Search Results (801)

The single von Willebrand factor C (SVWC) domain-containing protein family represents a crucial class of immune molecules recently identified in insects and crustaceans. Initially regarded as functional analogs of vertebrate interferons (IFNs) due to their virus-induced expression and activation of the Janus kinase-signal transducer and activator of the transcription (JAK-STAT) pathway, recent studies have revealed that SVWC proteins possess far more complex functions. Many SVWC members are themselves a novel class of pattern recognition receptors (PRRs) that can directly bind to viruses and bacteria. Importantly, SVWCs are not a single entity but a highly diverse family—multiple subtypes exist in Drosophila, Bombyx mori, and shrimp—a gene expansion that implies functional differentiation. This review systematically examines the multifunctionality of SVWC proteins in insects and crustaceans, with a particular focus on the functional specialization driven by subtype diversity. We delve into the complex regulatory networks governing SVWC expression, including the differential activation by nuclear factor kappa B (NF-κB) pathways (Dorsal, Rel-2, Relish) and interferon regulatory factor (IRF) pathways. We detail the unique signaling mechanism by which SVWCs activate the JAK-STAT pathway via integrins, rather than the canonical Domeless receptor. Furthermore, we extend the discussion to the emerging roles of SVWCs as PRRs in humoral immunity (activating Toll/IMD pathways to induce antimicrobial peptides) and cellular immunity (mediating hemocyte phagocytosis). Based on current evidence, We propose that diverse SVWC subtypes may recognize distinct pathogens, bind to different integrin receptors, and activate specific STAT variants via disparate upstream induction pathways, thereby establishing a systematic and hierarchical immunoregulatory network. This understanding positions the SVWC protein family as a central hub in the insect immune network and offers a novel perspective on the complexity and evolution of invertebrate immunity. Full article

C. burnetii (Cb) is an obligate intracellular bacterial pathogen that replicates within alveolar macrophages following aerosol infection. Unlike most intracellular bacteria, Cb establishes a lysosome-derived replicative niche (Coxiella-containing vacuole or CCV) through the action of its Type IVB secretion system (T4BSS). This system translocates a large repertoire of effector proteins into the host cytoplasm after phagosome acidification. These effectors interfere with diverse signaling pathways to co-opt host processes, such as vesicle trafficking, ubiquitylation, gene expression and lipid metabolism, promoting pathogen survival without triggering robust proinflammatory signaling or host cell death pathways. This effector-triggered immune silencing is particularly unique given the central role of macrophages as innate immune sentinels. In this review, we examine Cb T4BSS effectors that have been characterized as central determinants of innate immunity modulation. We discuss innate immune sensing pathways potentially engaged during infection, including Toll-like receptors, NOD-like receptors, RIG-I-like receptors, inflammasomes, and interferon signaling pathways, and highlight evidence indicating that these pathways are actively suppressed. Emphasis is placed on effector-mediated regulation of NF-κB signaling, type I interferon responses, and inflammasome activation. Finally, we address unresolved questions related to effector-triggered immunity, redundancy in immune suppression, and discrepancies between in vitro and in vivo infection models. Full article

Microbiome research is shifting from a focus on “whole microorganisms” to an emphasis on microbial functional components. This review systematically describes how the effects of microbial communities on the host are mediated by bioactive functional components released by microbes. These components primarily exert their effects through interactions with host Pattern Recognition Receptors (PRRs) and metabolic sensing receptors, thereby regulating host immune, metabolic, and barrier function networks. The biological effects of these functional components are highly context-dependent. Under homeostasis, metabolites such as SCFAs and bile acids promote mucosal immune tolerance and maintain epithelial barrier integrity. However, the same signals can become deleterious under dysbiosis, driving inflammation and contributing to colorectal tumorigenesis. Mechanistic dissection of individual components, such as lipopolysaccharide (LPS), is now propelling a transition in clinical translation from whole-microbe-based interventions toward component-oriented diagnostics and therapeutics. Component-oriented diagnostics and therapeutics use defined microbial molecules rather than whole microorganisms. Microbial nucleic acids (e.g., HPV DNA), metabolites (e.g., SCFAs), and proteins can serve as biomarkers for disease risk, diagnosis, and prognosis. Therapeutic strategies include targeted modulation of beneficial components, neutralization of harmful molecules, and engineered microbial delivery. Full article

