scholarly journals Enhanced Replication of Mouse Adenovirus Type 1 following Virus-Induced Degradation of Protein Kinase R (PKR)

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Danielle E. Goodman ◽  
Carla D. Pretto ◽  
Tomas A. Krepostman ◽  
Kelly E. Carnahan ◽  
Katherine R. Spindler
Keyword(s):  
Immune System ◽  
Protein Kinase ◽  
Innate Immune System ◽  
Rna Viruses ◽  
Adenovirus Type ◽  
Antiviral Response ◽  
Innate Immune ◽  
Protein Kinase R ◽  
Dna Virus

ABSTRACTProtein kinase R (PKR) plays a major role in activating host immunity during infection by sensing double-stranded RNA (dsRNA) produced by viruses. Once activated by dsRNA, PKR phosphorylates the translation factor eukaryotic initiation factor 2α (eIF2α), halting cellular translation. Many viruses have methods of inhibiting PKR activation or its downstream effects, circumventing protein synthesis shutdown. These include sequestering dsRNA or producing proteins that bind to and inhibit PKR activation. Here we describe our finding that in multiple cell types, PKR was depleted during mouse adenovirus type 1 (MAV-1) infection. MAV-1 did not appear to be targeting PKR at the transcriptional or translational level, because total PKR mRNA levels and levels of PKR mRNA bound to polysomes were unchanged or increased during MAV-1 infection. However, inhibiting the proteasome reduced the PKR depletion seen in MAV-1-infected cells, whereas inhibiting the lysosome had no effect. This suggests that proteasomal degradation alone is responsible for PKR degradation during MAV-1 infection. Time course experiments indicated that the degradation occurs early after infection. Infecting cells with UV-inactivated virus prevented PKR degradation, whereas inhibiting viral DNA replication did not. Together, these results suggest that an early viral gene is responsible. Degradation of PKR is a rare mechanism to oppose PKR activity, and it has been described in only six RNA viruses. To our knowledge, this is the first example of a DNA virus counteracting PKR by degrading it.IMPORTANCEThe first line of defense in cells during viral infection is the innate immune system, which is activated by different viral products. PKR is a part of this innate immune system and is induced by interferon and activated by dsRNA produced by DNA and RNA viruses. PKR is such an important part of the antiviral response that many viral families have gene products to counteract its activation or the resulting effects of its activity. Although a few RNA viruses degrade PKR, this method of counteracting PKR has not been reported for any DNA viruses. MAV-1 does not encode virus-associated RNAs, a human adenoviral defense against PKR activation. Instead, MAV-1 degrades PKR, and it is the first DNA virus reported to do so. The innate immune evasion by PKR degradation is a previously unidentified way for a DNA virus to circumvent the host antiviral response.

scholarly journals Enhanced replication of mouse adenovirus type 1 following virus-induced degradation of protein kinase R (PKR)

2019 ◽  
Author(s):  
Danielle E. Goodman ◽  
Carla D. Pretto ◽  
Tomas A. Krepostman ◽  
Kelly E. Carnahan ◽  
Katherine R. Spindler
Keyword(s):  
Immune System ◽  
Protein Kinase ◽  
Innate Immune System ◽  
Rna Viruses ◽  
Adenovirus Type ◽  
Antiviral Response ◽  
Innate Immune ◽  
Protein Kinase R ◽  
Dna Virus

AbstractProtein kinase R (PKR) plays a major role in activating host immunity during infection by sensing dsRNA produced by viruses. Once activated by dsRNA, PKR phosphorylates the translation factor eIF2α, halting cellular translation. Many viruses have methods of inhibiting PKR activation or its downstream effects, circumventing protein synthesis shutdown. These include sequestering dsRNA or producing proteins that bind to and inhibit PKR activation. Here we describe our finding that in multiple cell types, PKR was depleted during mouse adenovirus type 1 (MAV-1) infection. MAV-1 did not appear to be targeting PKR at a transcriptional or translational level because total PKR mRNA levels and levels of PKR mRNA bound to polysomes were unchanged or increased during MAV-1 infection. However, inhibiting the proteasome reduced the PKR depletion seen in MAV-1-infected cells, whereas inhibiting the lysosome had no effect. This suggests that proteasomal degradation alone is responsible for PKR degradation during MAV-1 infection. Time course experiments indicate that the degradation occurs early after infection. Infecting cells with UV-inactivated virus prevented PKR degradation, whereas inhibiting viral DNA replication did not. Together these results suggest that an early viral gene is responsible. Degradation of PKR is a rare mechanism to oppose PKR activity, and it has only been described in six RNA viruses. To our knowledge, this is the first example of a DNA virus counteracting PKR by degrading it.ImportanceThe first line of defense in cells during viral infection is the innate immune system, which is activated by different viral products. PKR is a part of this innate immune system and is induced by interferon and activated by dsRNA produced by DNA and RNA viruses. PKR is such an important part of the antiviral response that many viral families have gene products to counteract its activation or the resulting effects of its activity. Although a few RNA viruses degrade PKR, this method of counteracting PKR has not been reported for any DNA viruses. MAV-1 does not encode virus-associated RNAs, a human adenoviral defense against PKR activation. Instead, MAV-1 degrades PKR, and it is the first DNA virus reported to do so. The innate immune evasion by PKR degradation is a previously unidentified way for a DNA virus to circumvent the host antiviral response.

