Search Results (1,068)

Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests that certain viruses exploit Suppressor of Cytokine Signaling 3 (SOCS3), a key immune checkpoint protein, to subvert host innate immunity by suppressing cytokine signaling. While SOCS3 has been implicated in various viral infections, its regulatory role in PCV2 replication remains undefined. This study aims to elucidate the mechanisms underlying the interplay between SOCS3 and PCV2 during viral pathogenesis. Porcine SOCS3 was amplified using RT-PCR and stably overexpressed in PK-15 cells through lentiviral delivery. Bioinformatics analysis facilitated the design of three siRNA candidates targeting SOCS3. We systematically investigated the effects of SOCS3 overexpression and knockdown on PCV2 replication kinetics and host antiviral responses by quantifying the viral DNA load and the mRNA levels of cytokines. PCV2 infection upregulated SOCS3 expression at both transcriptional and translational levels in PK-15 cells. Functional studies revealed that SOCS3 overexpression markedly enhanced viral replication, whereas its knockdown suppressed viral proliferation. Intriguingly, SOCS3-mediated immune modulation exhibited a divergent regulation of antiviral cytokines: PCV2-infected SOCS3-overexpressing cells showed elevated IFN-β but suppressed TNF-α expressions, whereas SOCS3 silencing conversely downregulated IFN-β while amplifying TNF-α responses. This study unveils a dual role of SOCS3 during subclinical porcine circovirus type 2 (PCV2) infection: it functions as a host-derived pro-viral factor that facilitates viral replication while simultaneously reshaping the cytokine milieu to suppress overt inflammatory responses. These findings provide novel insights into the mechanisms underlying PCV2 immune evasion and persistence and establish a theoretical framework for the development of host-targeted control strategies. Although our results identify SOCS3 as a key host determinant of PCV2 persistence, the precise molecular pathways involved require rigorous experimental validation. Full article

The rabies virus (RABV) phosphoprotein (P protein) has multiple functions, including acting as the essential non-catalytic cofactor of the viral polymerase (L protein) for genome replication and transcription; the principal viral antagonist of the interferon (IFN)-mediated innate immune response; and the chaperone for the viral nucleoprotein (N protein). Although P protein is known to undergo phosphorylation by cellular kinases, the location and functions of the phosphorylation sites remains poorly defined. Here, we report the identification by mass-spectrometry (MS) of residues of P protein that are modified by phosphorylation in mammalian cells, including several novel sites. Analysis of P protein with phospho-mimetic and phospho-inhibitory mutations of three novel residues/clusters that were commonly identified by MS (Ser48, Ser183/187, Ser217/219/220) indicate that phosphorylation at each of these sites does not have a major influence on nuclear trafficking or antagonistic functions toward IFN signalling pathways. However, phosphorylation of Ser48 in the N-terminus of P protein impaired function in transcription/replication and in the formation of replication structures that contain complexes of P and N proteins, suggestive of altered interactions of these proteins. The crystal structure of P protein containing the S48E phospho-mimetic mutation indicates that Ser48 phosphorylation facilitates the binding of residues 41–52 of P protein into the RNA-binding groove of non-RNA-bound N protein (N⁰), primarily through the formation of a salt bridge with Arg434 of N protein. These data indicate that Ser48 modification regulates the cycling of P-N⁰ chaperone complexes that deliver N protein to RNA to enable transcription/replication, such that enhanced interaction due to S48E phospho-mimetic mutation reduces N protein delivery to the RNA, inhibiting subsequent transcription/replication processes. These data are, to our knowledge, the first to implicate phosphorylation of RABV P protein in conserved replication functions of the P gene. 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