Respiratory infections remain a leading cause of morbidity and mortality worldwide, highlighting the urgent need to better understand host defense mechanisms in the respiratory tract. Recent advances in sequencing technologies have challenged the traditional view of the lungs as sterile organs and revealed the presence of a distinct, low-biomass microbial community known as the lung microbiota. These microbial populations interact closely with airway epithelial cells and immune cells to maintain respiratory homeostasis and regulate host immune responses. In healthy lungs, microbial communities dominated by Firmicutes, Bacteroidetes, and Proteobacteria contribute to immune regulation through interactions with innate and adaptive immune pathways. Microbiota-derived signals are detected by pattern recognition receptors, activating signaling pathways that regulate cytokine production, immune cell recruitment, and T-cell differentiation. In the respiratory mucosa, microbial stimulation can also induce epithelial and antigen-presenting cells to produce B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), which promote immunoglobulin A (IgA) class-switch recombination and support mucosal antibody responses. During pulmonary infection, disruption of microbial communities can lead to dysbiosis that amplifies inflammatory responses, impairs epithelial barrier integrity, and increases susceptibility to secondary bacterial infections. In addition to local microbial interactions, the gut–lung axis represents a key communication pathway linking intestinal microbiota with respiratory immunity through microbial metabolites such as short-chain fatty acids (SCFAs) and immune signaling networks. This review summarizes current insights into microbiota–immune crosstalk in the lung during pulmonary infection and discusses how these interactions may inform mucosal vaccine development. A deeper understanding of host–microbiota interactions may enable microbiome-informed vaccines and therapeutic strategies to improve protection against respiratory diseases. Full article

Both plants and animals have developed a sophisticated two-tiered innate immune system. This involves an initial recognition of microbial patterns conserved on the cell surface (PAMP-triggered immunity) and a subsequent more specific intracellular recognition of pathogenic effectors or their activities (effector-triggered immunity). A common fundamental feature is the use of NLR-like intracellular receptors to detect insider threats. Both plant NLRs (receptors containing nucleotide-binding domains and leucine-rich repeats) and animal NLRs (NOD-like receptors) share a modular tripartite architecture, typically featuring a central nucleotide-binding domain (NBD/NOD) and C-terminal leucine-rich repeats (LRRs). The NBD/NOD is crucial for facilitating the exchange of ADP/ATP, acting as a molecular switch to promote oligomerization and activation of NLRs in both kingdoms. In this review, we summarize the similarities and differences between plant and animal molecular perception and immunity mechanisms. Additionally, we highlight the fact that some human pathogens can infect plants, and crucially, some plant pathogens are capable of causing disease in humans. This suggests conserved molecular strategies to invade and manipulate host cells belonging to different biological kingdoms, uncovering that plant and human pathology may benefit from future investigations in their respective fields. Full article

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis and Crohn’s disease, are associated with an increased risk of colorectal cancer through mechanisms driven by persistent mucosal inflammation. Chronic inflammatory signaling, recurrent epithelial injury, and altered tissue repair processes progressively reshape the intestinal microenvironment, promoting genomic instability and facilitating the development of colitis-associated colorectal cancer (CAC). Despite the well-established link between inflammation and tumorigenesis, only a subset of patients with long-standing IBD develops malignancy, highlighting the complexity of the regulatory effects of the ongoing inflammation on the tumor initiation and progression. This review discusses the multifaceted roles of innate and adaptive immune responses in CAC pathogenesis. Innate immune signaling mediated by pattern recognition receptors, particularly Toll-like receptors, integrates microbial and damage-associated signals to activate inflammatory pathways that regulate epithelial proliferation, survival, and tumor-promoting cytokine networks. Tumor-associated macrophages, neutrophils, and myeloid-derived suppressor cells contribute to carcinogenesis by sustaining chronic inflammation, promoting immunosuppression, and remodeling the tumor microenvironment, although under specific conditions these cells can also support antitumor immunity. Innate lymphocyte subsets participate in immune surveillance and epithelial homeostasis, yet may also amplify inflammatory circuits that influence tumor development. Adaptive immune populations further shape CAC evolution, as CD4⁺ T-helper subsets, CD8⁺ cytotoxic T lymphocytes, regulatory T cells, and B cells exert divergent effects depending on cytokine milieu, immune context, and disease stage. Understanding immune-cell plasticity and the molecular pathways governing these processes may facilitate the identification of predictive biomarkers and the development of targeted immunomodulatory strategies aimed at preventing CAC. Full article