scholarly journals Terminal uridylyltransferases target RNA viruses as part of the innate immune system

2018 ◽  
Vol 25 (9) ◽  
pp. 778-786 ◽  
Author(s):  
Jérémie Le Pen ◽  
Hongbing Jiang ◽  
Tomás Di Domenico ◽  
Emma Kneuss ◽  
Joanna Kosałka ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Rna Viruses ◽  
Innate Immune ◽  
Target Rna

scholarly journals RNA Sensor MDA5 Suppresses LINE-1 Retrotransposition By Regulating The Promoter Activity of LINE-1 5’-UTR

2021 ◽  
Author(s):  
Jiaxiu Yan ◽  
Yifei Zhao ◽  
Juan Du ◽  
Yu Wang ◽  
Shaohua Wang ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Promoter Activity ◽  
Feedback Loop ◽  
Innate Immune ◽  
Functional Region ◽  
Protein Levels ◽  
Long Interspersed Elements ◽  
Associated Proteins

Abstract Background: Type 1 long interspersed elements, or LINE-1, are the only active retroelements in human cells. The retrotransposition process of LINE-1 can trigger the activation of the innate immune system and has been proposed to play a role in the development of several autoimmune diseases, including Aicardi-Goutières syndrome (AGS). In contrast, all known AGS-associated proteins, except MDA5, have been reported to affect LINE-1 activity. Thus, MDA5 is likely to also function as a LINE-1 suppressor. Results: MDA5 was found to potently suppress LINE-1 activity in a reporter-based LINE-1 retrotransposition assay. Although MDA5 is an endogenous RNA sensor able to activate the innate immune system, increased interferon (IFN) expression only weakly contributed to MDA5-mediated LINE-1 suppression. Instead, MDA5 effectively reduced the levels of LINE-1 ORF1p and ORF2p, as a result of the MDA5-mediated downregulation of the promoter activity of LINE-1 5’-UTR, and the subsequent generation of LINE-1 RNA. Interestingly, despite MDA5 being a multi-domain protein, the N-terminal 2CARD domain alone is sufficient to inhibit LINE-1 activity. Conclusion: Our data reveal that MDA5 functions as a promoter regulator and suppresses the promoter activity of LINE-1 5’-UTR. Consequently, MDA5 reduces LINE-1 RNA and protein levels, and ultimately inhibits LINE-1 retrotransposition. In contrast, MDA5-induced IFN expression only plays a mild role in MDA5-mediated LINE-1 suppression. In addition, the N-terminal 2CARD domain was found to be a functional region for MDA5 upon inhibition of LINE-1 replication. Thus, our data suggest that besides being an initiator of the innate immune system, MDA5 is also an effector against LINE-1 activity, potentially forming a feedback loop by suppressing LINE-1-induced innate immune activation.

scholarly journals Identification of hub genes related to the progression of type 1 diabetes by computational analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
G. Prashanth ◽  
Basavaraj Vastrad ◽  
Anandkumar Tengli ◽  
Chanabasayya Vastrad ◽  
Iranna Kotturshetti
Keyword(s):  
Immune System ◽  
Regulatory Network ◽  
Innate Immune System ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Hub Genes

