Search Results (270)

Interferon (IFN) signaling plays vital roles in host defense against viral infection. However, a variety of observations have been reported in the literature regarding the roles of IFN signaling in COVID-19. Thus, it would be important to reach a clearer picture regarding the activation or suppression of IFN signaling in COVID-19. In this work, regulation of marker genes for IFN signaling was examined in natural infection, viral challenge, and vaccination based on 13 public transcriptome datasets. Three subsets of interferon-stimulated genes (ISGs) were selected for detailed examination, including one set of marker genes for type I IFN signaling (ISGa) and two sets of marker genes for type II IFN signaling (IFN-γ signaling, GBPs for the GBP gene cluster, and HLAd for the HLA-D gene cluster). In natural infection, activation of ISGa and GBPs was accompanied by the suppression of HLAd in hospitalized patients. Suppression of GBPs was also observed in certain critical conditions. The scale of regulation was much greater for ISGa than that of GBPs and HLAd. In addition, the suppression of HLAd was correlated with disease severity, and it took much longer for HLAd to return to the level of healthy controls than that for ISGa and GBPs. Upon viral challenge, the activation of ISGa and GBPs was similar to that of natural infection, while the suppression of HLAd was not observed. Moreover, GBPs’ return to the pre-infection level was at a faster pace than that of ISGa. Upon COVID-19 vaccination, activation was observed for all of these three gene sets, and the scale of activation was comparable for ISGa and GBPs. Notably, it took a much shorter time for GBPs and ISGa to return to the level of healthy controls than that in COVID-19 infection. In addition, the baseline values and transient activation of these gene sets were also associated with subsequent vaccination response. The intricate balance of IFN signaling was demonstrated in mild breakthrough infection, where attenuated response was observed in people with prior vaccination compared to that in vaccine-naïve subjects. Overall, distinctive temporal profiles of IFN signaling were observed in natural infection, viral challenge, and vaccination. The features observed in this work may provide novel insights into the disease management and vaccine development. Full article

Interferon-induced transmembrane protein 3 (IFITM3) is a member of the family of interferon-stimulated genes (ISGs) that inhibits a diverse array of enveloped viruses which enter host cells by endocytosis. Porcine reproductive and respiratory syndrome virus (PRRSV) is an enveloped RNA virus causing significant economic losses to the swine industry. Very little is known regarding how IFITM3 restricts PRRSV. In this study, the role of IFITM3 in PRRSV infection was studied in vitro using MARC-145 cells. IFITM3 over-expression reduced PRRSV replication, while the siRNA-induced knockdown of endogenous IFITM3 increased PRRSV RNA copies and virus titers. The colocalization of the virus with IFITM3 was observed at both 3 and 24 h post infection (hpi). Quantitative analysis of confocal microscopic images showed that an average of 73% of IFITM3-expressing cells were stained positive for PRRSV at 3 hpi, while only an average of 27% of IFITM3-expressing cells were stained positive for PRRSV at 24 hpi. These findings suggest that IFITM3 may restrict PRRSV at the post-entry steps. Future studies are needed to better understand the mechanisms by which this restriction factor inhibits PRRSV. Full article

The B-cell adapter for PI3K (BCAP) is a protein that connects membrane receptor signaling to the PI3K pathway. In fibroblasts or dendritic cells, priming the cGAS nucleic-acid-sensing pathway increases BCAP expression and enhances type I interferon (IFN-I) production upon lipopolysaccharide (LPS) stimulation. These findings corroborate the idea that BCAP may bias cytokine production toward IFN during inflammation, indicating its potential involvement in IFN-driven diseases like systemic lupus erythematosus (SLE). We investigate the role of BCAP in regulating the inflammatory response in SLE and its relationship with IFN-mediated inflammation. BCAP gene expression and IFN signature were analyzed in 36 subjects with SLE and 20 healthy controls. Two cellular models were used to assess BCAP’s role in LPS response and IFN signaling after cGAS stimulation. We found a correlation between BCAP and interferon-stimulated gene (ISG) expression in SLE. In a cellular model, tofacitinib and anifrolumab, acting as IFN signaling “inhibitors”, blocked BCAP overexpression triggered by cGAS, confirming BCAP as an ISG. Additional studies in BCAP^−/− cells revealed that, in the absence of BCAP, these cells exhibited diminished IFN production upon LPS stimulation following prior exposure to cGAMP. Overall, BCAP is an ISG that acts as a positive regulator of Toll-like receptor 4-mediated IFN production. We speculate that its increased expression in SLE may contribute to a positive feedback loop, enhancing IFN production during bacterial infections. Full article