Orf virus (ORFV) is a globally distributed zoonotic parapoxvirus that causes a highly contagious mucocutaneous disease in small ruminants. Despite the urgent demand for vaccination-based control, no licensed vaccines are currently available universally. In this study, we generated two recombinant Sendai virus (SeV) vectors expressing ORFV 011 (rSeV-GFP-B2L) and ORFV 059 (rSeV-GFP-059) genes and evaluated their ability to stimulate antiviral responses in vitro. Following the transduction, we assessed transgene expression, innate immune activation, induction of interferon-stimulated genes (A3Z1, OBST2, SAMHD1), and antiviral activity. Both vectors significantly upregulated pattern recognition receptors (TLRs, RIG-I) and type I interferon (IFN-β) genes, with rSeV-GFP-059 inducing the strongest response. Remarkably, OBST2 was robustly upregulated, suggesting a potential role in restricting ORFV replication. Antiviral activity assays revealed a marked reduction in ORFV DNA copies and a mild decrease in ORFV RNA transcription in rSeV-GFP-059-transduced cells, particularly at later time points, accompanied by complete abrogation of the typical cytopathic effect. Collectively, these results demonstrate that SeV-based vectors, particularly rSeV-GFP-059, efficiently prime antiviral immunity and suppress ORFV replication, establishing a promising platform for further in vivo vaccine evaluation in sheep. Full article

Glioblastoma (GBM) remains among the most treatment-refractory human malignancies. It is characterized by profound radioresistance and a highly immunosuppressive tumor microenvironment, limiting the durable efficacy of radiotherapy. Beyond direct cytotoxicity, ionizing radiation can induce immunogenic cell death and the release of damage-associated molecular patterns (DAMPs), including surface-exposed calreticulin, HMGB1, extracellular ATP/adenosine, and tumor-derived DNA. These signals engage pattern-recognition receptors and cGAS–STING–type I interferon pathways, transiently promoting antigen presentation and immune activation. In GBM, however, DAMP signaling frequently evolves toward chronic inflammation and immune suppression, characterized by myeloid cell recruitment, adenosine accumulation, and immune checkpoint upregulation, thereby contributing to tumor regrowth and radioresistance. This dual immune-regulatory role of DAMPs highlights the importance of temporal and contextual interpretation of radiation-induced immune responses. In this review, we summarize current mechanistic and translational evidence on DAMP-mediated immunomodulation in GBM radiotherapy; discuss modality-dependent considerations across photon, proton, and high-LET irradiation; and evaluate the emerging potential of DAMPs as dynamic biomarkers of treatment response. We further outline how integration of DAMP profiling with liquid biopsy, imaging, and nanotheranostic platforms may support biologically informed and adaptive radiotherapy strategies for glioblastoma. Full article

Zinc and iron are essential micronutrients in crop nutrition, and polymer-based nanogels have emerged as promising carriers to modulate their availability in sustainable agricultural systems. Here, a polymeric model receptor was designed to investigate how the nature and position of electron-donating (–NH₂) and electron-withdrawing (–NO₂) substituents control the recognition of Zn²⁺ and Fe²⁺ cations. Using a combination of density functional theory calculations, energy decomposition analysis with natural orbitals for chemical valence (EDA–NOCV), electrostatic potential (ESP) mapping, and quantum theory of atoms in molecules (QTAIM) method, the receptor–cation interactions are dissected into electrostatic, Pauli repulsion, orbital, and dispersion contributions. The results show that complex stability is governed mainly by orbital and electrostatic terms, with Fe²⁺ forming the most stable complex (−393.57 kcal mol⁻¹) with regard to a Zn²⁺ similar complex (−288.80 kcal mol⁻¹). Zn²⁺ complexes exhibit a broad tunability with substituent pattern. Electron-donating groups systematically strengthen both electrostatic and orbital components, whereas nitro substituents display a pronounced positional effect, ranging from strong destabilization to significant stabilization of Zn²⁺ binding. These findings establish molecular-level guidelines for engineering polymeric nanogels with tunable affinity and selectivity toward micronutrient cations in agricultural applications. Full article

