Curcuminoids Suppress EV-D68 Infection via the CRYAB-RBM26 Axis by Reversing Viral Hijacking of Nucleic Acid Metabolism and Activating IFN Pathways
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Tingting Chen
PROVIDER: PXD066985 | iProX | Wed Aug 06 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:The interferon (IFN) response is crucial for antiviral activity, but its overstimulation can lead to a wide range of autoimmune disorders. The cytoplasmic pattern recognition receptor RIG-I detects viral double stranded RNAs (dsRNAs) and endogenous polymerase III transcripts carrying a 5′-triphosphate (5′-ppp) or 5′-diphosphate (5′-pp) moiety, triggering phosphorylation of IRF3 and IFN immune response. While many viral RNAs initiate with 5′-ppp-adenosine (5′-pppA) and most endogenous Pol III transcripts in higher eukaryotes start with 5′-ppp-guanosine (5′-pppG), no apparent reason for this bias has been identified so far. Here we demonstrate that dsRNAs initiating with 5′-pppA trigger stronger RIG-I/IFN response than those starting with 5′-pppG. We show that several GTP-binding proteins interact preferentially with 5′-pppG RNAs. Finally, supplementation with guanosine, but not adenosine, which rapidly increases intracellular concentrations of GTP and ATP respectively, eliminates the difference in immunogenicity between 5′-pppG and 5′-pppA RNAs. Our findings suggest that 5′-pppG RNAs may enable certain RNA viruses and Pol III transcripts to limit detection by innate immune receptors. These results offer new insights into the sequence-dependent activation of the RIG-I/IFN pathway and have important implications for both antiviral immunity and the role of Pol III-derived RNAs in autoimmune diseases.
2026-05-07 | PXD065769 | Pride
Project description:Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies and have been successfully employed for the treatment of viral diseases. Humans express twelve IFN-alpha (α) subtypes, which activate downstream signalling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in type I IFN immunity and the presence of anti- IFN autoantibodies account for very severe courses of COVID-19, therefore, early administration of type I IFNs may be protective against life-threatening disease. Here we comprehensively analysed the antiviral activity of all IFNα subtypes against SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate and low antiviral IFNs. In particular IFNα5 showed superior antiviral activity against SARS-CoV-2 infection. Dose-dependency studies further displayed additive effects upon co-administered with the broad antiviral drug remdesivir in cell culture. Transcriptomics of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in type I IFN signalling pathways, negative regulation of viral processes and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multi-modular definition of antiviral host responses mediated by defined type I IFNs. This knowledge shall support the development of novel therapeutic approaches against SARS-CoV-2.
2022-02-09 | PXD026079 | Pride
Project description:A single high dose of IFN? activates powerful cellular responses in which many antiviral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells down-regulate this initial response rapidly. However, the expression of many antiviral proteins that do no harm is sustained, prolonging a substantial part of the initial antiviral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFN?-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced antiviral genes that show prolonged expression are driven by distinct interferon stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFN?, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase of other IFN?-induced proteins, and to constitutive resistance to DNA damage. We classified genes into U-ISGF3-induced genes and classical ISGF3-induced genes using microarray data. We identified 150 genes that are up-regulated by IFN? after 6 h. Among these IFN?-induced genes, only 29 (20%) were induced by the up-regulation of Y701F-STAT1, indicating that these are induced by U-ISGF3. Among the remaining 121 IFN?-induced genes (150 minus 29), 73 are induced by IFN? as well as IFN?, and 48 are induced only by IFN?. Total 5 RNA samples were analyzed in duplicate on microarray chips. Untreated cells and empty vector-transfected cells were the control of IFN treated cells and Y701F-STAT1-transfected cells, respectively.
