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ISGs work with co-factors in varied ways to inhibit viral replication through diverse mechanisms. (A) YTHDF2 recognizes m⁶A methylation on the ϵ in HBV RNA transcripts, recruiting catalytic ISG20 to degrade HBV RNA. (B) ZAP recruits TRIM25 to ubiquitinate other host proteins, which may alter their native cellular or viral-associated activities in order to inhibit viral translation. (C) ZAP recognizes CG motifs in viral RNA and forms a complex with TRIM25 and the endonuclease KHNYN, which then putatively cleaves ZAP-bound RNA. (D) SHFL inhibits DENV replication by interacting with the viral RNA 3’UTR binding proteins PABPC1 and LARP1 and potentially inhibiting recruitment of further translation machinery.
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Interferon (IFN) signaling induces the expression of a wide array of genes, collectively referred to as IFN-stimulated genes (ISGs) that generally function to inhibit viral replication. RNA viruses are frequently targeted by ISGs through recognition of viral replicative intermediates and molecular features associated with viral genomes, or the lack...
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Previous studies have implicated both zinc finger antiviral protein (ZAP) and oligoadenylate synthetase 3 (OAS3)/RNase L in the attenuation of RNA viruses with elevated CpG and UpA dinucleotides. Mechanisms and interrelationships between these two pathways were investigated using an echovirus 7 (E7) replicon with compositionally modified sequences...
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... Upon sensing viral RNA, RIG-I and MDA5 initiate downstream signaling by interacting with the mitochondrial antiviral signaling protein (MAVS), which forms prion-like aggregates that convert other MAVS on the mitochondrial outer membrane into prion-like aggregates [19]. This MAVS activation triggers an antiviral signaling cascade that induces interferon (IFN) regulatory factors (IRFs) and nuclear factor kappa B (NF-κB), leading to the transcription of IFNstimulated genes (ISGs) and inflammatory cytokines [20][21][22][23][24]. ...
... Our data indicate significant IRF3 and NF-κB p65 phosphorylation following 3p-hpRNA stimulation, suggesting a conserved RIG-I-mediated signaling mechanism across multiple cell types, including MSCs [21,31,46]. This activation led to increased production of type I and III IFNs and the transcription of ISGs and inflammatory cytokines, reinforcing the immunomodulatory and antiviral properties of UC-MSCs [24]. The upregulation of IFN-I and IFN-III observed in UC-MSCs is consistent with findings in fibroblasts and lung epithelial cells infected with IAV, where these cytokines are essential for mounting an antiviral response [47]. ...
Mesenchymal stromal cells (MSCs) represent a promising therapeutic approach in viral infection management. However, their interaction with viruses remains poorly understood. MSCs can support antiviral immune responses and act as viral reservoirs, potentially compromising their therapeutic potential. Innate immune system recognition of viral pathogens involves pattern recognition receptors (PRRs), including RIG-I-like receptors (RLRs), which activate mitochondrial antiviral signaling protein (MAVS). MAVS triggers antiviral pathways like IRF3 and NF-κB, leading to interferon (IFN) production and pro-inflammatory responses. This study explores the antiviral response in umbilical cord-derived MSCs (UC-MSCs) through targeted stimulation with influenza A virus-derived 5′triphosphate-RNA (3p-hpRNA), a RIG-I agonist. By investigating MAVS activation, we provide mechanistic insights into the immune response at the molecular level. Our findings reveal that 3p-hpRNA stimulation triggers immune activation of the IRF3 and NF-κB pathways through MAVS. Subsequently, this leads to the induction of type I and III IFNs, IFN-stimulated genes (ISGs), and pro-inflammatory cytokines. Critically, this immune activation occurs without compromising mitochondrial integrity. UC-MSCs retain their capacity for mitochondrial transfer to recipient cells. These results highlight the adaptability of UC-MSCs, offering a nuanced understanding of immune responses balancing activation with metabolic integrity. Finally, our research provides mechanistic evidence for MSC-based interventions against viral infections.