The collection of perivitelline fluid (PVF) from early-stage post-activation zebrafish (Danio rerio) eggs/embryos poses a significant challenge owing to the liability of the egg/embryo to sustain damage and rupture during handling. Rupture of the blastoderm and/or yolk presents a major risk of PVF sample contamination. Previous efforts to extract PVF at such early stages have employed formalin fixation to enhance the structural integrity of the blastoderm and yolk syncytial layer, thereby reducing the likelihood of contamination. While this approach successfully mitigates blastoderm and yolk rupture, formaldehyde fixation may cause issues with downstream proteomic analyses. Recent findings indicate that zebrafish PVF contains a range of maternally inherited proteins involved in innate immune defence. However, current extraction methods compromise the reliability of downstream protein analyses, raising concerns that fixation-induced protein crosslinking may obscure the presence of maternally inherited proteins during the earliest stages of development. The micro-aspiration technique described here allows for the precise extraction of PVF from living, water-activated eggs with minimal disruption to the blastodisc and yolk. This method reduces the risk of contamination from other non-target proteinaceous egg sources and eliminates the need for formalin fixation, thereby improving the integrity of PVF samples and enhancing the reliability of subsequent downstream analyses. Full article

This study investigated the immunonutritional potential of high-molecular-weight (Mw~85 kDa), non-degraded chitosan (NCS) and gamma-radiation-degraded, low-molecular-weight chitosan (RCS) incorporated into aquafeeds for Nile tilapia (Oreochromis niloticus). RCS was produced by γ-irradiation (10 kGy) in the presence of 0.25% (w/v) H₂O₂, yielding low-viscosity, colloidally stable nanoparticles with Mw ranging from 10 to 13 kDa. Five diets were formulated: a control, NCS at 0.50%, and RCS at 0.025%, 0.050%, and 0.075%. No adverse effects on growth were observed, confirming safety. Immune gene expression (e.g., ifng1, nfκb, tnf), antioxidant markers (e.g., reduced MDA, increased GSH and GR), and nonspecific humoral responses (lysozyme, IgM, and bactericidal activity) were significantly enhanced in the NCS-0.50, RCS-0.050, and RCS-0.075 groups. Notably, these benefits were achieved with RCS at 10-fold lower concentrations than NCS. Following challenge with Edwardsiella tarda, fish fed RCS-0.050 and RCS-0.075 diets exhibited the highest survival rates and relative percent survival, highlighting robust activation of innate and adaptive immunity alongside redox defense. These results support the use of low-Mw RCS as a biologically potent, cost-effective alternative to traditional high-Mw chitosan in functional aquafeeds. RCS-0.050 and RCS-0.075 show strong potential as immunonutritional agents to enhance fish health and disease resistance in aquaculture. Full article

Drug resistance in Candida may result in either a fitness cost or a fitness advantage. Candida auris, whose intrinsic drug resistance remains unclear, has emerged as a significant human pathogen. We aimed to investigate whether Candida fitness, including early interaction with the host innate immune system, depends on the antifungal susceptibility phenotype and putative-associated resistance mutations. We compared interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor α production by human colorectal adenocarcinoma cells stimulated by fluconazole-susceptible and fluconazole-resistant strains of Candida albicans, C. parapsilosis, C. tropicalis, and C. glabrata, as well as fluconazole-resistant C. auris strains. Sensitive Candida strains induced lower cytokine levels compared with C. auris and resistant strains, except for TNF a. Resistant strains induced cytokine levels like C. auris, except for higher IL-1β and lower TNF-α. Susceptible strains exhibited cytokine profiles distinct from those of resistant strains. C. auris induced cytokine levels comparable to resistant strains but displayed profiles resembling those of susceptible strains. This study highlights the relationship among antifungal susceptibility, fungal fitness and host early immunity. C. auris behavior appears to be between fluconazole-sensitive and fluconazole-resistant strains. Understanding these dynamics may enhance the knowledge of the survival and reproduction of resistant Candida and the epidemiology of fungal infections. Full article