The receptor for advanced glycation end-products (RAGE) is a lung-enriched pattern recognition receptor implicated in inflammatory responses. Its role in ferroptosis-mediated lung injury during viral infection, however, remains unclear. Here, we combined bioinformatics analysis with in vitro and in vivo experimental validation to investigate the RAGE–ferroptosis axis in influenza virus infection. Cross-analysis of RAGE- and ferroptosis-related genes identified overlapping candidates, suggesting functional crosstalk. Influenza-infected A549 cells exhibited ferroptotic cell death, characterized by Fe²⁺ accumulation, reactive oxygen species (ROS) elevation, and lipid peroxidation, which was markedly attenuated by the RAGE inhibitor FPS-ZM1. In A/PR/8/34 (H1N1)-infected female C57BL/6J mice, FPS-ZM1 treatment improved survival, reduced lung injury, restored redox balance, and modulated key ferroptosis regulators ACSL4, POR, and GPX4. Moreover, RAGE inhibition decreased M1 macrophage and neutrophil infiltration and reduced pro-inflammatory cytokines. Collectively, these findings reveal that RAGE activation drives ferroptosis and amplifies oxidative stress–associated lung injury, whereas RAGE inhibition mitigates tissue damage via the ACSL4/POR/GPX4 pathway and immunomodulation. This study identifies the RAGE–ferroptosis axis as a potential therapeutic target for severe pulmonary inflammation. Full article

Listeria monocytogenes (L. monocytogenes) is a significant zoonotic pathogen responsible for listeriosis, a foodborne infection with high mortality. The inflammasome, an innate immune complex, plays a critical role in controlling pathogenic infections through its rapid inflammatory output. During L. monocytogenes infection, pore-forming toxins such as listeriolysin-O and flagellin are quickly recognized by pattern recognition receptors (PRRs), triggering inflammatory responses and activating the host’s anti-infection immunity. However, excessive or chronic inflammasome activation and subsequent interleukin-1β (IL-1β) release are implicated in the pathogenesis of L. monocytogenes. Although inflammasome activation is an effective defense against L. monocytogenes, the bacterium has evolved multiple mechanisms to inhibit this immune pathway. Hence, research on inflammasomes activation is crucial for better understanding the pathogenic mechanism of L. monocytogenes. In this review, we highlight recent advances in the understanding of the molecular mechanisms of inflammasome activation by L. monocytogenes infection. We then discuss advances in the role of the inflammasome pathway in the pathogenesis of L. monocytogenes, along with an overview of the applications of inflammasome inhibitors. Extensive studies into the mechanisms by which L. monocytogenes activates the inflammasome could lead to the discovery of novel therapeutic targets and strategies to fight L. monocytogenes infections. Full article

As a non-invasive mucosal immunization strategy, intranasal vaccines are highly promising for preventing respiratory infectious diseases. Among them, recombinant subunit vaccines represent a safe and ideal option, as they induce targeted mucosal immunity without the safety risks associated with live-vectored or nucleic acid vaccines. However, nasal mucosal defenses rapidly clear antigens before immune activation, limiting protective efficacy. Therefore, intranasal vaccine adjuvants—key regulators of immune response intensity, duration, and type—are essential to overcome mucosal tolerance and improve immunogenicity. Based on a systematic search and analysis of 127 peer-reviewed articles (2010–2026) in PubMed, Web of Science, and Embase, this study comprehensively summarizes the mechanisms, applications, and limitations of existing and candidate adjuvants for intranasal vaccines. This review systematically categorizes and discusses the nasal mucosal barrier, major adjuvant types (e.g., pattern recognition receptor agonists, cytokine adjuvants, and carrier adjuvants), and their mechanisms of action. It also identifies key bottlenecks: insufficient mucosal targeting, inconsistent global safety evaluation standards for adjuvants, and interference from pre-existing antibodies in humans. Furthermore, this review highlights future development directions, including biomimetic adjuvants, pH-responsive nanoadjuvants, and thermostable vaccine formulations. This systematic review clarifies key scientific and technical barriers in intranasal vaccine adjuvant development. The findings provide valuable references for advancing the translation of intranasal vaccines from emergency countermeasures to routine, accessible preventive tools for respiratory infectious diseases. Full article

