Search Results (51)

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

As an evolutionarily conserved and ubiquitous mechanism of host defense, non-immune cells in vertebrates possess the intrinsic ability to autonomously detect and combat intracellular pathogens. This process, termed cell-autonomous immunity, is distinct from classical innate immunity. In this review, we comprehensively examine the defense mechanisms employed by non-immune cells in response to intracellular pathogen invasion. We provide a detailed analysis of the cytosolic sensors that recognize aberrant nucleic acids, lipopolysaccharide (LPS), and other pathogen-associated molecular patterns (PAMPs). Specifically, we elucidate the molecular mechanisms underlying key signaling pathways, including the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)-mitochondrial antiviral signaling (MAVS) axis, and the guanylate-binding proteins (GBPs)-mediated pathway. Furthermore, we critically evaluate the involvement of these pathways in the pathogenesis of various diseases, including autoimmune disorders, inflammatory conditions, and malignancies, while highlighting their potential as therapeutic targets. 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

In order to detect and respond to invading pathogens, mammals have evolved a battery of pattern recognition receptors. Among these, RIG-I-like receptors (RLR) are cytosolic RNA sensors that play an essential role in the innate immune response against RNA viruses, including coronaviruses. In return, coronaviruses have acquired diverse strategies to impair RLR-mediated immune responses to enable productive infection. Viral innate immune evasion mechanisms have been well studied for highly pathogenic human coronaviruses (HCoVs), and often, these activities are thought to be linked to the severe symptoms these viruses can cause. Whether other coronaviruses, including human common cold coronaviruses, display similar activities has remained understudied. Here, we present evidence that the main protease (Mpro) of common cold HCoV-229E acts as an interferon (IFN) and NF-κB antagonist by disrupting RLR-mediated antiviral signalling. Furthermore, we show that HCoV-229E, HCoV-OC43 and MERS-CoV Mpros are able to directly cleave NEMO. We also show that HCoV-229E Mpro induces the cleavage and/or degradation of multiple other RLR pathway components, including MDA5, TBK1 and IKKε. Finally, we show that HCoV-229E infection leads to a delayed innate immune response that is accompanied by a decrease in NEMO protein levels. Our results suggest that NEMO degradation during HCoV-229E infection could be mediated, in part, by cellular degradation pathways, in addition to viral Mpro-mediated cleavage. Altogether, our research unveils innate immune evasion activities of the Mpros of low-pathogenic coronaviruses, which, despite their low pathogenicity, appear to share functionalities previously described for highly pathogenic HCoVs. Full article

The yellow catfish (Pelteobagrus fulvidraco) industry has expanded to a certain scale and is an important part of aquaculture in China, but frequent diseases have caused huge economic losses. Comprehending the fish’s immune mechanisms, particularly the regulation of the interferon (IFN) response, is of paramount importance for future drug development and disease-resistant molecular breeding. Notably, the role of atypical protein kinases, such as the RIO kinase family, in immune regulation is poorly defined. Here, we investigated the roles of yellow catfish RIO kinases, PfRIOK1 and PfRIOK2, in modulating the IFN response through their interaction with PfTBK1, a key player in the RLR signaling pathway. Mechanically, PfRIOK1 and PfRIOK2 negatively regulate the IFN response by interacting with the RIO domains to target and degrade PfTBK1. Our findings reveal that the overexpression of PfRIOK1 and PfRIOK2 led to the decreased expression of IFN-related genes and enhanced viral replication in vitro. Additionally, PfRIOK1 and PfRIOK2 could inhibit PfTBK1-mediated antiviral responses in infected cells. These results suggest that PfRIOK1 and PfRIOK2 act as negative regulators of the IFN response in yellow catfish, providing new insights into the regulatory mechanisms of fish innate immunity and offering target molecules for molecular design breeding in aquaculture. Full article

