scholarly journals uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Magnani ◽  
Filippo Macchi ◽  
Bhavani P. Madakashira ◽  
Chi Zhang ◽  
Fatima Alaydaroos ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Cell Death ◽  
Transposable Elements ◽  
Cellular Damage ◽  
Interferon Response ◽  
Type I ◽  
Dna Hypomethylation ◽  
Direct Role ◽  
Double Stranded Rna

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells.

PS02.176: LINE-1 METHYLATION LEVEL AND LOCAL IMMUNE RESPONSE IN ESOPHAGEAL CANCER

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 172-172
Author(s):  
Yoshifumi Baba ◽  
Taisuke Yagi ◽  
Yuki Kiyozumi ◽  
Yukiharu Hiyoshi ◽  
Masaaki Iwatsuki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Esophageal Cancer ◽  
Methylation Level ◽  
Cpg Island ◽  
Surrogate Marker ◽  
Esophageal Tumor ◽  
Local Immune Response ◽  
Dna Hypomethylation ◽  
Response Status

Abstract Background In cancer cells, DNA methylation may be altered in two principle ways; global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Since Long interspersed element-1 (LINE-1 or L1; a repetitive DNA retrotransposon) constitutes a substantial portion (approximately 17%) of the human genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA methylation. In previous studies, we demonstrated that LINE-1 hypomethylation was strongly associated with a poor prognosis in esophageal cancer, supporting its potential role as a prognostic marker (Ann Surg 2012). We also found that LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6 (Clin Cancer Res 2014). Given that immunotherapy, as represented by PD-1/PD-L1-targeting antibodies, has increasingly gained attention as a novel treatment strategy for esophageal cancer, better understanding of local immune response status in esophageal cancer is important. The aim of this study is to evaluate the relationship between LINE-1 methylation level and local immune response in esophageal cancer. Methods Using a non-biased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (CD8 expression) by immunohistochemical analysis (Ann Surg 2017). Results TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001). TIL-negative cases demonstrated significantly lower LINE-1 methylation level compared with TIL-positive cases (P = 0.012). This finding certainly supports that LINE-1 methylation level may influence the local immune response status. Conclusion PD-L1 expression was not related with LINE-1 methylation level. Further investigations in this field would provide deeper insights into esophageal tumor immunology and assist the development of new therapeutic strategies against esophageal cancer. Disclosure All authors have declared no conflicts of interest.

scholarly journals Canine Influenza Virus is Mildly Restricted by Canine Tetherin Protein

Viruses ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 565
Author(s):  
Yun Zheng ◽  
Xiangqi Hao ◽  
Qingxu Zheng ◽  
Xi Lin ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cellular Damage ◽  
Interferon Response ◽  
Type I ◽  
Canine Influenza Virus ◽  
Immune Factor ◽  
Canine Influenza ◽  
The Impact

Tetherin (BST2/CD317/HM1.24) has emerged as a key host-cell ·defence molecule that acts by inhibiting the release and spread of diverse enveloped virions from infected cells. We analysed the biological features of canine tetherin and found it to be an unstable hydrophilic type I transmembrane protein with one transmembrane domain, no signal peptide, and multiple glycosylation and phosphorylation sites. Furthermore, the tissue expression profile of canine tetherin revealed that it was particularly abundant in immune organs. The canine tetherin gene contains an interferon response element sequence that can be regulated and expressed by canine IFN-α. A CCK-8 assay showed that canine tetherin was effective in helping mitigate cellular damage caused by canine influenza virus (CIV) infection. Additionally, we found that the overexpression of canine tetherin inhibited replication of the CIV and that interference with the canine tetherin gene enhanced CIV replication in cells. The impact of canine tetherin on CIV replication was mild. However, these results elucidate the role of the innate immune factor, canine tetherin, during CIV infection for the first time.

