Search Results (809)

Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition. Full article

The barbel chub (Squaliobarbus curriculus) exhibits remarkable resistance to grass carp reovirus (GCRV), a devastating pathogen in aquaculture. To reveal the molecular basis of this resistance, we investigated complement factor D (DF)—a rate-limiting serine protease governing alternative complement pathway activation. Molecular cloning revealed that the barbel chub DF (ScDF) gene encodes a 1251-bp cDNA sequence translating into a 250-amino acid protein. Crucially, bioinformatic characterization identified a unique N-glycosylation site at Asn¹³⁹ in ScDF, representing a structural divergence absent in grass carp (Ctenopharyngodon idella) DF (CiDF). While retaining a conserved Tryp_SPc domain harboring the catalytic triad (His⁶¹, Asp¹⁰⁹, and Ser²⁰⁴) and substrate-binding residues (Asp¹⁹⁸, Ser²¹⁹, and Gly²²¹), sequence and phylogenetic analyses confirmed ScDF’s evolutionary conservation, displaying 94.4% amino acid identity with CiDF and clustering within the Cyprinidae. Expression profiling revealed constitutive ScDF dominance in the liver, and secondary prominence was observed in the heart. Upon GCRV challenge in S. curriculus kidney (SCK) cells, ScDF transcription surged to a 438-fold increase versus uninfected controls at 6 h post-infection (hpi; p < 0.001)—significantly preceding the 168-hpi response peak documented for CiDF in grass carp. Functional validation showed that ScDF overexpression suppressed key viral capsid genes (VP2, VP5, and VP7) and upregulated the interferon regulator IRF9. Moreover, recombinant ScDF protein incubation induced interferon pathway genes and complement C3 expression. Collectively, ScDF’s rapid early induction (peaking at 6 hpi) and multi-pathway coordination may contribute to barbel chub’s GCRV resistance. These findings may provide molecular insights into the barbel chub’s high GCRV resistance compared to grass carp and novel perspectives for anti-GCRV breeding strategies in fish. Full article

Recent preclinical and clinical studies have confirmed the essential role of interferons in the host’s immune response against malignant cells. Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer strongly associated with Merkel cell polyomavirus (MCPyV). Despite progress in understanding MCC pathogenesis, the role of innate immune signaling, particularly interferon-γ (IFN γ) and its downstream pathways, remains underexplored. This review summarizes recent findings on IFN-γ in MCC, highlighting its dual role in promoting both antitumor immunity and immune evasion. IFN-γ enhances cytotoxic T cell responses, upregulates MHC class I/II expression, and induces tumor cell apoptosis. Transcriptomic studies have shown that IFN-γ treatment upregulates immune-regulatory genes including PD-L1, HLA-A/B/C, and IDO1 by over threefold; it also activates APOBEC3B and 3G, contributing to antiviral defense and tumor editing. Clinically, immune checkpoint inhibitors (ICIs) such as pembrolizumab and avelumab yield objective response rates of 30–56% and two-year overall survival rates exceeding 60% in advanced MCC. However, approximately 50% of patients do not respond, in part due to IFN-γ signaling deficiencies. This review further discusses IFN-γ’s crosstalk with the STAT1/3/5 pathways and emerging combination strategies aimed at restoring immune sensitivity. Understanding these mechanisms may inform personalized immunotherapeutic approaches and guide the development of IFN-γ–based interventions in MCC. Full article

Background: Cerebral aneurysm (CA) is a focal or diffuse pathological dilation of the cerebral arterial wall that arises due to various etiological factors. It represents a serious vascular condition, particularly affecting the elderly, and carries a high risk of rupture and neurological morbidity. Clonidine (CL), an α2-adrenergic receptor agonist, has been reported to suppress aneurysm progression; however, its underlying molecular mechanisms, especially in relation to cerebral endothelial dysfunction, remain unclear. This study aimed to investigate the potential of CL to mitigate CA development by modulating apoptosis, inflammation, and oxidative stress in an Angiotensin II (Ang II)-induced endothelial injury model. Methods: Human brain microvascular endothelial cells (HBMECs) were used to establish an in vitro model of endothelial dysfunction by treating cells with 1 µM Ang II for 48 h. CL was administered 2 h prior to Ang II exposure at concentrations of 0.1, 1, and 10 µM. Cell viability was assessed using the MTT assay. Oxidative stress markers, including reactive oxygen species (ROS) and Nitric Oxide (NO), were measured using 2′,7′–dichlorofluorescin diacetate (DCFDA). Gene expression levels of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP-2 and MMP-9), high mobility group box 1 (HMGB1), and nuclear factor kappa B (NF-κB) were quantified using RT-qPCR. Levels of proinflammatory cytokines; tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and interferon-gamma (IFN-γ); were measured using commercial ELISA kits. Results: Ang II significantly increased ROS production and reduced NO levels, accompanied by heightened proinflammatory cytokine release and endothelial dysfunction. MTT assay revealed a marked decrease in cell viability following Ang II treatment (34.18%), whereas CL preserved cell viability in a concentration-dependent manner: 44.24% at 0.1 µM, 66.56% at 1 µM, and 81.74% at 10 µM. CL treatment also significantly attenuated ROS generation and inflammatory cytokine levels (p < 0.05). Furthermore, the expression of VEGF, HMGB1, NF-κB, MMP-2, and MMP-9 was significantly downregulated in response to CL. Conclusions: CL exerts a protective effect on endothelial cells by reducing oxidative stress and suppressing proinflammatory signaling pathways in Ang II-induced injury. These results support the potential of CL to mitigate endothelial injury in vitro, though further in vivo studies are required to confirm its translational relevance. Full article