Acute hepatopancreatic necrosis disease (AHPND), caused by the bacterium Vibrio parahaemolyticus, is a major threat to global shrimp aquaculture. In this study, we evaluated the therapeutic effects of phage therapy in Litopenaeus vannamei challenged with AHPND-causing Vibrio parahaemolyticus. Phage application at various concentrations significantly improved shrimp survival, with the 1 ppm group demonstrating the highest survival rate. Enzymatic assays revealed that phage-treated shrimp exhibited enhanced immune enzyme activities, including acid phosphatase (ACP), alkaline phosphatase (AKP), and lysozyme (LZM). In addition, antioxidant defenses such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX), and total antioxidant capacity (T-AOC) significantly improved, accompanied by reduced malondialdehyde (MDA) levels. Serum biochemical analyses demonstrated marked improvements in lipid metabolism, particularly reductions in triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL), alongside higher levels of beneficial high-density lipoprotein (HDL). Transcriptomic analysis identified 2274 differentially expressed genes (DEGs), notably enriched in pathways involving fatty acid metabolism, peroxisome functions, lysosomes, and Toll-like receptor (TLR) signaling. Specifically, phage treatment upregulated immune and metabolic regulatory genes, including Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MYD88), interleukin-1β (IL-1β), nuclear factor erythroid 2-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor (PPAR), indicating activation of innate immunity and antioxidant defense pathways. These findings suggest that phage therapy induces protective immunometabolic adaptations beyond its direct antibacterial effects, thereby providing an ecologically sustainable alternative to antibiotics for managing bacterial diseases in shrimp aquaculture. Full article

During commercial pig production, weaning is a major stressor that disrupts the gut microbiome, compromises intestinal barrier integrity, and increases the susceptibility of piglets to pathogens. This often results in post-weaning diarrhoea (PWD), leading to growth retardation, morbidity, and economic loss. This study investigated the effects of dietary xylo-oligosaccharide (XOS) supplementation on the growth performance and gut health of 216 piglets with naturally occurring PWD. Piglets received either 0 (CON), 50 (XOS-50), or 500 (XOS-500) mg XOS/kg feed from weaning at 28 days of age (d1) for 54 days. XOS-500 significantly improved body weight at d22 and d54, but had no effect on average daily gain, daily feed intake (DFI), or feed conversion ratio. The intestinal microbiota alpha-diversity was unaffected by XOS, though jejunal beta diversity differed between CON and XOS-500 groups at d22. Jejunal Chao richness correlated positively with d54 body weight, while ileal Chao richness correlated negatively with DFI. Salmonella was present in all diet groups but did not differ in abundance; however, the levels were negatively correlated with alpha diversity. XOSs increased Lactobacillus (d22, d54) and Clostridium_XI (d22), while reducing Veillonellaceae spp. (d22). XOSs reduced jejunal goblet cell (GC) density at d22 but increased duodenal and jejunal GCs and reduced duodenal crypt depth at d54. XOSs upregulated the genes for the tight junction proteins CLDN2, CLDN3, ALPI, and ZO-1, while downregulating the cytokine IL-8. These findings highlight XOSs’ potential to improve growth and gut health in weaning piglets with naturally occurring PWD, to maintain productivity and enhance welfare. Full article

Helicobacter pylori infection represents one of the most prevalent and persistent bacterial infections worldwide, closely linked to a spectrum of gastroduodenal diseases, including chronic gastritis, peptic ulceration, and gastric cancer. Recent advances have shed light on the critical role of endogenous lectins, particularly galectins, in modulating host–pathogen interactions within the gastric mucosa. Galectins are β-galactoside-binding proteins with highly conserved structures but diverse biological functions, ranging from regulation of innate and adaptive immunity to modulation of cell signaling, apoptosis, and epithelial integrity. This review provides a comprehensive synthesis of current knowledge on the involvement of key galectin family members—especially Galectin-1, -2, -3, -8, and -9—in the context of H. pylori infection. Their dual roles in enhancing mucosal defense and facilitating bacterial persistence are examined along with their contributions to immune evasion, inflammation, and gastric carcinogenesis. Understanding the interplay between galectins and H. pylori enhances our knowledge of mucosal immunity. This interaction may also reveal potential biomarkers for disease progression and identify novel therapeutic targets. Modulating galectin-mediated pathways could improve outcomes in H. pylori-associated diseases. Full article