RNA sensors as a mechanism of innate immune evasion among SARS-CoV2, HIV and Nipah viruses

2021 ◽  
Vol 22 ◽  
Author(s):  
Dalia Cicily Kattiparambil Dixon ◽  
Chameli Ratan ◽  
Bhagyalakshmi Nair ◽  
Sabitha Mangalath ◽  
Rachy Abraham ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Vaccine Development ◽  
Innate Immune ◽  
Interferon Response ◽  
Host Immune System ◽  
Type I ◽  
Adaptive Responses ◽  
Rna Sensors

: Innate immunity is the first line of defence elicited by the host immune system to fight against invading pathogens such as viruses and bacteria. From this elementary immune response, the more complex antigen-specific adaptive responses are recruited to provide a long-lasting memory against the pathogens. Innate immunity gets activated when the host cell utilizes a diverse set of receptors known as pattern recognition receptors (PRR) to recognize the viruses that have penetrated the host and respond with cellular processes like complement system, phagocytosis, cytokine release and inflammation and destruction of NK cells. Viral RNA or DNA or viral intermediate products are recognized by receptors like toll-like receptors(TLRs), nucleotide oligomerization domain(NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) thereby, inducing type I interferon response (IFN) and other proinflammatory cytokines in infected cells or other immune cells. But certain viruses can evade the host innate immune response to replicate efficiently, triggering the spread of the viral infection. The present review describes the similarity in the mechanism chosen by viruses from different families -HIV, SARS-CoV2 and Nipah viruses to evade the innate immune response and how efficiently they establish the infection in the host. The review also addresses the stages of developments of various vaccines against these viral diseases and the challenges encountered by the researchers during vaccine development.

Identification of a Novel Toll-Like Receptor-Independent Immunoadjuvant Pathway That Depends upon Programmed Cell Death.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 775-775
Author(s):  
Kasper Hoebe ◽  
Edith Janssen ◽  
Bruce Beutler
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Immune Responses ◽  
Ultraviolet Light ◽  
Adaptive Immune Response ◽  
Type I ◽  
Toll Like Receptors ◽  
Adjuvant Effect ◽  
Tlr Signaling ◽  
Adaptive Immune

Abstract Molecules of microbial origin, and synthetic derivatives of these molecules, have long been used for their immuno-adjuvant effect, and as the key sensors of microbial infection, Toll-like receptors (TLRs) are thought to be essential for adjuvanticity. To the contrary, we now demonstrate the existence of a robust, TLR-independent pathway for adjuvant effect: one that is actually far stronger than the TLR-dependent pathway. Activation of Toll-like receptors (TLRs) and the subsequent production of cytokines such as type I interferon leads to the maturation of dendritic cells (DCs) with upregulation of MHC molecules and costimulatory molecules such as CD40, CD80 and CD86, allowing for optimal interaction between DCs and T-cells. We have determined that TLR signal transduction is minimally dependent upon two adapter proteins, MyD88 and TRIF. In compound homozygous mutant (DKO) mice that lack functional MyD88 and TRIF, there is complete abrogation of all TLR signaling. Such animals therefore comprise a unique model with which to study TLR-independent immune responses. We have now used DKO mice to determine whether an adaptive immune response can be obtained in the absence of TLR signaling. As expected, adjuvanticity obtained via “classical” microbial adjuvants such as complete Freund’s adjuvant or LPS was completely absent in DKO mice. However, subcutaneous administration of syngeneic murine cells expressing ovalbumin and rendered apoptotic by exposure to ultraviolet light resulted in a strong T-cell response in vivo, with impressive production of interferon-g by CD8+ cells and efficient killing of EL-4 cells that expressed CD8-specific OVA peptides, both in wildtype and DKO mice. Adjuvanticity was observed only in the context of apoptosis, in that living cells, not exposed to ultraviolet light before injection, induced little or no response. Moreover, the mixture of the protein antigen with apoptotic cells was insufficient to induce an adaptive immune response; rather, only cells that expressed the protein prior to induction of apoptosis were stimulatory. These results indicate the existence of a specific, cell death-dependent mechanism for adjuvanticity that is TLR-independent and induced by endogenous molecules. We propose that this new adjuvant pathway is of fundamental importance to immune responses at large. We believe that it is required for initiation of the adaptive immune response witnessed in the context of allograft rejection, graft-versus-host disease, and autoimmune diseases as well.