Background: Vaccines represent one of the most affordable and efficient tools for controlling infectious diseases; however, the development of efficacious vaccines against complex pathogens remains a major challenge. Adjuvants play a relevant role in enhancing vaccine-induced immune responses. One such molecule is interferon-stimulated gene 15 (ISG15), a key modulator of antiviral immunity that acts both through ISGylation-dependent mechanisms and as a cytokine-like molecule. Methods: In this study, we assessed the immunostimulatory potential of ISG15 as an adjuvant in Modified Vaccinia virus Ankara (MVA)-based vaccine candidates targeting Zika virus (ZIKV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Early innate responses and immune cell infiltration were analyzed in immunized mice by flow cytometry and cytokine profiling. To elucidate the underlying mechanism of action of ISG15, in vitro co-infection studies were performed in macrophages. Finally, we evaluated the magnitude and functional quality of the elicited antigen-specific cellular immune responses in vivo. Results: Analysis of early innate responses revealed both platform- and variant-specific effects. ISG15AA preferentially promoted natural killer (NK) cell recruitment at the injection site, whereas ISG15GG enhanced myeloid cell infiltration in draining lymph nodes (DLNs), particularly when delivered via MVA. Moreover, in vitro co-infection of macrophages with MVA-based vaccine vectors and the ISG15AA mutant led to a marked increase in proinflammatory cytokine production, highlighting a dominant role for the extracellular, ISGylation-independent functions of ISG15 in shaping vaccine-induced immunity. Notably, co-infection of ISG15 with MVA-ZIKV and MVA-SARS-CoV-2 vaccine candidates enhanced the magnitude of antigen-specific immune responses in both vaccine models. Conclusions: ISG15, particularly in its ISGylation-deficient form, acts as a promising immunomodulatory adjuvant for viral vaccines, enhancing both innate and adaptive immune responses. Consistent with previous findings in the context of Human Immunodeficiency virus type 1 (HIV-1) vaccines, this study further supports the potential of ISG15 as an effective adjuvant for vaccines targeting viral infections such as ZIKV and SARS-CoV-2. Full article

The immediate-early protein IE180 of pseudorabies virus (PRV) is a multifunctional regulator of viral and host gene expression. However, its role in modulating antiviral immune responses remains poorly understood. Here, we demonstrate that IE180 overexpression significantly inhibits PRV and H1N1 influenza virus replication in Hep2 and A549 cells, respectively. Mechanistically, IE180 activates the type I interferon (IFN-I) pathway by enhancing IFN-β promoter activity and IFN transcription, leading to upregulated expression of interferon-stimulated genes (ISGs). Notably, IE180 failed to suppress PRV or H1N1 replication in Vero cells, which lack functional IFN-I signaling, confirming the dependence of its antiviral function on the IFN-I pathway. Domain mapping revealed that the ICP4-Like2 domain of IE180 is critical for IFN-β activation and antiviral activity. These findings establish IE180 as a novel viral immunomodulator that activates host innate immunity to restrict viral replication, providing insights into PRV-host interactions and potential therapeutic strategies. Full article

Interferon (IFN)-induced proteins with tetratricopeptide repeats (IFITs) are key interferon-stimulated genes (ISGs), and in humans include IFIT1, IFIT2, IFIT3 and IFIT5. These proteins are primarily known for their role in the innate immune response to pathogens. However, growing evidence suggests that IFITs participate in a range of other cellular processes, including cancer development and progression. Notably, IFITs may behave in either a pro-oncogenic or tumor suppressive fashion depending on cancer types and emphasizing their potential dual function in tumorigenesis. Importantly, IFITs have shown potential to be utilized as clinical biomarkers in oncology. Their aberrant expression has been correlated with survival and other clinical outcomes, including resistance to radiotherapy, chemotherapy, targeted treatments and immunotherapy in various cancers. Additionally, they have also been reported to be a part of various clinical predictive models in cancers. This review provides an overview of the current understanding of IFIT proteins’ involvement in cancers, with an emphasis on their emerging roles as clinically relevant biomarkers. Full article

