scholarly journals NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses

2021 ◽  
Author(s):  
Hongyun Wang ◽  
Lu Zhang ◽  
Cong Zeng ◽  
Jiangpeng Feng ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Viral Infection ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Negative Regulator ◽  
Interferon Response ◽  
Rna Modification ◽  
Type I ◽  
Mrna Levels ◽  
Interferon Responses

5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, can negatively regulate type I interferon responses during viral infection. NSUN2 specifically mediates m5C methylation of IRF3 mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-β production. Knockout or knockdown of NSUN2 could enhance type I interferon responses and downstream ISG expression after viral infection in vitro. And in vivo, the antiviral innate responses is more dramatically enhanced in Nsun2+/− mice than in Nsun2+/+ mice. Four highly m5C methylated cytosines in IRF3 mRNA were identified, and their mutation could enhance the cellular IRF3 mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), Zika virus (ZIKV), or especially SARS-CoV-2 resulted in a reduction in endogenous levels of NSUN2. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover of IRF3 mRNA, while endogenous NSUN2 levels decrease after viral infection to boost antiviral responses for the effective elimination of viruses. Our results suggest a paradigm of innate antiviral immune responses ingeniously involving NSUN2-mediated m5C modification.

scholarly journals Comparison of Type I Interferon Expression in Adult and Neonatal Mice during Respiratory Viral Infection

10.29007/ltkw ◽  
2019 ◽  
Author(s):  
Zifeng Liang
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Mouse Models ◽  
Post Infection ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Killer Cell ◽  
Type I ◽  
Respiratory Viral Infection ◽  
Neonatal Mice

The aim of this paper is to identify the difference of type I interferon expression in 2- day neonatal and six-to-eight-weeks adult mice infected by Sendai virus (SeV), a single- stranded RNA virus of the family Paramyxoviridae. Sendai virus mimics the influence of respiratory syncytial virus (RSV) on humans, but does not infect humans. Although RSV has a fatal impact on people across age groups, little is understood about this common virus and the disparity between neonatal and adult immune response to it. It has been suggested by past findings that Type I interferon mRNA is present in higher levels in adults than in neonates, however there is a greater amount of interferon proteins in neonates rather than adults. To test the hypothesis that neonates are more capable of interferon production and preventing the translation of viral protein, I observed mouse models of respiratory viral infection and determined the expression of IFN-α1, IFN-α2, IFN-α5, IFN-α6, IFN-α7, IFN-β in archived mouse lung tissue samples harvested on different days post-infection with quantitative real time PCR. Expression of Glyceraldehyde 3-phosphate dehydrogenase(GAPDH), a housekeeping gene expressed constitutively in all mouse models, was used as a positive control of the experiment. To determine the ideal concentration of primer used in qPCR, primer reconstitution, primer optimization, and gel electrophoresis were conducted in advance. In addition, technical replicates and biological replicates were used to reduce error and confirm results in qPCR. In accordance with previous discovery, I found an upward trend in adults’ interferon expression from post-infection day 1 to day 5, and levels off in day 7. In contrast, neonatal levels were much higher on day 1 and remained high over the course of infection. This explains how type I interferon expression is altered in neonates to help them clear the virus at the same efficiency as adults without causing inflammation. Future research on immune response differences in human infection should focus on the evaluation of interferon protein amounts, as well as the analysis of activation of molecules downstream of the type I interferon receptors, such as signal transducer and activator of transcription (STAT) protein family. It is also crucial to compare immune cells like macrophages and natural killer cell activity in adult and neonatal mice during viral infection.

scholarly journals Timing and Magnitude of Type I Interferon Responses by Distinct Sensors Impact CD8 T Cell Exhaustion and Chronic Viral Infection

2012 ◽  
Vol 11 (6) ◽  
pp. 631-642 ◽  
Author(s):  
Yaming Wang ◽  
Melissa Swiecki ◽  
Marina Cella ◽  
Gottfried Alber ◽  
Robert D. Schreiber ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
Type I Interferon ◽  
Cd8 T Cell ◽  
Chronic Viral Infection ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Interferon Responses

scholarly journals Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

2018 ◽  
Author(s):  
Shaylynn Miller ◽  
Patrick Coit ◽  
Elizabeth Gensterblum-Miller ◽  
Paul Renauer ◽  
Nathan C Kilian ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide

AbstractObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.MethodsGenome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. Co-incubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.ConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.

scholarly journals The Scorpion Venom Peptide Smp76 Inhibits Viral Infection by Regulating Type-I Interferon Response

2018 ◽  
Vol 33 (6) ◽  
pp. 545-556 ◽  
Author(s):  
Zhenglin Ji ◽  
Fangfang Li ◽  
Zhiqiang Xia ◽  
Xingchen Guo ◽  
Minjun Gao ◽  
...  
Keyword(s):  
Viral Infection ◽  
Type I Interferon ◽  
Scorpion Venom ◽  
Interferon Response ◽  
Type I ◽  
Venom Peptide

A8.16 T helper lymphocytes and monocytes as biosensors of type I interferon responses in viral infection and autoimmunity