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 Endogenous mitochondrial double‐stranded RNA is not an activator of the type I interferon response in human pancreatic beta cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra Coomans de Brachène ◽  
Angela Castela ◽  
Anyïshai E. Musuaya ◽  
Lorella Marselli ◽  
Piero Marchetti ◽  
...  
Keyword(s):  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Viral Infections ◽  
Human Islets ◽  
Interferon Response ◽  
Interferon Α ◽  
Type I ◽  
Type I Ifn ◽  
Danger Signal ◽  
Double Stranded Rna

Abstract Background Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to viral infections. However, not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other “danger signals”. Accumulation of mitochondrial double-stranded RNA (mtdsRNA; a danger signal), secondary to silencing of members of the mitochondrial degradosome, PNPT1 and SUV3, has been described to activate the innate immune response. Methods To evaluate whether mtdsRNA represents a “danger signal” for pancreatic beta cells in the context of T1D, we silenced PNPT1 and/or SUV3 in slowly proliferating human insulin-secreting EndoC-βH1 cells and in non-proliferating primary human beta cells and evaluated dsRNA accumulation by immunofluorescence and the type I IFN response by western blotting and RT-qPCR. Results Only the simultaneous silencing of PNPT1/SUV3 induced dsRNA accumulation in EndoC-βH1 cells but not in dispersed human islets, and there was no induction of a type I IFN response. By contrast, silencing of these two genes individually was enough to induce dsRNA accumulation in fibroblasts present in the human islet preparations. Conclusions These data suggest that accumulation of endogenous mtdsRNA following degradosome knockdown depends on the proliferative capacity of the cells and is not a mediator of the type I IFN response in human pancreatic beta cells.

scholarly journals The intensity of the immune response to LPS and E. coli regulates the induction of preterm labor in Rhesus Macaques

2021 ◽  
Author(s):  
Monica Cappelletti ◽  
Pietro Presicce ◽  
Feyiang Ma ◽  
Paranthaman Senthamaraikannan ◽  
Lisa Miller ◽  
...  
Keyword(s):  
Immune Response ◽  
Rhesus Macaque ◽  
Preterm Labor ◽  
Iron Homeostasis ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Neutrophil Infiltration ◽  
Interferon Response ◽  
Type I ◽  
E Coli

Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed Rhesus macaque models of IUI driven by lipopolysaccharyde (LPS) or live  E. coli . PTL did not occur in LPS challenged Rhesus macaque while  E. coli  infected animals frequently delivered preterm. Although LPS and live  E. coli  both caused immune cell infiltration,  E. coli  infected animals showed higher levels of inflammatory mediators, particularly IL6 and prostaglandins, in the chorioamnion decidua and amniotic fluid. Neutrophil infiltration in the chorion was a common feature to both LPS and  E. coli . However, neutrophilic infiltration and  IL6 and PTGS2 expression in the amnion was specifically induced by live  E. coli . RNASeq analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon response, chemotaxis, sumoylation and iron homeostasis were upregulated in the  E. coli group compared to the LPS group. Our data suggest that intensity of the host immune response to IUI may determine susceptibility to PTL.

scholarly journals Human Cytomegalovirus Immediate Early 86-kDa Protein Blocks Transcription and Induces Degradation of the Immature Interleukin-1β Protein during Virion-Mediated Activation of the AIM2 Inflammasome

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sara Botto ◽  
Jinu Abraham ◽  
Nobuyo Mizuno ◽  
Kara Pryke ◽  
Bryan Gall ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Innate Immune ◽  
Host Cells ◽  
Interleukin 1Β ◽  
Immediate Early ◽  
Interferon Response ◽  
Type I