Plant-based biomaterials are increasingly recognized as bio-instructive platforms capable of actively modulating immune responses rather than functioning solely as passive structural supports. In this context, the term plant-based refers to photosynthetic biomass-derived platforms, including both terrestrial plants and marine macroalgae, reflecting their shared richness in polysaccharides and secondary metabolites relevant to immune engineering and regenerative medicine. This review critically synthesizes current evidence on plant-derived polysaccharides and phytochemicals, including algal sulfated polysaccharides (fucoidan, alginate, carrageenan, and ulvan), terrestrial plant polysaccharides (e.g., Lycium barbarum and Aloe vera derivatives), polyphenols, and other secondary metabolites such as terpenoids and alkaloids, highlighting their roles as immunomodulators in biomedical contexts. Key mechanisms include macrophage polarization along an M1–M2 continuum, pattern recognition receptor engagement, redox and metabolic regulation, and crosstalk between innate and adaptive immunity, with emphasis on context-dependent signaling and structural heterogeneity. Material design parameters, including molecular weight and chemical functionalization, are critical determinants of immune responses. Advanced delivery systems, such as hydrogels, nanocomposites, phytosomes, and plant-derived extracellular vesicles (EVs), enable improved stability and spatiotemporal control. Applications in wound and musculoskeletal regeneration are discussed alongside translational challenges, including variability, reproducibility, regulatory issues, and the need for standardized characterization and immune validation. Full article

Scavenger Receptors (SRs) comprise a structurally diverse group of pattern recognition receptors (PRRs) involved in sensing non-self (microbial-associated molecular patterns) or altered-self ligands. CD5 and CD6 are class I SRs (SR-I) preferentially expressed by lymphoid cells and characterized by the presence of several tandem scavenger receptor cysteine-rich (SRCR) domain repeats. Both receptors interact with diverse microbial structures, including tegumental antigens from Echinococcus granulosus sensu lato (s.l.), the cestode parasite responsible for cystic echinococcosis (CE). This is notable as very few PRRs are currently known to detect parasitic helminths and because the infusion of recombinant soluble CD5 and CD6 proteins has shown prophylactic effects in murine secondary CE. Herein, the role of CD5 and CD6 in early immune responses to E. granulosus s.l. tegumental antigens (PSEx) was analyzed using CD5 (Cd5^−/−) and CD6 (Cd6^−/−)-deficient mice. Peritoneal B cells and macrophages from wild-type mice displayed specific and dose-dependent PSEx binding, which was impaired in those from Cd5^−/− and Cd6^−/− mice, supporting direct and/or indirect roles in parasite recognition. Additionally, in vivo exposure of peritoneal exudate cells (PECs) from Cd5^−/− and Cd6^−/− mice to PSEx showed altered activation profiles, including changes in CD80/CD86 expression, impaired early production of natural polyreactive antibodies, and cytokine shift from a Th1/Th17 to a Th2 profile. These findings strongly support the involvement of CD5 and CD6 receptors in the early immune recognition of E. granulosus s.l. antigens by PECs and influence immune responses critical for host resistance, highlighting their relevance in host–parasite interactions. Full article

The immunosuppressive nature of porcine reproductive and respiratory syndrome virus (PRRSV) remains the central obstacle to its effective control. Conventional microRNA (miRNA)-based antiviral approaches are limited by their modest potency and the high risk of viral escape. Here, we rationally designed an engineered miRNA carrying a 5′-triphosphate (5′-PPP) terminus that integrates RIG-I-driven innate immune activation and sequence-specific gene silencing within a single molecule. In vitro-transcribed 5′-PPP miRNAs are efficiently recognized by the pattern-recognition receptor RIG-I, triggering a robust type I interferon response that counteracts PRRSV-induced immunosuppression. In MARC-145 cells, one such construct, 5′-PPP BZL-sRNA-20, potently inhibited PRRSV replication through the synergistic action of immune activation and gene silencing. However, in porcine alveolar macrophages (PAMs)—the natural host cells for PRRSV—the antiviral effect depended primarily on 5′-PPP-induced interferon responses, with the targeting sequence providing limited or context-dependent benefits. Dual-luciferase assays confirmed that the gene-silencing activity depends on 5′-PPP modification, which enhances the stability of BZL-sRNA-20. This bifunctional strategy establishes an “immune activation plus targeting” paradigm by simultaneously acting as a RIG-I ligand that triggers broad antiviral responses and specifically cleaves viral RNA via direct base-pairing to conserved regions of the PRRSV genome. These findings reveal the potential of engineered 5′-PPP miRNAs as immunomodulatory antiviral agents, while highlighting that the contribution of RNAi targeting varies depending on the cellular context. Full article