
Cerebellar Lesions

The demyelinating canine distemper virus (CDV)-leukoencephalitis represents a translational animal model for multiple sclerosis. The present study investigated the expression of type I interferon (IFN-I) pathway members in CDV-induced cerebellar lesions to gain an insight into their role in lesion development. Gene expression of 110 manually selected genes in acute, subacute and chronic lesions was analyzed using pre-existing microarray data. Interferon regulatory factor (IRF) 3, IRF7, signal transducer and activator of transcription (STAT) 1, STAT2, MX protein, protein kinase R (PKR), 2′-5′-oligoadenylate synthetase (OAS) 1 and interferon-stimulated gene (ISG) 15 expression were also evaluated using immunohistochemistry. Cellular origin of STAT1, STAT2, MX and PKR were determined using immunofluorescence. CDV infection caused an increased expression of the antiviral effector proteins MX, PKR, OAS1 and ISG15, which probably contributed to a restricted viral replication, particularly in neurons and oligodendrocytes. This increase might be partly mediated by IRF-dependent pathways due to the lack of changes in IFN-I levels and absence of STAT2 in astrocytes. Nevertheless, activated microglia/macrophages showed a strong expression of STAT1, STAT2 and MX proteins in later stages of the disease, indicating a strong activation of the IFN-I signaling cascade, which might be involved in the aggravation of bystander demyelination.

scholarly journals Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis

2020 ◽  
Author(s):  
Alex Rosenberg ◽  
L. David Sibley
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Host Cell ◽  
Kinase Domain ◽  
Effector Proteins ◽  
Type I ◽  
Immune Functions ◽  
Protein Kinase R ◽  
Repressor Complex

SummaryDuring infection, Toxoplasma gondii translocates effector proteins directly into its host cell to subvert various signaling pathways. Here we characterize a novel secreted effector that localizes to the host cell nucleus where it modulates NCoR/SMRT repressor complex levels to repress interferon regulated genes involved in cell death. Type I and type II interferons upregulate many genes including protein kinase R (PKR), inducing formation of the necrosome complex that activates Mixed Lineage Kinase Domain Like Pseudokinase (MLKL) to execute necrotic cell death. Toxoplasma NCoR/SMRT modulator (TgNSM) acts together with another secreted effector TgIST, previously shown to down-modulate IFN-γ signaling to block immune functions. Together TgNSM and TgIST block IFN driven expression of PKR and MLKL, thus preventing host cell necroptotic death. The mechanism of action of TgNSM highlights a previously unappreciated role of NCoR/SMRT in regulation of necroptosis, assuring survival of intracellular cysts, and maintenance of chronic infection.

scholarly journals Accessory Protein 5a Is a Major Antagonist of the Antiviral Action of Interferon against Murine Coronavirus

2010 ◽  
Vol 84 (16) ◽  
pp. 8262-8274 ◽  
Author(s):  
Cheri A. Koetzner ◽  
Lili Kuo ◽  
Scott J. Goebel ◽  
Amy B. Dean ◽  
Monica M. Parker ◽  
...  
Keyword(s):  
Hepatitis Virus ◽  
Prototype Strain ◽  
Initiation Factor ◽  
Type I ◽  
Oligoadenylate Synthetase ◽  
Knockout Mutant ◽  
Protein Kinase R ◽  
Spike Gene