Viral infections persistently challenge global health through immune evasion and zoonotic transmission. Dendritic cells (DCs) play a central role in antiviral immunity by detecting viral nucleic acids via conserved pattern recognition receptors, triggering interferon-driven innate responses and cross-presentation-mediated activation of cytotoxic CD8⁺ T cells. This study synthesizes DC-centric defense mechanisms against viral subversion, encompassing divergent nucleic acid sensing pathways for zoonotic DNA and RNA viruses, viral counterstrategies targeting DC maturation and interferon signaling, and functional specialization of DC subsets in immune coordination. Despite advances in DC-based vaccine platforms, clinical translation is hindered by cellular heterogeneity, immunosuppressive microenvironments, and limitations in antigen delivery. Future research should aim to enhance the efficiency of DC-mediated immunity, thereby establishing a robust scientific foundation for the development of next-generation vaccines and antiviral therapies. A more in-depth exploration of DC functions and regulatory mechanisms may unlock novel strategies for antiviral intervention, ultimately paving the way for improved prevention and treatment of viral infections. Full article

Bovine endometritis is a common postpartum disease that significantly impairs reproductive performance and reduces economic sustainability in dairy and beef cattle. It is primarily caused by gram-negative and -positive bacteria, triggering strong inflammatory responses in the endometrium. Serum amyloid A (SAA) is an acute-phase protein and precursor of amyloid A (AA) in AA amyloidosis. In cattle, multiple SAA isoforms have been identified; however, the biological functions of SAA3 remain unclear. Hence, this study investigated the role of SAA3 in bovine endometrial epithelial cells (BEnEpCs) following stimulation with gram-negative or -positive bacterial antigens. BEnEpCs were treated with lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and, subsequently, the expression levels of SAA3 and SAA1 mRNA were compared by real-time PCR. To further investigate protein-level changes, immunocytochemistry (ICC) was performed to assess the expressions of SAA3 and SAA1. These analyses revealed that SAA3 mRNA expression was significantly enhanced by LPS and LTA, whereas SAA1 mRNA remained undetectable or showed only minimal responsiveness. Notably, only SAA3 protein expression increased in response to stimulation. These results indicate that SAA3 plays a crucial role in the innate immune response of BEnEpCs against gram-negative bacteria. Our in vitro findings may facilitate understanding of the innate immune activity in bovine uterus. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article

Heat shock proteins (HSPs) play a key role in enhancing insect resilience to abiotic and biotic stresses by preserving cellular integrity and modulating immune responses. This review summarizes the main functions of HSPs in insects, including protein stabilization, interaction with antioxidant systems, and involvement in the innate immune response. The expression of HSPs under environmental conditions reflects their evolutionary adaptation to various stressors, including thermal changes, chemical exposure, and pathogens. Future research should focus on the interaction between HSPs and other stress response systems to improve our understanding of insect adaptation. Furthermore, in the context of global climate change, HSPs emerge as a crucial resilience factor and potential biomarkers for environmental monitoring. Full article

Periodontitis is a multifactorial disease linked to host immune response and genetic predisposition. The TLR4 Asp299Gly single-nucleotide polymorphism (SNP, rs4986790) has been associated with altered responses to bacterial lipopolysaccharide (LPS) and may influence susceptibility to inflammatory diseases. Given the central role of TLR4 in innate immune recognition of periodontal pathogens, this study investigates the role of rs4986790 in modulating susceptibility to periodontal inflammatory destruction. A total of 1410 individuals from four populations were genotyped, with findings indicating a significant protective effect of the polymorphic allele. Functional assays demonstrated enhanced IL-8 secretion and increased sensitivity to CD14 inhibition in cells expressing the variant receptor. These results suggest that rs4986790 modifies the LPS response via TLR4, potentially offering protection against periodontal breakdown. Full article

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK⁺ CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain. Full article