... Upon closer inspection of the genes included in the innate immunity cluster, we recognized that most of these genes were downregulated in hnRNP A1-expressing cells compared to the parental CB3 cells and the hnRNP A1Bexpressing CB3 cells (Fig. 3C). Since many of the genes are considered as interferon stimulated genes 28 , we confirmed that this observation was not due to a differential expression of Toll-like receptors (TLRs), including TLR3 which is responsible for viral dsRNA recognition 29 (data not shown). Given these results, we proposed that in basal conditions, hnRNP A1, but not hnRNP A1B, represses the expression of genes that contribute to innate immunity and, more precisely, to the dsRNA response. ...
Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) is a highly abundant RNA binding protein alternatively spliced in two main isoforms named, hnRNP A1 and hnRNP A1B. While being ubiquitously expressed, both isoforms have different cellular localizations and are differentially expressed in tissues during development and aging. To improve our understanding of the cellular function of each isoform, we performed RNA sequencing in cells exclusively expressing hnRNP A1 or hnRNP A1B. As expected, some genes were commonly regulated, however > 300 genes were differentially regulated by the two isoforms. Functional annotation indicated an enrichment for genes implicated in cellular defense, especially for innate immunity and dsRNA response. Here, we demonstrate that in basal conditions, hnRNP A1, but not hnRNP A1B, represses interferon stimulated genes including the family of dsRNA sensors oligoadenylate synthases (OASs). Thus, the dsRNA-mediated interferon antiviral response can be potentiated by the loss of hnRNP A1-mediated repression.
... TYK2 is associated with the type I IFN receptor, which is ubiquitously expressed on most cell types and plays a crucial role in innate and adaptive immune responses. Binding of type I IFN to its receptor kicks off a cascade of phosphorylation events result in expression of interferon stimulated genes (ISGs, SI Appendix, Table S3) and other proinflammatory cytokines (22,23). We employed a mouse model of acute IFN challenge and measured ISG signature and CXCL10 protein, to assess target engagement and the pharmacokinetic/pharmacodynamic (PK/ PD) relationship of multiple TYK2 inhibitors. ...
GWAS have identified tyrosine kinase 2 (TYK2) variants in multiple inflammatory disorders, specifically a protective hypomorphic TYK2 allele (P1104A) in multiple sclerosis (MS). Impaired TYK2 signaling within the central nervous system (CNS) may impart the protective effects of TYK2 P1104A allele in MS. We deployed brain-penetrant TYK2 inhibitors (cTYK2i) alongside the peripherally restricted TYK2 inhibitor (pTYK2i; BMS-986165) to untangle the contributions of central TYK2 inhibition in diverse models of neuroinflammation. While pTYK2i had little impact, cTYK2i reduced clinical score, lymphoid cell infiltration, and cytokines/chemokines in experimental autoimmune encephalomyelitis (EAE). Microglial activation was attenuated in cTYK2i-treated EAE spinal cords and circulating neurofilament light (NfL) was reduced in plasma and cerebral spinal fluid (CSF). Additionally, cTYK2i was protective in an antibody-mediated mouse model of primary progressive MS (PPMS). Finally, we demonstrate TYK2 inhibition has a robust impact on a unique subset of activated astrocytes termed Interferon-Responsive-Reactive-Astrocytes (IRRA). The data presented herein identify a key role for CNS TYK2 signaling in regulating neuroinflammation and solidify TYK2 as a potential therapeutic target for MS.
... Therefore, using the Tabula Sapiens single-cell transcriptomic atlas [30], we explored the constitutive expression of ISGs that were specific to human cardiac cells as well as hPMECs (Fig 4C). We first evaluated the expression of 66 known antiviral interferon-stimulated genes in human cardiac cell types [38][39][40][41]. We selected for genes that were universally expressed in hCMECs, setting a cut-off value of expression in >70% of cells, yielding 5 genes of interest: IFITM1, IFITM2, IFITM3, BST2, and CD74 (Fig 4C). ...