ABSTRACT The type I interferon (IFN) response plays an essential role in the control of in vivo infection by the coronavirus mouse hepatitis virus (MHV). However, in vitro, most strains of MHV are largely resistant to the action of this cytokine, suggesting that MHV encodes one or more functions that antagonize or evade the IFN system. A particular strain of MHV, MHV-S, exhibited orders-of-magnitude higher sensitivity to IFN than prototype strain MHV-A59. Through construction of interstrain chimeric recombinants, the basis for the enhanced IFN sensitivity of MHV-S was found to map entirely to the region downstream of the spike gene, at the 3′ end of the genome. Sequence analysis revealed that the major difference between the two strains in this region is the absence of gene 5a from MHV-S. Creation of a gene 5a knockout mutant of MHV-A59 demonstrated that a major component of IFN resistance maps to gene 5a. Conversely, insertion of gene 5a, or its homologs from related group 2 coronaviruses, at an upstream genomic position in an MHV-A59/S chimera restored IFN resistance. This is the first demonstration of a coronavirus gene product that can protect that same virus from the antiviral state induced by IFN. Neither protein kinase R, which phosphorylates eukaryotic initiation factor 2, nor oligoadenylate synthetase, which activates RNase L, was differentially activated in IFN-treated cells infected with MHV-A59 or MHV-S. Thus, the major IFN-induced antiviral activities that are specifically inhibited by MHV, and possibly by other coronaviruses, remain to be identified.

scholarly journals Severe acute respiratory syndrome coronavirus papain-like protease suppressed alpha interferon-induced responses through downregulation of extracellular signal-regulated kinase 1-mediated signalling pathways

2011 ◽  
Vol 92 (5) ◽  
pp. 1127-1140 ◽  
Author(s):  
Shih-Wein Li ◽  
Chien-Chen Lai ◽  
Jia-Fong Ping ◽  
Fuu-Jen Tsai ◽  
Lei Wan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Time Dependent ◽  
Signalling Pathways ◽  
Type I ◽  
Induced Responses ◽  
Type I Ifn ◽  
Oligoadenylate Synthetase ◽  
Protein Kinase R ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro), a deubiquitinating enzyme, reportedly blocks poly I : C-induced activation of interferon regulatory factor 3 and nuclear factor kappa B, reducing interferon (IFN) induction. This study investigated type I IFN antagonist mechanism of PLpro in human promonocytes. PLpro antagonized IFN-α-induced responses such as interferon-stimulated response element- and AP-1-driven promoter activation, protein kinase R, 2′-5′-oligoadenylate synthetase (OAS), interleukin (IL)-6 and IL-8 expression, and signal transducers and activators of transcription (STAT) 1 (Tyr701), STAT1 (Ser727) and c-Jun phosphorylation. A proteomics approach demonstrated downregulation of extracellular signal-regulated kinase (ERK) 1 and upregulation of ubiquitin-conjugating enzyme (UBC) E2-25k as inhibitory mechanism of PLpro on IFN-α-induced responses. IFN-α treatment significantly induced mRNA expression of UBC E2-25k, but not ERK1, causing time-dependent decrease of ERK1, but not ERK2, in PLpro-expressing cells. Poly-ubiquitination of ERK1 showed a relationship between ERK1 and ubiquitin proteasome signalling pathways associated with IFN antagonism by PLpro. Combination treatment of IFN-α and the proteasome inhibitor MG-132 showed a time-dependent restoration of ERK1 protein levels and significant increase of ERK1, STAT1 and c-Jun phosphorylation in PLpro-expressing cells. Importantly, PD098059 (an ERK1/2 inhibitor) treatment significantly reduced IFN-α-induced ERK1 and STAT1 phosphorylation, inhibiting IFN-α-induced expression of 2′-5′-OAS in vector control cells and PLpro-expressing cells. Overall results proved downregulation of ERK1 by ubiquitin proteasomes and suppression of interaction between ERK1 and STAT1 as type I IFN antagonist function of SARS-CoV PLpro.

scholarly journals ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 315
Author(s):  
Barkha Ramnani ◽  
Praveen Manivannan ◽  
Sarah Jaggernauth ◽  
Krishnamurthy Malathi
Keyword(s):  
Cellular Proliferation ◽  
Viral Infections ◽  
Antiviral Effect ◽  
Host Protein ◽  
Type I ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Interferon Stimulated Genes ◽  
Antiviral Effects ◽  
Increased Activity

Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway. Here, we show that the ATP-binding cassette E1 (ABCE1) transporter, identified as an inhibitor of RNase L, regulates RNase L activity and RNase L-induced autophagy during viral infections. ABCE1 knockdown cells show increased RNase L activity when activated by 2-5A. Compared to parental cells, the autophagy-inducing activity of RNase L in ABCE1-depleted cells is enhanced with early onset. RNase L activation in ABCE1-depleted cells inhibits cellular proliferation and sensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting a switch from autophagy to apoptosis. ABCE1 regulates autophagy during EMCV infection, and enhanced autophagy in ABCE1 knockdown cells promotes EMCV replication. We identify ABCE1 as a host protein that inhibits the OAS/RNase L pathway by regulating RNase L activity, potentially affecting antiviral effects.

scholarly journals Two Domains of the V Protein of Virulent Canine Distemper Virus Selectively Inhibit STAT1 and STAT2 Nuclear Import

2010 ◽  
Vol 84 (13) ◽  
pp. 6328-6343 ◽  
Author(s):  
Anne Röthlisberger ◽  
Dominique Wiener ◽  
Matthias Schweizer ◽  
Ernst Peterhans ◽  
Andreas Zurbriggen ◽  
...  
Keyword(s):  
Nuclear Import ◽  
Canine Distemper Virus ◽  
Molecular Mechanisms ◽  
Systemic Infection ◽  
Type I ◽  
Single Mutation ◽  
Canine Distemper ◽  
V Protein ◽  
Antiviral State ◽  
P Gene

ABSTRACT Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-α/β)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-α/β-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-α/β-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-α/β-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-α/β-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-α/β-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-α/β evasion among the morbilliviruses.

scholarly journals Amino-Terminal Precursor Sequence Modulates Canine Distemper Virus Fusion Protein Function

2002 ◽  
Vol 76 (9) ◽  
pp. 4172-4180 ◽  
Author(s):  
Veronika von Messling ◽  
Roberto Cattaneo
Keyword(s):  
Canine Distemper Virus ◽  
Signal Sequence ◽  
Classical Type ◽  
Activation Process ◽  
Type I ◽  
Canine Distemper ◽  
Hydrophobic Region ◽  
Proteolytic Activation ◽  
F Protein ◽  
Amino Terminal

ABSTRACT The fusion (F) proteins of most paramyxoviruses are classical type I glycoproteins with a short hydrophobic leader sequence closely following the translation initiation codon. The predicted reading frame of the canine distemper virus (CDV) F protein is more complex, with a short hydrophobic sequence beginning 115 codons downstream of the first AUG. To verify if the sequence between the first AUG and the hydrophobic region is translated, we produced a specific antiserum that indeed detected a short-lived F protein precursor that we named PreF0. A peptide resulting from PreF0 cleavage was identified and named Pre, and its half-life was measured to be about 30 min. PreF0 cleavage was completed before proteolytic activation of F0 into its F1 and F2 subunits by furin. To test the hypothesis that the Pre peptide may influence protein activity, we compared the function of F proteins synthesized with that peptide to that of F proteins synthesized with a shorter amino-terminal signal sequence. F proteins synthesized with the Pre peptide were more stable and less active. Thus, the Pre peptide modulates the function of the CDV F protein. Interestingly, a distinct two-hit activation process has been recently described for human respiratory syncytial virus, another paramyxovirus.

scholarly journals Subcellular Localization of MxB Determines Its Antiviral Potential against Influenza A Virus

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Fiona Steiner ◽  
Jovan Pavlovic
Keyword(s):  
Antiviral Activity ◽  
Subcellular Localization ◽  
Influenza A Virus ◽  
Influenza A ◽  
Effector Proteins ◽  
Pivotal Role ◽  
Common Mechanism ◽  
Type I ◽  
N Terminus ◽  
Mx Protein