ABSTRACTSecretion of interleukin-1β (IL-1β) represents a fundamental innate immune response to microbial infection that, at the molecular level, occurs following activation of proteolytic caspases that cleave the immature protein into a secretable form. Human cytomegalovirus (HCMV) is the archetypal betaherpesvirus that is invariably capable of lifelong infection through the activity of numerous virally encoded immune evasion phenotypes. Innate immune pathways responsive to cytoplasmic double-stranded DNA (dsDNA) are known to be activated in response to contact between HCMV and host cells. Here, we used clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9 (Cas9) genome editing to demonstrate that the dsDNA receptorabsentinmelanoma 2 (AIM2) is required for secretion of IL-1β following HCMV infection. Furthermore, dsDNA-responsive innate signaling induced by HCMV infection that leads to activation of the type I interferon response is also shown, unexpectedly, to play a contributory role in IL-1β secretion. Importantly, we also show that rendering virus particles inactive by UV exposure leads to substantially increased IL-1β processing and secretion and that live HCMV can inhibit this, suggesting the virus encodes factors that confer an inhibitory effect on this response. Further examination revealed that ectopic expression of the immediate early (IE) 86-kDa protein (IE86) is actually associated with a block in transcription of the pro-IL-1β gene and, independently, diminishment of the immature protein. Overall, these results reveal two new and distinct phenotypes conferred by the HCMV IE86 protein, as well as an unusual circumstance in which a single herpesviral protein exhibits inhibitory effects on multiple molecular processes within the same innate immune response.IMPORTANCEPersistent infection with HCMV is associated with the operation of diverse evasion phenotypes directed at antiviral immunity. Obstruction of intrinsic and innate immune responses is typically conferred by viral proteins either associated with the viral particle or expressed immediately after entry. In line with this, numerous phenotypes are attributed to the HCMV IE86 protein that involve interference with innate immune processes via transcriptional and protein-directed mechanisms. We describe novel IE86-mediated phenotypes aimed at virus-induced secretion of IL-1β. Intriguingly, while many viruses target the function of the molecular scaffold required for IL-1β maturation to prevent this response, we find that HCMV and IE86 target the IL-1β protein specifically. Moreover, we show that IE86 impairs both the synthesis of the IL-1β transcript and the stability of the immature protein. This indicates an unusual phenomenon in which a single viral protein exhibits two molecularly separate evasion phenotypes directed at a single innate cytokine.

The NLR (NBD-LRR containing) Family of Intracellular Sensors in Inflammation and Immune Response.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-22-SCI-22
Author(s):  
Jenny P-Y. Ting
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Gene Family ◽  
Conflicts Of Interest ◽  
Type I ◽  
Nucleotide Binding Domain ◽  
Large Gene Family ◽  
Large Gene ◽  
Leucine Rich Repeats ◽  
Production Cell

Abstract Abstract SCI-22 The NLR gene family encodes proteins that are comprised of conserved nucleotide-binding domain (NBD) and leucine rich-repeats (LRR). These genes are conserved from plants, lower animals to mammals. Family members include CIITA, NOD1, NOD2, and NLRP3. Several of these genes are genetically linked to immunodeficiency, inflammatory and immune diseases. This large gene family controls a number of innate responses, including inflammasome function leading to IL-1b/IL-18 production, cell death and type I IFN production. This talk will discuss the broad function of this family of genes, with emphasis on their regulation of inflammation and innate immunity, and their divergent roles in pathogen responses. Disclosures No relevant conflicts of interest to declare.

scholarly journals Integrated Transcriptomic and Proteomic Analysis of Red Blood Cells from Rainbow Trout Challenged with VHSV Point Towards Novel Immunomodulant Targets

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 63 ◽  
Author(s):  
Nombela ◽  
Lopez-Lorigados ◽  
Salvador-Mira ◽  
Puente-Marin ◽  
Chico ◽  
...  
Keyword(s):  
Immune Response ◽  
Rainbow Trout ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Antigen Processing ◽  
Head Kidney ◽  
Interferon Response ◽  
Type I ◽  
Fish Viruses

Teleost red blood cells (RBCs) are nucleated and therefore can propagate cellular responses to exogenous stimuli. RBCs can mount an immune response against a variety of fish viruses, including the viral septicemia hemorrhagic virus (VHSV), which is one of the most prevalent fish viruses resulting in aquaculture losses. In this work, RBCs from blood and head kidney samples of rainbow trout challenged with VHSV were analyzed via transcriptomic and proteomic analyses. We detected an overrepresentation of differentially expressed genes (DEGs) related to the type I interferon response and signaling in RBCs from the head kidney and related to complement activation in RBCs from blood. Antigen processing and presentation of peptide antigen was overrepresented in RBCs from both tissues. DEGs shared by both tissues showed an opposite expression profile. In summary, this work has demonstrated that teleost RBCs can modulate the immune response during an in vivo viral infection, thus implicating RBCs as cell targets for the development of novel immunomodulants.

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