Arthropod-borne viruses (arboviruses) constitute a significant ongoing public health threat, as the mechanisms of pathogenesis remain incompletely understood. Cardiovascular symptomatology is emerging as an important manifestation of arboviral infection. We have recently studied the cardiac tropism implicated in cardiac infection in mice for the alphavirus chikungunya virus (CHIKV), and we therefore sought to evaluate the cardiac tropism of other emerging alphaviruses and arboviruses. Using human primary cardiac cells, we found that arboviruses from diverse viral families were able to replicate within these cells. Interestingly, we noted that while the closely related alphavirus Mayaro virus (MAYV) could replicate to high titers in primary human cardiac microvascular endothelial cells, pulmonary, and brain endothelial cells, the Indian Ocean Lineage of CHIKV (CHIKV-IOL) was restricted in all endothelial cells tested. Upon further investigation, we discovered that this restriction occurs at both entry and egress stages. Additionally, we observed that compared to CHIKV, MAYV may antagonize or evade the innate immune response more efficiently in human cardiac endothelial cells to increase infection. Overall, this study explores the tropism of arboviruses in human primary cardiac cells and characterizes the strain-specific restriction of CHIKV-IOL in human endothelial cells. Further work is needed to understand how the differential restriction of alphaviruses in human endothelial cells impacts pathogenesis in a living model, as well as the specific host factors responsible.
... In a naïve cell infected by a virus, antiviral sensors are activated upon their interaction with viral PAMPs, which then triggers interferon synthesis. Interferon molecules interact with the interferon receptors initiating a signalling cascade that ends in the synthesis of interferonstimulated genes (ISGs) (Schoggins et al. 2011;Yang and Li 2020). ISGs include not only sensors, but also effector molecules that target a wide range of processes in the viral lifecycle to supress infection. ...
Cytoplasmic viruses interact intricately with the nuclear pore complex and nuclear import/export machineries, affecting nuclear-cytoplasmic trafficking. This can lead to the selective accumulation of nuclear RNA-binding proteins (RBPs) in the cytoplasm. Pioneering research has shown that relocated RBPs serve as an intrinsic defence mechanism against viruses, which involves RNA export, splicing and nucleolar factors. For instance, the U2 small nuclear ribonucleoprotein (snRNP) relocates to the cytoplasm in infected cells and uses U2 snRNA to interact with viral genomes, repressing viral replication and gene expression. Here, we describe these emerging host-virus interactions and discuss the remaining questions to elucidate their antiviral mechanisms.
... The degree of overlap of the transcriptional changes between the three cell lines was very low, resulting in only 22 commonly up-regulated genes after CM-272 treatment ( Figure 4A). Notably, an up-regulated set of 13-genes was identified ( Figure 4B) that includes key cytokines and regulators primarily involved in type I interferon (IFN) signaling pathway (IRF7, GBP1, CCL3), innate immune response (THBS1, CCR2, CCL2) and defense response to virus (OASL, IFI6, IFI27) 43,44 . Among the 13-genes 'core', OASL and IFI6 were among the highest expressed of the anti-viral regulators in all three cell lines ( Figure 4C) and are known to target different stages of the viral replication cycle by preventing the formation of virus-induced endoplasmic reticulum membrane invaginations 45 . ...