2013-09-18 | E-GEOD-50954 | biostudies-arrayexpress
Project description:Type-I (e.g. IFN-alpha, IFN-beta) and type-II IFNs (IFN-gamma) have antiviral, antiproliferative, and immunomodulatory properties. Both types of IFN signal through the Jak/STAT pathway to elicit antiviral activity, yet IFN-gamma is thought to do so only through STAT1 homodimers while type-I IFNs activate both STAT1- and STAT2-containing complexes such as ISGF3. Here we show that ISGF3II - composed of phosphorylated STAT1, unphosphorylated STAT2, and IRF9 - also plays a role in IFN-gamma-mediated antiviral activity in humans. Using phosphorylated STAT1 as a marker for IFN signaling, western blot analysis of IFN-alpha2a treated human A549 cells revealed that pSTAT1 (Y701) levels peaked at 1h, decreased by 6h, and remained at low levels for up to 48h. Cells treated with IFN-gamma showed a biphasic pSTAT1 response with an early peak at 1-2h and a second peak at 15-24h. Gene expression microarray following IFN-gamma treatment for 24h indicated an induction of antiviral genes that are induced by ISGF3 and associated with a type-1 IFN response. Induction of these genes by autocrine type-I and type-III IFN signaling was ruled out using neutralizing antibodies to these IFNs in biological assays and by qRT-PCR. Despite the absence of autocrine IFNs, IFN-gamma treatment induced formation of ISGF3II. This novel transcription factor complex binds to ISRE promoter sequences, as shown by ChIP analysis of the PKR promoter. STAT2 and IRF9 knockdown in A549 cells reversed IFN-gamma-mediated ISRE induction and antiviral activity - implicating ISGF3II formation as a significant component of the cellular response and biological activity of IFN-gamma. Two treatments using three biological replicates each were performed using three million A549 cells. Each was seeded overnight in 10mL complete RPMI and treated. Three were treated with alpha-IFN and three treated with gamma-IFN for 24h. Control samples were left untreated.
2011-01-19 | E-GEOD-25113 | biostudies-arrayexpress
Project description:Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in its ability to be sexually transmitted. The testes have been implicated as sites of long-term ZIKV replication, and our previous studies have identified Sertoli cells (SC), the nurse cells of the seminiferous epithelium that govern spermatogenesis, as major targets of ZIKV infection. To improve our understanding of the host-ZIKV interaction within human testicular cells, we analyzed ZIKV-induced proteome changes in SC and mixed seminiferous tubule cells (STC) using high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that ZIKV infection in SC and STC induced distinct IFN-stimulated proteins and impacted pathways and functional networks associated with innate antiviral defense. IFN signaling was the most significantly enriched pathway and MX1 was the most abundant IFN-stimulated protein in both SC and STC. Increased levels of MX1 at later time points of infection coincided with diminished propagation of ZIKV in SC, whereas silencing of MX1 and IFIT1 enhanced peak ZIKV titers in SC. Furthermore, although downstream IFN-I signaling was found to be functional and restricted ZIKV replication in SC, in comparison to A549 cells, SC exhibited dampened expression of IFN-I/III-stimulated genes despite higher levels of virus progeny and IFN-I/III transcripts. Together, this study highlights the IFN-I/III response as a driver of the antiviral state that limits ZIKV infection in SC and suggests that delayed and reduced robustness of innate antiviral defense in SC may contribute to ZIKV persistence in the testes.
2021-09-10 | PXD025133 | Pride
Project description:Transcriptome analysis of RNA samples from human PBMCs of IFN-beta treated multiple sclerosis patients. Interferon (IFN)-b-1a (Avonex) and longer half-life, polyethylene glycol-conjugated IFN-b-1a (PEG-IFN-b-1a, Plegridy), may generate different molecular responses. At 6 h, non-PEGylated IFN-b-1a injection upregulated expression of 136 genes and PEG-IFN-b-1a upregulated 85. At 24 h, induction was maximal; IFN-b-1a upregulated476 genes and PEG-IFN-b-1a now upregulated 598. Long-term PEG-IFN-b-1a therapy increased expression of antiviral and immune-regulatory genes (IFIH1, TLR8, IRF5, TNFSF10 [TRAIL], STAT3, JAK2, IL15, and RB1) and IFN signaling pathways (IFNB1, IFNA2, IFNG, IRF7), but downregulated expression of inflammatory genes (TNF, IL1B, and SMAD7). Long-term PEG-IFN-b-1a induced longer and stronger expression of Th1, Th2, Th17, chemokine, and antiviral proteins than long-term IFN-b-1a. Long-term therapy also primed the immune system, evoking higher gene and protein induction after IFN reinjection at 7 months than at 1 month of PEG-IFN-b-1a treatment. Both forms of IFN-b balanced correlations of expression among these genes and proteins, with positive correlations between Th1 and Th2 families, quelling the ‘‘cytokine storm’’ of untreated MS. Both IFNs induced long-term, potentially beneficial, molecular effects on immune and possibly neuroprotective pathways in MS.