Abstract Background Type 1 diabetes (T1D) is a serious threat to childhood life and has fairly complicated pathogenesis. Profound attempts have been made to enlighten the pathogenesis, but the molecular mechanisms of T1D are still not well known. Methods To identify the candidate genes in the progression of T1D, expression profiling by high throughput sequencing dataset GSE123658 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and gene ontology (GO) and pathway enrichment analyses were performed. The protein-protein interaction network (PPI), modules, target gene - miRNA regulatory network and target gene - TF regulatory network analysis were constructed and analyzed using HIPPIE, miRNet, NetworkAnalyst and Cytoscape. Finally, validation of hub genes was conducted by using ROC (Receiver operating characteristic) curve and RT-PCR analysis. A molecular docking study was performed. Results A total of 284 DEGs were identified, consisting of 142 up regulated genes and 142 down regulated genes. The gene ontology (GO) and pathways of the DEGs include cell-cell signaling, vesicle fusion, plasma membrane, signaling receptor activity, lipid binding, signaling by GPCR and innate immune system. Four hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell-cell signaling, cytokine signaling in immune system, signaling by GPCR and innate immune system. ROC curve and RT-PCR analysis showed that EGFR, GRIN2B, GJA1, CAP2, MIF, POLR2A, PRKACA, GABARAP, TLN1 and PXN might be involved in the advancement of T1D. Molecular docking studies showed high docking score. Conclusions DEGs and hub genes identified in the present investigation help us understand the molecular mechanisms underlying the advancement of T1D, and provide candidate targets for diagnosis and treatment of T1D.

scholarly journals LA RESPUESTA INMUNITARIA FRENTE AL VIRUS SARS-CoV-2

2020 ◽  
Vol 3 (9) ◽  
pp. 64-86
Author(s):  
SERGIO ROBERTO AGUILAR-RUIZ ◽  
FRANCISCO JAVIER SÁNCHEZ-PEÑA
Keyword(s):  
Immune System ◽  
Viral Entry ◽  
Immune Cells ◽  
Innate Immune System ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Adaptive Immune ◽  
Infected Cells ◽  
Systemic Pathology

The immune response against SARS-CoV-2 is similar to that against other viruses, where the innate immune system acts at early stages through the secretion of type 1 interferon (type 1 IFN), which prevents viral replication and the activation of natural killer (NK) cells. Later, the adaptive immune system acts through CD8+ cytotoxic T-lymphocytes and antibody production, which aim to destroy infected cells and block viral entry into cells. All the above leads to the elimination of the virus and mild symptomatology. However, in individuals with a weakened immune system, the viral infection spreads and leads to a potent inflammatory response, which leads to the recruitment of immune cells to the lungs, where they can cause severe pulmonary and even systemic pathology.

scholarly journals Evidence for Innate Immune System Activation in HIV Type 1–Infected Elite Controllers

2013 ◽  
Vol 209 (6) ◽  
pp. 931-939 ◽  
Author(s):  
Sonya Krishnan ◽  
Eleanor M. P. Wilson ◽  
Virginia Sheikh ◽  
Adam Rupert ◽  
Daniel Mendoza ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Elite Controllers ◽  
Immune System Activation ◽  
System Activation ◽  
Hiv Type 1

Innate Immune-mediated Antiviral Response to SARS-CoV-2 and Convalescent sera a potential Prophylactic and Therapeutic Agent to Tackle COVID-19 (Preprint)

2020 ◽  
Author(s):  
Abdullah Abdullah ◽  
Shah Faisal
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Viral Replication ◽  
Innate Immune System ◽  
Passive Immunization ◽  
Innate Immune ◽  
Alveolar Cells ◽  
Experimental Drugs ◽  
Immune Mediated

UNSTRUCTURED The whole world is confronting the pandemic of SARS-CoV-2. And unfortunately there is no vaccine to prevent from novel coronavirus infection. Beside several experimental drugs, the strong immune responses and convalescent sera are the current two potential options to tackle COVID-19 infection. When the virus get enter into the lungs the innate immune system activated. Innate immune-mediated antiviral responses is initiated by the recognition of viral invasion through PAMPs. In coronavirus the pathogen associated molecular patterns are recognized by toll like receptors (TLR-3 & 7), endosomal ribonucleic acid receptors, RNA in cytosol and by pattern recognition receptor (PRR RIG-1) in the alveolar cells and site of invasion. Nuclear factor (NF-κB) and interferon regulatory transcription factor (IRF3) are activated in response to above recognition episode and translocate to nucleus. These transcription factors in the nucleus initiate the expression of interferon type 1 and pro-inflammatory cytokine storm, which leads to first line of defense at site of viral entrance. The effectiveness of innate immune system greatly relies on type 1 interferon’s and its cascade, because of their role in inhibition of viral replication and initiation of adaptive immune responses. The successful interferon type 1 response put down the viral replication and transmission at prompt point. Passive immunization is the administering of antibodies into infected patients which is taken from recovered individuals. The convalescent sera of the recovered COVID-19 patients contains antiviral neutralizing antibodies and used for the purpose of prophylaxis in exposed and therapeutically in infected individuals by SARS-CoV-2. The convalescent sera is found effective when administered early at the onset of symptoms.

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