Epigenetic dysregulation is a hallmark of Acute Myeloid Leukemia (AML), with mutations in DNA Methyltransferases (e.g., DNMT3A) being frequent and promising therapeutic targets. DNMTs form complexes with Histone Methyltransferases (HMTs), driving gene silencing loop via chromatin methylation crosstalk. However, potential connections between this DNMTs/HMTs cooperative activity and oncogenic requirements across the AML mutational spectrum remain poorly understood. Here, we demonstrate that AMLs carrying DNMT3A and Nucleophosmin (NPM1) mutations exhibit a specific epigenetic vulnerability toward a complex formed by DNMTs and G9a, a specific histone H3 Lysine 9 Methyltransferase (H3K9-HMT). Dual inhibition of DNMT/G9a restores differentiation, reduces tumor growth, and spares healthy progenitors compared to standard hypomethylating agents. Mechanistically, DNMT/G9a regulates NPM1 stability, inhibits HOXA9/MEIS1 activity, and triggers interferons (IFN) response via viral mimicry pathways by modulating hypermethylated retrotransposons. Collectively, our data unravel specific epigenetic vulnerabilities within the complex AML mutational landscape and provide a compelling rationale for the design of personalized epigenetic therapies with enhanced efficacy and safer clinical outcomes.
... Additionally, when SARS-CoV-2 infects a host, it triggers various epigenetic modifications in the host's cells, which notably affect the immune response [12,15,16,18,19,73]. Such alterations may activate pathways that create an antiviral setting, allowing the host to express Interferon-Stimulated Genes (ISGs) and additional immune-related components that bolster defenses against viral replication [74,75]. Fang et al. examined the link between levels of Histone 3-Lysine 9 Dimethylation (H3K9me2) and Interferon (IFN) expression in vitro. ...
... Over the past few decades, hundreds of interferon-stimulated genes (ISGs) have been identified [47,66]. Among them, several well-known classical ISGs are directly associated with antiviral activity, including PKR (protein kinase R, an interferon-induced dsRNA-activated protein kinase), OSA (2'-5'-oligoadenylate synthetase), RNase L, ADAR1 (adenosine deaminase acting on RNA), MxA/ Mx1 (myxovirus resistance protein 1), iNOS (inducible nitric oxide synthase), as well as MHC I and MHC II [8,47,67]. ...
Hepatitis B virus (HBV) is a hepatotropic DNA virus that can cause acute or chronic hepatitis, representing a significant global health concern. By 2019, approximately 296 million individuals were chronically infected with HBV, with 1.5 million new cases annually and 820,000 deaths due to HBV-related cirrhosis and liver cancer. Current treatments for chronic hepatitis B include nucleotide analogs (NAs) and interferons (IFNs), particularly IFN-α. NAs, such as entecavir and tenofovir, inhibit viral reverse transcription, while IFN-α exerts antiviral effects by directly suppressing viral replication, modulating viral genome epigenetics, degrading cccDNA, and activating immune responses. Despite its potential, IFN-α shows limited clinical efficacy, partly due to HBV’s interference with the IFN signaling pathway. HBV encodes proteins like HBc, Pol, HBsAg, and HBx that disrupt IFN-α function. For example, HBV Pol inhibits STAT1 phosphorylation, HBsAg suppresses STAT3 phosphorylation, and HBx interferes with IFN-α efficacy through multiple mechanisms. Additionally, HBV downregulates key genes in the IFN signaling pathway, further diminishing IFN-α’s antiviral effects. Understanding these interactions is crucial for improving IFN-α-based therapies. Future research may focus on overcoming HBV resistance by targeting viral proteins or optimizing IFN-α delivery. In summary, HBV’s ability to resist IFN-α limits its therapeutic effectiveness, highlighting the need for new strategies to enhance treatment outcomes.
... On gene ontology analysis, the upregulated DEPs were involved in biological processes, viz., interferonstimulated genes expression, response to interferon, antiviral response pathways, modulation of immune response, etc. (Fig. 2c). This surge in the initial response may be to train the immune genes to counter the viral infection (Schneider et al. 2014;Yang and Li 2020). However, the downregulated DEPs were associated with intermediate filament organization, TCA cycle, and respiratory electron transport (Fig. 2d). ...