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Project description:In acute HIV infection immune activation may provide target cells and drive virus replication, which innate immunity may limit. Thus, the net effects of inflammatory mediators, including type I interferon (IFN-I), are unclear. Here, we block IFN-I signaling during pathogenic acute SIV infection with an IFN-I receptor antagonist. Delayed antiviral gene expression, increased SIV reservoir, increased CD4 T cell depletion and accelerated progression to AIDS and death ensue despite decreased T cell activation. In contrast, IFNα2a treatment initially upregulates antiviral genes and prevents systemic SIV infection after rectal challenge. Antiviral gene expression normalizes, and infection ensues with fewer transmitted/founder variants. Continued IFNα2a treatment causes delayed antiviral gene expression, increased SIV reservoir and increased CCR5+ CD4 T cell loss. Thus, the precise timing of antiviral gene expression has a profound impact on disease course. The benefits of early antiviral activity outweigh the harms of increased immune activation in acute SIV infection. SRA Study accession: SRP034563, BioProject ID:PRJNA231884
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2026-02-23 | PXD064360 | Pride
Project description:Iron withholding controls infections by limiting the pathogens’ access to iron from the host. Viruses directly utilize intracellular materials, including iron, to complete their life cycles. Emerging evidence suggests the importance of withholding iron in limiting viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host’s antiviral defense remain unknown. Here we show that viral infections facilitate the polyubiquitination and degradation of ferroportin (FPN1, the only cellular iron exporter) by upregulating the host E3 ubiquitin ligase DTX3L, leading to an elevation in cellular iron levels. Excessive ferrous suppresses type I IFN responses and autophagy by promoting TBK1 hydroxylation and STING carbonylation in macrophages. FPN1 deficiency suppresses host antiviral defense and facilitates viral replication in vitro and in vivo, while DTX3L deficiency has the opposite effect. These results reveal that viruses hijack host FPN1 to disrupt iron withholding and achieve immune escape, and suggest that iron homeostasis maintained by FPN1 is required for the optimal activation of TBK1- and STING-dependent antiviral responses.
2025-01-01 | GSE280144 | GEO
Project description:Viruses target mitochondria, critical for antiviral defense and metabolism, to evade immunity. While mitochondrial antiviral-signaling protein (MAVS) is known for its regulation of type I interferon (IFN) signaling, we discover that its overarching primary role is safeguarding mitochondrial integrity against virus- and toxin-induced mitophagy. This function is critical in enacting a potent, IFN/NF-κB-independent antiviral response. Using SARS-CoV-2 (CoV-2) infection model, where disruption of MAVS aggregation and induction of mitophagy were observed, we demonstrate that functional MAVS prevents CoV-2-induced mitophagy and restricts viral replication without engaging type I or III interferon (IFN), and NF-κB pathways. Employing MAVS-knockout and MAVS:IFNAR1 double-knockout cells, and inhibition studies, our results further establish MAVS as a critical protector against virus- and chemical mitotoxin-induced mitophagy. Loss of MAVS results in increased mitochondrial membrane depolarization, reduced oxidative potential, and increased PINK1-dependent mitophagy leading to elevated viral replication-all reversed by MAVS supplementation. The IFN-independent antiviral immunity generated by MAVS-driven mitochondrial safeguarding conferred robust protection against mitophagy-inducing viruses, such as CoV-2 and JEV, but not DENV, which does not trigger mitophagy. By facilitating the mitochondrial integrity, MAVS governs the overall innate antiviral immunity- integrating IFN-dependent and IFN-independent mechanisms- and energy metabolism in the host cells. Thus, the regulation of these central functions makes MAVS a prime target for subverting host defenses and cellular energy homeostasis. These insights underscoring MAVS’s wider role in sustaining mitochondrial homeostasis positions it as a promising target for antiviral strategies.
2025-04-30 | GSE293066 | GEO