Porcine epidemic diarrhea virus (PEDV) infection induces severe, often fatal, watery diarrhea and vomiting in neonatal piglets, characterized by profound dehydration, villus atrophy, and catastrophic mortality rates approaching 100% in unprotected herds. This study developed a composite probiotic from Min-pig-derived Lactobacillus crispatus LCM233, Ligilactobacillus salivarius LSM231, and Lactiplantibacillus plantarum LPM239, which exhibited synergistic growth, potent acid/bile salt tolerance, and broad-spectrum antimicrobial activity against pathogens. In vitro, the probiotic combination disrupted pathogen ultrastructure and inhibited PEDV replication in IPI-2I cells. In vivo, PEDV-infected piglets administered with the multi-strain probiotic exhibited decreased viral loads in anal and nasal swabs, as well as in intestinal tissues. This intervention was associated with the alleviation of diarrhea symptoms and improved weight gain. Furthermore, the multi-strain probiotic facilitated the repair of intestinal villi and tight junctions, increased the number of goblet cells, downregulated pro-inflammatory cytokines, enhanced the expression of barrier proteins, and upregulated antiviral interferon-stimulated genes. These findings demonstrate that the multi-strain probiotic mitigates PEDV-induced damage by restoring intestinal barrier homeostasis and modulating immune responses, providing a novel strategy for controlling PEDV infections. 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

SLE is characterized by the generation of a variety of autoantibodies including anti-dsDNA autoantibodies, causing damage in various organs. If autoimmunity is defined by the generation of a variety of autoantibodies against the self, SLE is the only disease to qualify. Identification of the SLE-causing factor must fulfill the following criteria: (i) the factor induces SLE, (ii) the factor is operating in active SLE and (iii) SLE heals after removal of the factor. All candidate factors are reviewed from this viewpoint in this review. As to the cause of SLE, high levels of interferon α can induce SLE; however, interferon α in most patients did not reach this high level. BAFF (B cell activating factor of the TNF family) is increased in SLE. BAFF itself induced some manifestation of SLE, whereas removal of interferon α or BAFF by an antibody (Ab) did not heal SLE. BXSB male mice with a duplicated TLR7 gene develop SLE; however, the gene Sle1 is also required for the development of SLE. In addition, sanroque mice develop a variety of autoantibodies and SLE; the sanroque mutation, which disrupts one of the repressors of ICOS, results in increased CCR7^lo CXCR5⁺Tfh cells, IL-21 and SLE. ICOS⁺T follicular helper (Tfh) cells increase in SLE and SLE-model (NZBxNZW)F1 mice, and the blockade of Tfh development ameliorated SLE, indicating the importance of Tfh cells in the pathogenesis of SLE. Self-organized criticality theory shows that SLE is caused by repeated infection, wherein SLE-inducing pathogens can vary individually depending on one’s HLA; however, the pathogen presented on HLA stimulates the T cell receptor (TCR) strongly beyond self-organized criticality. This stimulation generates TCR-revised, autoreactive DOCK8⁺Tfh cells, which induced a variety of autoantibodies and SLE. The SARS-CoV-2 virus is an example pathogen because SLE occurs after SARS-CoV-2 infection and vaccination. DOCK8⁺Tfh cells and SLE decreased after conventional or anti-DOCK Ab therapies. Thus, DOCK8⁺Tfh cells newly generated after repeated infection fulfill the criteria (i), (ii) and (iii) as the cause of SLE. Full article