ABSTRACT Mx proteins are interferon (IFN) type I (α/β)- and type III (λ)-induced effector proteins with intrinsic antiviral activity. Mammalian Mx proteins show different subcellular localizations and distinct yet partially overlapping viral specificities. However, the precise mechanism(s) of antiviral action are still unresolved. Human MxA accumulates in the cytoplasm and inhibits a wide variety of RNA and DNA viruses, among them influenza A virus (IAV). In contrast, MxB, the second human Mx protein, localizes via its amino (N) terminus to the outer nuclear membrane at or near nuclear pores and inhibits the nuclear import of incoming human immunodeficiency viruses (HIV) and herpesviruses, but not that of IAV. Here, we evaluated whether the antiviral specificity of MxB is determined by its subcellular localization. For this purpose, we redirected MxB to the nucleus or cytoplasm by either attaching a nuclear localization signal to its N terminus or by exchanging the N terminus of MxB with that of MxA. Interestingly, ectopic expression of these MxB variants in the nucleus or in the cytoplasm rendered the host cells resistant to IAV, revealing that the capacity of MxB to block IAV replication critically depends on the site where the protein accumulates in the infected cell. Furthermore, coimmunoprecipitation (co-IP) assays demonstrated that MxB physically interacted with the nucleoprotein (NP) of IAV. Taken together, the data indicate that the subcellular localization of the MxB protein plays a pivotal role in determining its antiviral specificity. IMPORTANCE The interferon system plays a pivotal role in the defense against viral infections. The dynamin-related Mx proteins form a small family of interferon-induced effector proteins with distinct antiviral specificities and subcellular localizations. So far, it is not clear whether the different virus specificities of Mx proteins are the result of distinct mechanisms of action or are due rather to their different subcellular localization. We show here that the human MxB protein, normally localized to the outer membrane of the cell nucleus, acquires antiviral activity against IAV when redirected to the nucleus or cytoplasm, subcellular sites where other members of the Mx protein family efficiently interfere with IAV replication. Our findings thus strongly suggest that Mx proteins act primarily through a common mechanism and that their viral specificity is at least in part determined by their individual subcellular localization.

scholarly journals Sustained replication of synthetic canine distemper virus defective genomes in vitro and in vivo

2021 ◽  
Author(s):  
Natasha Tilston-Lunel ◽  
Stephen R. Welch ◽  
Sham Nambulli ◽  
Rory D. de Vries ◽  
Gregory Ho ◽  
...  
Keyword(s):  
Canine Distemper Virus ◽  
Genomic Sequence ◽  
Lymphoid Tissues ◽  
Therapeutic Effects ◽  
Type I ◽  
Dependent Manner ◽  
Vaccine Adjuvants ◽  
Canine Distemper

Defective interfering (DI) genomes restrict viral replication and induce type-I interferon. Since DI genomes have been proposed as vaccine adjuvants or therapeutic antiviral agents, it is important to understand their generation, delineate their mechanism of action, develop robust production capacities, assess their safety and in vivo longevity and determine their long-term effects. To address this, we generated a recombinant (r) canine distemper virus (CDV) from an entirely synthetic molecular clone designed using the genomic sequence from a clinical isolate obtained from a free-ranging raccoon with distemper. rCDV was serially passaged in vitro to identify DI genomes that naturally arise during rCDV replication. Defective genomes were identified by Sanger and next-generation sequencing techniques and predominant genomes were synthetically generated and cloned into T7-driven plasmids. Fully encapsidated DI particles (DIPs) were then generated using a rationally attenuated rCDV as a producer virus to drive DI genome replication. We demonstrate these DIPs interfere with rCDV replication in a dose-dependent manner in vitro. Finally, we show sustained replication of a fluorescent DIP in experimentally infected ferrets over a period of 14 days. Most importantly, DIPs were isolated from the lymphoid tissues which are a major site of CDV replication. Our established pipeline for detection, generation and assaying DIPs is transferable to highly pathogenic paramyxoviruses and will allow qualitative and quantitative assessment of the therapeutic effects of DIP administration on disease outcome.

scholarly journals Positive natural selection in primate genes of the type I interferon response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena N. Judd ◽  
Alison R. Gilchrist ◽  
Nicholas R. Meyerson ◽  
Sara L. Sawyer
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Interferon Stimulated Genes ◽  
Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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