The article characterises platelets, pointing out the role and contribution of their numerous receptors determining their specific and broad immune activity. Three types of platelet receptors are described, that is, extracellular and intracellular receptors—TLR (toll-like receptors), NLR (NOD-like receptor), and RLR (RIG-I-like receptor); extracellular receptors—selectins and integrins; and their other extracellular receptors—CLR (C-type lectin receptor), CD (cluster of differentiation), TNF (tumour necrosis factor), among others. Outlining the contribution of these numerous platelet receptors to the intravascular immunity, it has been shown that they are formed by their fusion with pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and lifestyle-associated molecular patterns (LAMPs). They are initiating and effector components of signal transduction of these cells, and their expression and quantity determine the specific and broad functions of platelets towards influencing vascular endothelial cells, but mainly PRRs (pattern recognition receptors) of blood immune cells. These facts make platelets the fundamental elements that shape not only intravascular homeostasis, as previously indicated, but they become the determinants of immunity in blood vessels. Describing the reactions of the characterised three groups of platelet receptors with PAMP, DAMP and LAMP molecules, the pathways and participation of platelets in the formation and construction of intravascular immune status, in physiological states, but mainly in pathological states, including bacterial and viral infections, are presented, making these cells essential elements in the health and disease of mammals, including humans. Full article

Neurological manifestations are a significant complication of coronavirus disease 2019 (COVID-19), but the underlying mechanisms are yet to be understood. Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced neuroinvasion and encephalitis were observed in K18-hACE2 mice, leading to mortality. Our goal in this study was to gain insights into the molecular pathogenesis of neurological manifestations in this mouse model. To analyze differentially expressed genes (DEGs) in the brains of mice following SARS-CoV-2 infection, we performed NanoString gene expression analysis using three individual animal samples at 1, 3, and 6 days post-infection. We identified the DEGs by comparing them to animals that were not infected with the virus. We found that genes upregulated at day 6 post-infection were mainly associated with Toll-like receptor (TLR) signaling, RIG-I-like receptor (RLR) signaling, and cell death pathways. However, downregulated genes were associated with neurodegeneration and synaptic signaling pathways. In correlation with gene expression profiles, a multiplexed immunoassay showed the upregulation of multiple cytokines and chemokines involved in inflammation and cell death in SARS-CoV-2-infected brains. Furthermore, the pathway analysis of DEGs indicated a possible link between TLR2-mediated signaling pathways and neuroinflammation, as well as pyroptosis and necroptosis in the brain. In conclusion, our work demonstrates neuroinflammation-associated gene expression profiles, which can provide key insight into the severe disease observed in COVID-19 patients. Full article

The Golgi apparatus, long recognized for its roles in protein processing and vesicular trafficking, has recently been identified as a crucial contributor to innate immune signaling pathways. This review discusses our expanding understanding of the Golgi apparatus’s involvement in initiating and activating these pathways. It highlights the significance of membrane connections between the Golgi and other organelles, such as the endoplasmic reticulum, mitochondria, endosomes, and autophagosomes. These connections are vital for the efficient transmission of innate immune signals and the activation of effector responses. Furthermore, the article delves into the Golgi apparatus’s roles in key immune pathways, including the inflammasome-mediated activation of caspase-1, the cGAS-STING pathway, and TLR/RLR signaling. Overall, this review aims to provide insights into the multifunctional nature of the Golgi apparatus and its impact on innate immunity. Full article