Andrographolide, fucoidan, or a combination of both compounds were evaluated to determine their effects on the antiviral response in the Atlantic salmon macrophage-like cell line (SHK-1) infected with infectious pancreatic necrosis virus (IPNV). We assessed the transcript expression levels of key molecules involved in the interferon (IFN)-dependent antiviral response, as well as the viral load in cells treated with these compounds. In non-infected cells, incubation with either fucoidan, andrographolide, or a mixture of both resulted in an increase in the transcript expression of IFNα1 and various interferon-stimulated genes (ISGs). In IPNV-infected cells, treatment with either fucoidan or andrographolide separately did not significantly enhance the antiviral response compared to that of infected cells that had not previously been treated with these compounds. In contrast, the combination of andrographolide and fucoidan led to a marked increase in the transcript expression of viperin and a significant reduction in viral load. Overall, combining andrographolide and fucoidan resulted in a greater reduction in IPNV viral load in infected cells than that noted when the compounds were administered individually. Our findings suggest that pre-incubation with this mixture promotes the establishment of a protective antiviral state against IPNV, likely mediated by an IFN-dependent response. Full article

Type I interferons (IFN-Is) play a dual role in the immune response to HIV-1, providing early antiviral defense while driving immune dysfunction in the chronic phase. During acute infection, robust IFN signaling is critical in controlling viral replication, activating innate immunity, and limiting reservoir establishment. However, sustained IFN-I activation during chronic infection fuels systemic inflammation, immune exhaustion, and fibrosis, particularly in lymphoid tissues such as gut-associated lymphoid tissue (GALT). Prolonged IFN-I exposure upregulates inhibitory receptors on T cells, impairs metabolic fitness, and fosters an immunosuppressive cytokine milieu that weakens overall immune responses. In contrast to natural SIV (Simian immunodeficiency virus) hosts, IFN-I responses are tightly regulated to prevent chronic immune activation and tissue damage. However, humans and non-natural hosts experience persistent Interferon Stimulated Gene (ISG) expression and IFN-I driven inflammation. Emerging therapeutic strategies seek to harness the antiviral benefits of IFN-I while mitigating its pathogenic effects. Approaches such as the IFNAR blockade, autophagy induction, JAK-STAT inhibition, and combined immune inhibitory blockade therapy show promise in restoring immune balance and enhancing T cell function. This review examines the mechanisms of IFN-I dysregulation in chronic HIV-1 infection and highlights novel interventions aimed at finetuning IFN-I signaling for therapeutic benefit. Full article

Innate immunity is an important component of the immune system and serves as the first line of defense for the host against the invasion of foreign pathogens. Viperin (RSAD2), a core member of the interferon-stimulated gene (ISG) family, plays a key role in innate immunity through direct inhibition of viral replication and modulation of the host immune–metabolic network. The intracellular expression of Viperin rises markedly after viral infection or interferon-induced induction, showing a wide range of antiviral activities. In recent years, the versatility of Viperin in viral infections, autoimmune diseases, and tumor immune metabolism has been gradually revealed. Here, we summarize and discuss the gene regulatory network, molecular functions, and multi-dimensional roles of Viperin in diseases to provide a theoretical basis for the development of broad-spectrum antiviral strategies and immunometabolic therapies based on Viperin. Full article

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. Full article

Orf virus (ORFV) is the type species of Parapoxvirus of the Poxviridae family that induces cutaneous pustular skin lesions in sheep and goats, and causes zoonotic infections in humans. Pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), leading to the triggering of the innate immune response through multiple signalling pathways involving type I interferons (IFNs). The major PAMPs generated during viral infection are nucleic acids, which are the most important molecules that are recognized by the host. The induction of type l IFNs leads to activation of the Janus kinase (JAK)-signal transducer activator of transcription (STAT) pathway, which results in the induction of hundreds of interferon-stimulated genes (ISGs), many of which encode proteins that have antiviral roles in eliminating virus infection and create an antiviral state. Genetic and functional analyses have revealed that ORFV, as found for other poxviruses, has evolved multiple immunomodulatory genes and strategies that manipulate the innate immune sensing response. Full article

Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD), leading to a serious health threat to young children. Probiotics are effective at treating or preventing gastrointestinal infections, especially viral infections. Probiotics against EV71 are mainly traditional lactic acid-producing bacteria, and most of them have been proven to be effective only in vitro. Here, we report that the marine bacterium Paraliobacillus zengyii X-1125 (P. zengyii) has promising anti-EV71 activity. The antiviral effect of P. zengyii against EV71 was assessed in different cell lines, and the viral RNA levels and titers were obviously reduced after treatment with P. zengyii. Furthermore, we established an EV71-infected mouse model to evaluate its antiviral efficacy in vivo. The oral administration of P. zengyii significantly decreased the viral loads in the hindlimb muscles, spleens, and ileums. Further research revealed that P. zengyii enhances the expression of type I interferon (IFN-I) in EV71-infected cells. Similarly, transcriptome analysis indicated that the expression of interferon-stimulated genes (ISGs) in EV71-infected mice significantly increased after P. zengyii treatment. Taken together, the results of this study indicated that P. zengyii markedly reduces EV71 infection by regulating the IFN response both in vivo and in vitro, providing a potential means to work against EV71 infection. Full article