Herpes simplex virus type 1 (HSV-1) is a globally prevalent pathogen that can infect a variety of animal species as well as humans. However, existing antiviral therapies are constrained in their capacity to effectively target viral latency and prevent recurrent infections. Antimicrobial peptides (AMPs), particularly cathelicidins, as part of innate immune system have demonstrated broad-spectrum efficacy against viral pathogens. In this study, four peptides derived from Elephas maximus cathelicidin EM were designed and optimized (EM-1 to EM-4). We identified low toxicity peptide derivatives through hemolytic and cytotoxicity assays, quantified their anti-HSV-1 activity by determining IC₅₀. Antiviral mechanisms were investigated using RT-qPCR and antiviral efficacy was ultimately validated in C57BL/6J mice through viral load quantification in brain, lung, and heart tissues. Our findings revealed that EM-1 significantly inhibited HSV-1 replication in U251 cells. In a murine footpad inoculation model, EM-1 administration substantially reduced viral loads and alleviated inflammatory responses. Histological assessment demonstrated that EM-1 treatment mitigated HSV-1 induced tissue damage in infected mice. We also found that EM-1 exerted its antiviral effects by upregulating the expression of interferon-gamma and its downstream genes, such as ISG15 and MX1. These findings indicated that EM-1 is a dual function peptide that inhibits replication of HSV-1 as well as enhances host antiviral immunity. Collectively, this study highlights the therapeutic potential of elephant cathelicidin derived peptides in antiviral development. 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

Natural killer (NK) cell adoptive immunotherapy is a promising therapeutic approach in which NK cells perform targeted lysis of tumor cells. Oncolytic viruses are also effective cancer therapeutic agents due to their ability to selectively target and kill tumor cells. Combination therapies that integrate NK cells and oncolytic viruses have been shown to enhance tumor killing compared to individual treatment strategies alone. Using in vitro expanded human NK cells (PM21-NK cells), we tested the relative ability of tumor cells infected with WT parainfluenza virus 5 (PIV5), which is a poor inducer of type 1 interferon (IFN-I), versus PIV5 P/V gene mutant, which is a strong inducer of IFN-I synthesis, to modulate NK cell activities. Both WT and P/V mutant viruses were capable of infecting PM21-NK cells and caused extensive cytopathic effects. Co-culturing of PM21-NK cells with virus-infected tumor cells resulted in spread of WT PIV5 to naïve NK cells, but NK cells were protected from spread of the P/V mutant virus by IFN-I induction. Direct treatment of PM21-NK cells with IFN-I or media from P/V-virus-infected tumor cells enhanced NK cell cytotoxicity, at least in part due to upregulation of the death ligand, TRAIL. IFN-I-treated PM21-NK cells also showed a decrease in IFN-γ secretion, a cytokine we have previously shown to reduce PM21-NK cell tumor killing. Our results highlight multiple mechanisms by which an IFN-I-inducing oncolytic virus can enhance NK-cell-mediated killing of target virus-infected and uninfected tumor cells. Full article

Marine heatwaves (MHWs) have recently become more frequent, intense, and prolonged, posing significant threats to marine life and fisheries. In this study, transcriptomic analysis was employed to investigate the genes and pathways in Seriola dumerili that respond to MHW-induced stress at 28 °C (T28) and 32 °C (T32), using 24 °C (T24) as the control. Transcriptome sequencing revealed that 17 differentially expressed genes (DEGs) belonging to the heat shock protein (HSP) families—HSP30, HSP40, HSP70, and HSP90—were significantly upregulated under short-lasting MHW stress in the T24-4d vs. T32-4d comparison. Additionally, genes related to oxidative stress (e.g., protein disulfide isomerase family A member 6 [pdia6]), immune responses (e.g., interferon regulatory factor 5 [irf5]), and energy metabolism (e.g., hexokinase-1 [hk1]) were also identified. Enrichment analysis of DEGs in the T24-4d vs. T32-4d group revealed that S. dumerili exhibited adaptive responses to MHWs through the upregulation of HSPs and the activation of antioxidant, energy metabolism, and immune response pathways. However, in the T24-13d vs. T32-13d group, DEGs associated with these pathways were either not significantly expressed or were downregulated. These findings indicate that S. dumerili is unable to sustain its adaptive responses under repeated, intense MHW exposure, resulting in the disorder of its antioxidant defense system, immune suppression, and metabolic dysfunction. This study provides valuable insights into the molecular responses of S. dumerili to MHWs and supports the selection for thermal resistance in this species. Full article