The role of the IFI6 gene has been described in several cancers, but its involvement in esophageal cancer (ESCA) remains unclear. This study aimed to identify novel prognostic indicators for ESCA-targeted therapy by investigating IFI6’s expression, epigenetic mechanisms, and signaling activities. We utilized public data from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) to analyze IFI6’s expression, clinical characteristics, gene function, pathways, and correlation with different immune cells in ESCA. The TIMER2.0 database was employed to assess the pan-cancer expression of IFI6, while UALCAN was used to examine its expression across tumor stages and histology subtypes. Additionally, the KEGG database helped identify related pathways. Our findings revealed 95 genes positively correlated and 15 genes negatively correlated with IFI6 in ESCA. IFI6 was over-expressed in ESCA and other cancers, impacting patient survival and showing higher expression in tumor tissues than normal tissues. IFI6 was also correlated with CD4+ T cells and B cell receptors (BCRs), both essential in immune response. GO Biological Process (GO BP) enrichment analysis indicated that IFI6 was primarily associated with the Type I interferon signaling pathway and the defense response to viruses. Intriguingly, KEGG pathway analysis demonstrated that IFI6 and its positively correlated genes in ESCA were mostly linked to the Cytosolic DNA-sensing pathway, which plays a crucial role in innate immunity and viral defense, and the RIG-I-like receptor (RLR) signaling pathway, which detects viral infections and activates immune responses. Pathways related to various viral infections were also identified. It is important to note that our study relied on online databases. Given that ESCA consists of two distinct subgroups (ESCC and EAC), most databases combine them into a single category. Future research should focus on evaluating IFI6 expression and its impact on each subgroup to gain more specific insights. In conclusion, inhibiting IFI6 using targeted therapy could be an effective strategy for treating ESCA considering its potential as a biomarker and correlation with immune cell factors. Full article

The field of nephrology has recently directed a considerable amount of attention towards the stimulator of interferon genes (STING) molecule since it appears to be a potent driver of chronic kidney disease (CKD). STING and its activator, the cyclic GMP-AMP synthase (cGAS), along with intracellular RIG-like receptors (RLRs) and toll-like receptors (TLRs), are potent inducers of type I interferon (IFN-I) expression. These cytokines have been long recognized as part of the mechanism used by the innate immune system to battle viral infections; however, their involvement in sterile inflammation remains unclear. Mounting evidence pointing to the involvement of the IFN-I pathway in sterile kidney inflammation provides potential insights into the complex interplay between the innate immune system and damage to the most sensitive segment of the nephron, the glomerulus. The STING pathway is often cited as one cause of renal disease not attributed to viral infections. Instead, this pathway can recognize and signal in response to host-derived nucleic acids, which are also recognized by RLRs and TLRs. It is still unclear, however, whether the development of renal diseases depends on subsequent IFN-I induction or other processes involved. This review aims to explore the main endogenous inducers of IFN-I in glomerular cells, to discuss what effects autocrine and paracrine signaling have on IFN-I induction, and to identify the pathways that are implicated in the development of glomerular damage. Full article

Pattern recognition receptors (PRRs) recognize danger signals such as PAMPs/MAMPs and DAMPs to initiate a protective immune response. TLRs, NLRs, CLRs, and RLRs are well-characterized PRRs of the host immune system. cGLRs have been recently identified as PRRs. In humans, the cGAS/STING signaling pathway is a part of cGLRs. cGAS recognizes cytosolic dsDNA as a PAMP or DAMP to initiate the STING-dependent immune response comprising type 1 IFN release, NF-κB activation, autophagy, and cellular senescence. The present article discusses the emergence of cGLRs as critical PRRs and how they regulate immune responses. We examined the role of cGAS/STING signaling, a well-studied cGLR system, in the activation of the immune system. The following sections discuss the role of cGAS/STING dysregulation in disease and how immune cross-talk with other PRRs maintains immune homeostasis. This understanding will lead to the design of better vaccines and immunotherapeutics for various diseases, including infections, autoimmunity, and cancers. Full article

Throughout their life cycle, viruses interact with cellular host factors, thereby influencing propagation, host range, cell tropism and pathogenesis. The hepatitis E virus (HEV) is an underestimated RNA virus in which knowledge of the virus–host interaction network to date is limited. Here, two related high-throughput mammalian two-hybrid approaches (MAPPIT and KISS) were used to screen for HEV-interacting host proteins. Promising hits were examined on protein function, involved pathway(s), and their relation to other viruses. We identified 37 ORF2 hits, 187 for ORF3 and 91 for ORF4. Several hits had functions in the life cycle of distinct viruses. We focused on SHARPIN and RNF5 as candidate hits for ORF3, as they are involved in the RLR-MAVS pathway and interferon (IFN) induction during viral infections. Knocking out (KO) SHARPIN and RNF5 resulted in a different IFN response upon ORF3 transfection, compared to wild-type cells. Moreover, infection was increased in SHARPIN KO cells and decreased in RNF5 KO cells. In conclusion, MAPPIT and KISS are valuable tools to study virus–host interactions, providing insights into the poorly understood HEV life cycle. We further provide evidence for two identified hits as new host factors in the HEV life cycle. Full article