2014 ◽  
Vol 73 (Suppl 1) ◽  
pp. A82.2-A82
Author(s):  
Chieko Kyogoku ◽  
Biljana Smiljanovic ◽  
Joachim R Grün ◽  
Ursula Schulte-Wrede ◽  
Tobias Alexander ◽  
...  
Keyword(s):  
Viral Infection ◽  
Type I Interferon ◽  
Type I ◽  
T Helper ◽  
T Helper Lymphocytes ◽  
Interferon Responses

scholarly journals Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

2020 ◽  
Author(s):  
Clare Eckold ◽  
Vinod Kumar ◽  
January Weiner ◽  
Bachti Alisjahbana ◽  
Anca-Lelia Riza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Expression Change ◽  
Tb Treatment ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Transcriptomic Signature ◽  
Interferon Responses

Abstract Background People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.

scholarly journals Vaccinia Virus-Mediated Inhibition of Type I Interferon Responses Is a Multifactorial Process Involving the Soluble Type I Interferon Receptor B18 and Intracellular Components

2008 ◽  
Vol 83 (4) ◽  
pp. 1563-1571 ◽  
Author(s):  
Zoe Waibler ◽  
Martina Anzaghe ◽  
Theresa Frenz ◽  
Astrid Schwantes ◽  
Christopher Pöhlmann ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Type I Interferon ◽  
Poly I:C ◽  
Host Responses ◽  
Type I ◽  
Immune Modulators ◽  
Modified Vaccinia Virus Ankara ◽  
Multistep Process ◽  
Interferon Responses

ABSTRACT Poxviruses such as virulent vaccinia virus (VACV) strain Western Reserve encode a broad range of immune modulators that interfere with host responses to infection. Upon more than 570 in vitro passages in chicken embryo fibroblasts (CEF), chorioallantois VACV Ankara (CVA) accumulated mutations that resulted in highly attenuated modified vaccinia virus Ankara (MVA). MVA infection of mice and of dendritic cells (DC) induced significant type I interferon (IFN) responses, whereas infection with VACV alone or in combination with MVA did not. These results implied that VACV expressed an IFN inhibitor(s) that was functionally deleted in MVA. To further characterize the IFN inhibitor(s), infection experiments were carried out with CVA strains isolated after 152 (CVA152) and 386 CEF passages (CVA386). Interestingly, neither CVA152 nor CVA386 induced IFN-α, whereas the latter variant did induce IFN-β. This pattern suggested a consecutive loss of inhibitors during MVA attenuation. Similar to supernatants of VACV- and CVA152-infected DC cultures, recombinantly expressed soluble IFN decoy receptor B18, which is encoded in the VACV genome, inhibited MVA-induced IFN-α but not IFN-β. In the same direction, a B18R-deficient VACV variant triggered only IFN-α, confirming B18 as the soluble IFN-α inhibitor. Interestingly, VACV infection inhibited IFN responses induced by a multitude of different stimuli, including oligodeoxynucleotides containing CpG motifs, poly(I:C), and vesicular stomatitis virus. Collectively, the data presented show that VACV-mediated IFN inhibition is a multistep process involving secreted factors such as B18 plus intracellular components that cooperate to efficiently shut off systemic IFN-α and IFN-β responses.

scholarly journals Type I Interferon Response Limits Astrovirus Replication and Protects against Increased Barrier PermeabilityIn VitroandIn Vivo

2015 ◽  
Vol 90 (4) ◽  
pp. 1988-1996 ◽  
Author(s):  
Shauna A. Marvin ◽  
C. Theodore Huerta ◽  
Bridgett Sharp ◽  
Pamela Freiden ◽  
Troy D. Cline ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Barrier Permeability ◽  
Type I Ifns ◽  
Human Astroviruses ◽  
Human Astrovirus ◽  
New Evidence

ABSTRACTLittle is known about intrinsic epithelial cell responses against astrovirus infection. Here we show that human astrovirus type 1 (HAstV-1) infection induces type I interferon (beta interferon [IFN-β]) production in differentiated Caco2 cells, which not only inhibits viral replication by blocking positive-strand viral RNA and capsid protein synthesis but also protects against HAstV-1-increased barrier permeability. Excitingly, we found similar resultsin vivousing a murine astrovirus (MuAstV) model, providing new evidence that virus-induced type I IFNs may protect against astrovirus replication and pathogenesisin vivo.IMPORTANCEHuman astroviruses are a major cause of pediatric diarrhea, yet little is known about the immune response. Here we show that type I interferon limits astrovirus infection and preserves barrier permeability bothin vitroandin vivo. Importantly, we characterized a new mouse model for studying astrovirus replication and pathogenesis.

scholarly journals Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation

2021 ◽  
Vol 22 (3) ◽  
pp. 1301
Author(s):  
Ioannis Kienes ◽  
Tanja Weidl ◽  
Nora Mirza ◽  
Mathias Chamaillard ◽  
Thomas A. Kufer
Keyword(s):  
Viral Infections ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Interferon Response ◽  
Type I ◽  
Interferon Signaling ◽  
Microbial Products ◽  
Interferon Responses

Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.

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