At weaning, piglets deal with numerous changes and stressors, which can lead to reduced feed intake, digestive disturbances, and gut inflammation. In this context, there is a compelling need to develop new and innovative nutritional strategies aimed at restoring intestinal balance in piglets after weaning and controlling the weaning-associated intestinal inflammation. This study investigated the effect of a diet, including a synbiotic additive (a mix of grape seed and camelina meals as the prebiotic and a lactobacilli mixture as the probiotic) on intestinal inflammation in piglets after weaning. An acute inflammation was induced by the intraperitoneally challenge with Escherichia coli lipopolysaccharide (LPS). The experimental groups were as follows: Control group (piglets fed a conventional corn-soybean meal-based diet), LPS group (piglets fed the Control diet and challenged with 80 µg/b.w. of LPS), SYN group (piglets fed a basal diet, including 5% prebiotic mix and 0.1% probiotic mix, SYN diet), and SYN+LPS group (piglets fed the SYN diet and challenged with 80 µg/b.w. of LPS). Using genomic and proteomic techniques, genes and proteins related to intestinal inflammation were measured in both the jejunum and colon. The results showed that the LPS challenge induced an exacerbated inflammatory response in the jejunum and colon of piglets, inducing an overexpression of a large palette of inflammation-related mediators, including lactate dehydrogenase (LDH) activity, cytokines (e.g., interleukin (IL)—IL-1β, IL-6, tumor necrosis factor alpha—TNF-α), and chemokines (e.g., monokine induced by interferon-gamma—MIG, regulated on activation, normal T cell expressed and secreted—RANTES). All these effects are prevented by the SYN diet, which controls the amplitude of intestinal inflammation induced by the LPS challenge in piglets. Overall, these results suggested that piglets, after weaning, fed the synbiotic diet are less susceptible to the LPS challenge. This diet might be used as a nutritional strategy to alleviate intestinal inflammation in piglets after weaning. Full article

Dengue virus (DENV) infection is strongly associated with dengue hemorrhagic fever and dengue shock syndrome, both of which carry mortality risks. Addressing the urgent need for effective dengue therapeutics, we identified sofalcone, a gastroprotective agent with antioxidant and anti-inflammatory properties, as a potential inhibitor of DENV replication. Sofalcone demonstrated efficacy against all four DENV serotypes, with the dose inhibiting 50% (IC50) value of 28.1 ± 0.42 μM against viral replication of DENV serotype 2, without significant cytotoxicity. Additionally, sofalcone significantly improved survival rates and reduced viral titers in DENV-infected ICR-suckling mice. Mechanistically, sofalcone induced heme oxygenase-1 (HO-1) expression via the nuclear factor-erythroid 2-reated factor 2 (Nrf2) pathway, which in turn suppressed viral protease activity and restored antiviral interferon (IFN) responses. This included dose-dependent stimulation of IFN downstream antiviral genes such as 2′-5′-oligoadenylate synthetase 1 (OAS1), OAS2, and OAS3. Given its established clinical use as an anti-gastric ulcer drug, sofalcone offers promising potential for rapid application in treating DENV infection. Full article

Particulate matter (PM) is a major environmental pollutant implicated in various respiratory diseases. However, its impact on the upper respiratory tract, particularly the nasal and paranasal sinus mucosa, remains poorly understood. This study aimed to investigate the acute inflammatory effects of PM exposure on the sinonasal mucosa and evaluate the natural recovery process in a controlled rat model. Ten-week-old male Sprague Dawley rats were exposed to incense-derived PM in a custom-designed exposure chamber for 2 h daily for seven consecutive days. Rats were sacrificed at 3, 7, and 14 days post-exposure. Histopathologic changes were assessed using hematoxylin and eosin and Alcian blue staining, and mucosal gene expression of inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-5 and MUC5AC was quantified using real-time reverse transcription polymerase chain reaction. PM exposure induced significant histological alterations, including epithelial thickening, inflammatory cell infiltration, and goblet cell hyperplasia, which peaked at 7 days post-exposure. Expression levels of TNF-α and IFN-γ were significantly elevated at 7 days compared to controls. The sinonasal mucosa in the 14-day post-exposure groups exhibited a remarkable decrease in goblet cell numbers, and IL-1β and TNF-α expression. Short-term exposure to high concentrations of PM resulted in acute inflammatory changes in the sinonasal mucosa of rats, including epithelial thickening and goblet cell hyperplasia. These changes were partially resolved after exposure ended, indicating that PM-induced sinonasal inflammation may be at least partially reversible. 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