... On gene ontology, the upregulated DEPs were enriched in the platelet aggregation pathway and immune response pathways (Fig. 3c). This enrichment acts as a defense to curtail virus propagation (Yang and Li 2020;Schrottmaier et al. 2022). In 48hpi, some of the important DEPs, viz., BCL2, NOTCH1, GSTP1, ARNT, CPEB2, CCNA2, etc., were found downregulated. ...
... The surge of expression of antiviral genes at 48hpi induced mechanisms that prevent viral replication viz. BST2, IFITs, OASs, etc. (Yang and Li 2020). The expression of common DEPs related to antiviral processes, viz., OASs, MX1, MX2, ISG15 was found to increase with time between 24 and 48hpi (Fig. 4b). ...
Japanese encephalitis virus (JEV) is a mosquito-borne neurotropic virus that claims thousands of children’s lives globally every year, causing neuropsychiatric sequelae. While neuronal cell pathogenesis is a terminal consequence of JEV infection, the virus hijacks macrophages during initial replication and propagation, making macrophages critical cells of host immune defense that dictate the outcomes of infection. Though a plethora of studies have been reported using various neuronal and immune cells, a global response of human macrophages to JEV infection is yet to be explored. In this study, we assessed the kinetics of global proteome dysregulation employing an in vitro JEV infection model using human monocyte-derived macrophages (THP-1). A comparative assessment of the proteome of the infected THP-1 cells revealed differential regulation of 428 proteins at 24 h post-infection (hpi), which was later increased to 443 by 48 h post-infection. Global gene ontology analysis of the differentially expressed proteins highlighted several critical pathways related to immune and metabolic processes that are known to play either proviral or antiviral effects during infection. Notably, several antiviral proteins, including STAT2, OAS1, MX1, MX2, RIG-I, ISG15, and ISG20, were significantly upregulated at both time points post-infection. In contrast, a considerable downregulation of BCL-2, an anti-apoptotic protein at 48hpi indicates the activation of cell death pathways. Further, gene set enrichment analysis identified the type I interferon signaling pathway as one of the top upregulated pathways following JEV infection in human macrophages. Altogether, this study demonstrates human macrophage responses to JEV infection at the proteome level for the first time, highlighting several critical and novel antiviral proteins and pathways that not only advance our understanding of anti-JEV immunity but also aid in developing strategies to control this acute global public health menace.
... The 3-(4-Hydroxyphenyl)propanoic acid is detected in the serum of mice and increases the expression of interferon-γ inducible protein 10 kDa (IP-10), also known as CXCL10, and type I IFN-stimulated genes, such as 2 ′ -5 ′ -oligoadenylate synthetase 2 (Oas2) and myxovirus (influenza virus) resistance 2 (Mx2), in the lungs of mice [109]. IP-10, Oas2, and Mx2 are associated with antiviral activities in the host [110][111][112]. Furthermore, 3-(4-hydroxyphenyl)propanoic acid suppressed influenza virus infection-induced mortality by enhancing type I interferon signaling in mice [109] (Figure 4A). ...
The gut microbiota metabolizes flavonoids, amino acids, dietary fiber, and other components of foods to produce a variety of gut microbiota-derived metabolites. Flavonoids are the largest group of polyphenols, and approximately 7000 flavonoids have been identified. A variety of phenolic acids are produced from flavonoids and amino acids through metabolic processes by the gut microbiota. Furthermore, these phenolic acids are easily absorbed. Phenolic acids generally represent phenolic compounds with one carboxylic acid group. Gut microbiota-derived phenolic acids have antiviral effects against several viruses, such as SARS-CoV-2 and influenza. Furthermore, phenolic acids influence the immune system by inhibiting the secretion of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α. In the nervous systems, phenolic acids may have protective effects against neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. Moreover, phenolic acids can improve levels of blood glucose, cholesterols, and triglycerides. Phenolic acids also improve cardiovascular functions, such as blood pressure and atherosclerotic lesions. This review focuses on the current knowledge of the effects of phenolic acids produced from food-derived flavonoids and amino acids by the gut microbiota on health and disease.