Chicken melanoma differentiation-associated gene 5 (MDA5) is a member of the RLRs family that recognizes the viral RNAs invading cells and activates downstream interferon regulatory pathways, thereby inhibiting viral replication. The caspase activation and recruitment domain (CARD) is the most important region in MDA5 protein. However, the antiviral and immune enhancement of MDA5 with the CARD region remains unclear. In this study, two truncated MDA5 genes with different CARD regions, namely MDA5-1 with CARD1 plus partial CARD2 domain and MDA5-2 with CARD1 plus complete CARD2 domain, were cloned via reverse transcription PCR and ligated into plasmid Flag-N vector to be Flag-MDA5-1 and Flag-MDA5-2 plasmids. DF-1 cells were transfected with two plasmids for 24 h and then inoculated with H9N2 virus (0.1 MOI) for 6 h to detect the levels of IFN-β, PKR, MAVS, and viral HA, NA, and NS proteins expression. The results showed that MDA5-1 and MDA5-2 increased the expression of IFN-β and PKR, activated the downstream molecule MAVS production, and inhibited the expression of HA, NA, and NS proteins. The knockdown of MDA5 genes confirmed that MDA5-2 had a stronger antiviral effect than that of MDA5-1. Furthermore, the recombinant proteins MDA5-1 and MDA5-2 were combined with H9N2 inactivated vaccine to immunize SPF chickens subcutaneously injected in the neck three times. The immune response of the immunized chicken was investigated. It was observed that the antibody titers and expressions of immune-related molecules from the chicken immunized with MDA5-1 and MDA5-2 group were increased, in which the inducing function of MDA5-2 groups was the highest among all immunization groups. These results suggested that the truncated MDA5 recombinant proteins with complete CARD2 region could play vital roles in antiviral and immune enhancement. This study provides important material for the further study of the immunoregulatory function and clinical applications of MDA5 protein. Full article

The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) play a crucial role as pattern-recognition receptors within the innate immune system. These receptors, present in various cell and tissue types, serve as essential sensors for viral infections, enhancing the immune system’s capacity to combat infections through the induction of type I interferons (IFN-I) and inflammatory cytokines. RLRs are involved in a variety of physiological and pathological processes, including viral infections, autoimmune disorders, and cancer. An increasing body of research has examined the possibility of RLRs or microRNAs as therapeutic targets for antiviral infections and malignancies, despite the fact that few studies have focused on the regulatory function of microRNAs on RLR signaling. Consequently, our main emphasis in this review is on elucidating the role of microRNAs in modulating the signaling pathways of RLRs in the context of cancer and viral infections. The aim is to establish a robust knowledge base that can serve as a basis for future comprehensive investigations into the interplay between microRNAs and RIG-I, while also facilitating the advancement of therapeutic drug development. Full article

Viral vectors play a pivotal role in the field of gene therapy, with several related drugs having already gained clinical approval from the EMA and FDA. However, numerous viral gene therapy vectors are currently undergoing pre-clinical research or participating in clinical trials. Despite advancements, the innate response remains a significant barrier impeding the clinical development of viral gene therapy. The innate immune response to viral gene therapy vectors and transgenes is still an important reason hindering its clinical development. Extensive studies have demonstrated that different DNA and RNA sensors can detect adenoviruses, adeno-associated viruses, and lentiviruses, thereby activating various innate immune pathways such as Toll-like receptor (TLR), cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING), and retinoic acid-inducible gene I–mitochondrial antiviral signaling protein (RLR-MAVS). This review focuses on elucidating the mechanisms underlying the innate immune response induced by three widely utilized viral vectors: adenovirus, adeno-associated virus, and lentivirus, as well as the strategies employed to circumvent innate immunity. Full article