The innate immune response, particularly the interferon-mediated pathway, serves as the first line of defense against viral infections. During virus infection, viral pathogen-associated molecular patterns (PAMPs) are recognized by host pattern recognition receptors (PRRs), triggering downstream signaling pathways. This leads to the activation of transcription factors like IRF3, IRF7, and NF-κB, which translocate to the nucleus and induce the production of type I interferons (IFN-α and IFN-β). Once secreted, type I interferons bind to their receptors (IFNARs) on the surfaces of infected and neighboring cells, activating the JAK-STAT pathway. This results in the formation of the ISGF3 complex (composed of STAT1, STAT2, and IRF9), which translocates to the nucleus and drives the expression of interferon-stimulated genes (ISGs). Some ISGs exert antiviral effects by directly or indirectly blocking infection and replication. Among these ISGs, ISG15 plays a crucial role in the ISGylation process, a ubiquitin-like modification that tags viral and host proteins, regulating immune responses and inhibiting viral replication. However, viruses have evolved counteractive strategies to evade ISG15-mediated immunity and ISGylation. This review first outlines the PAMP-PRR-induced pathways leading to the production of cytokines and ISGs, followed by a summary of ISGylation’s role in antiviral defense and viral evasion mechanisms targeting ISG15 and ISGYlation. Full article

Infection of cells with the human cytomegalovirus (HCMV) triggers the expression of interferon-stimulated genes (ISGs). ISGs encode proteins with antiviral functions, such as inhibiting viral replication, promoting cell death of infected cells and enhancing immune responses. HCMV has evolved mechanisms to evade the antiviral effects of ISGs. The viral proteins encoded by the viral genes US7, US8, and US9 have been shown to interfere with interferon induction. US7 to US9 are embedded in a cluster of HCMV genes, termed US2 to US11. The individual members of this gene family interfere on multiple levels with innate and adaptive immune responses to HCMV infection. Using viral mutants with different deletions in US2 to US11, we addressed the question if genes other than US7 to US9 would also influence the IFN responses. Surprisingly, deletion of the complete US2 to US11 gene region led to reduced levels of selected ISGs. Cells infected with viruses in which individual US2 to US11 genes were deleted showed a less pronounced reduction of the selected ISGs. The experiments including RNA-seq analyses indicate that genes of the US2 to US11 gene family have a complex interaction with the IFN-ISG response which is likely regulated on the level of ISG protein stability. As US2–US11 are dispensable for replication in cell culture, the genomic region was frequently used for the insertion of bacterial artificial chromosome vectors in the process of cloning the complete HCMV genome. The results shown here must be considered when viruses derived from BACs with US2–US11 deletions are used and whether appropriate controls must be applied. Full article

The recognition of cytosolic nucleic acids is a critical step in the host immune response against danger signals, such as molecular patterns from pathogens or tissue damage. Nonetheless, over-reactivity to self-nucleic acids leads to the sustained production of type I interferon (IFN), mediated either by cGAS or RLR, contributing to the pathogenesis of certain autoimmune diseases, such as Aicardi–Goutières syndrome (AGS). Therefore, inhibiting excessive IFN production represents a potential therapeutic strategy for such autoimmune conditions. In this study, we discovered that petroselinic acid (PA), a natural compound isolated from Apiaceae family plants, effectively suppresses type I IFN production induced by cytosolic nucleic acids. Mechanistic investigations revealed that PA inhibits the phosphorylation of TBK1 and IRF3, which are key nodal proteins within the type I interferon pathway. Notably, molecular docking suggests potential binding between PA and cytosolic nucleic acid sensors, such as cGAS and RIG-I. Moreover, we found that PA effectively attenuates the expression of type I IFN and their downstream interferon-stimulated genes (ISGs) in models of AGS autoimmune disease characterized by excessive nucleic acid accumulation. Thus, our research identifies a natural compound that offers a promising strategy for treating autoimmune diseases resulting from aberrant self-nucleic acid recognition and the hyperactivation of type I interferon. Full article