What can be regarded as a seedling of the contemporary aquaculture in the Mediterranean began back in the 1950s. The development of the industry did not always align with the development of ichthyopathology, a veterinary discipline aimed at identifying and combating fish diseases. Therefore, and due to the lack of published data, we are not always able to pinpoint the first outbreaks that accompanied the increase in aquaculture production. Nonetheless, fish pathogens, and parasites in particular, have shown diversity related to host species, their farming conditions and geography. Two parasite species currently regarded as dominant in Mediterranean aquaculture are the histozoic myxozoan Enteromyxum leei and the haematophagous polyopisthocotylean Sparicotyle chrysophrii, both of which infect gilthead seabream (Sparus aurata). The interactions between parasite and host with regard to the immune activity of both have been well studied using conventional immunology and omics approaches. For the remaining parasite-fish systems, our understanding of host responses and parasite mitigation mechanisms is still vague and mostly transposed from what we know of other systems. This review compiles the knowledge on fish response to the most frequent and economically important parasites in Mediterranean aquaculture, highlights the gaps and suggests further directions.

Immunotherapy is an emerging strategy that awakens the intrinsic immune system for cancer treatment. Generally, successful immunotherapy of malignant tumours relies on the effective production of tumour-associated antigens and their lymph node delivery, antigen processing and presentation for T-cell activation, and the dismantling of the immunosuppressive tumour microenvironment. Toll-like receptor (TLR) agonists are potent stimulants in cancer immunotherapy, which can directly activate antigen-presenting cells (APCs) and further induce T cell activation for antitumour immune response and convert immunosuppressive tumour microenvironment to an immunogenic one for cooperative tumour ablation. However, TLR agonists for effective cancer immunotherapy have encountered essential challenges, such as insufficient immune activation and systemic side effects. In recent years, nano-immunomodulators with TLR agonists have been employed for tumour- and/or lymph node-targeted immune activation to improve the antitumour immune response and alleviate their systemic toxicities, providing a promising strategy for enhanced cancer immunotherapy. Herein, we introduce the recent progress in developing various TLR nano-immunomodulators for cancer immunotherapy via APC activation and tumour microenvironment remodelling. Upon elucidating the rational design principles of nano-immunomodulators, we elucidate the advancement of TLR nanoagonists to break the barriers in effective and safe Toll-like receptor stimulation for potent cancer immunotherapy.

Fish are exposed to numerous stressors which negatively affect their immune response and increase infection susceptibility. The risk of bacterial infections results in the excessive and preventive use of antibiotics. Therefore, we aimed to study how antibiotic treatment and restraint stress will affect the stress response, microbiota composition, gut morphology, and inflammatory reaction in common carp. Both restraint stress and antibiotic treatment increased cortisol level. Moreover, antibiotics induced dysbiosis in fish gut, manifested by a decrease in the total abundance of bacteria, and a shift in bacteria diversity, including a reduced number of Aeromonas, Bacteroides, Barnesiellaceae, Cetobacterium and Shewanella and an increased abundance of Flavobacterium. To a lesser extent, stress modified gut microbiota, as it decreased bacteria number and slightly changed the microbiota composition by decreasing Cetobacterium abundance and increasing Vibrio abundance. Microbiota of the antibiotic-treated and stressed fish shifted from the beneficial bacterial genera - Cetobacterium and Bacteroides, to the increased presence of unfavorable bacteria such as Brevinema, Flavobacterium and Desulfovibrionaceae. Stress and antibiotic-induced changes in the gut microbiota were related to the changes in the gut morphology when the higher abundance of goblet and rodlet cells and increased secretion activity of goblet cells were observed. Moreover, up-regulation of the expression of genes encoding pro-inflammatory mediators and cytokines involved in the Th17 immune response was present in the gut of the antibiotic-treated and stressed fish. We conclude that in carp antibiotics and stress alter the abundance and composition of the microbiota and induce Th17-dependent inflammatory reaction in the gut. Moreover, our results strongly suggest the interplay of the stress axis and the brain-gut-microbiota axis.

Receptor-interacting protein kinase 3 (RIP3), a serine/threonine kinase of the RIP family, has emerged as a critical regulator of necroptosis, a necrosis-like form of cell demise. However, recent research has revealed that overactivated RIP3 might also be involved in the regulation of other cell death forms, such as pyroptosis, autophagy, mitochondrial permeability transition pore (mPTP)-necrosis and ferroptosis, and operates in diverse cellular compartments. RIP3 can therefore affect inflammation, oxidative stress and energy metabolism, further underscoring its pivotal role in cellular homeostasis. Furthermore, elevated circulating levels of RIP3 have been observed in cardiac disorders such as heart failure, myocardial infarction, and coronary artery disease and might correlate with disease severity and worse prognostic outcomes. On the contrary, the pharmacological inhibition of RIP3 has shown protective effects due to complex mechanisms involving necroptosis retardation, prevention of immune cell infiltration, and mitigation of cardiac cells mitochondrial damage. A detailed understanding of the complexity of RIP3's function in the heart may favour its diagnostic potential and lead to the development of future therapeutic interventions.

Over the past several decades, viral vector-based vaccines have emerged as some of the most versatile and potent platforms in modern vaccinology. Their capacity to deliver genetic material encoding target antigens directly into host cells enables strong cellular and humoral immune responses, often superior to what traditional inactivated or subunit vaccines can achieve. This has accelerated their application to a wide array of pathogens and disease targets, from well-established threats like HIV and malaria to emerging infections such as Ebola, Zika, and SARS-CoV-2. The COVID-19 pandemic further highlighted the agility of viral vector platforms, with several adenovirus-based vaccines quickly authorized and deployed on a global scale. Despite these advances, significant challenges remain. One major hurdle is pre-existing immunity against commonly used vector backbones, which can blunt vaccine immunogenicity. Rare but serious adverse events, including vector-associated inflammatory responses and conditions like vaccine-induced immune thrombotic thrombocytopenia (VITT), have raised important safety considerations. Additionally, scaling up manufacturing, ensuring consistency in large-scale production, meeting rigorous regulatory standards, and maintaining equitable global access to these vaccines present profound logistical and ethical dilemmas. In response to these challenges, the field is evolving rapidly. Sophisticated engineering strategies, such as integrase-defective lentiviral vectors, insect-specific flaviviruses, chimeric capsids to evade neutralizing antibodies, and plug-and-play self-amplifying RNA approaches, seek to bolster safety, enhance immunogenicity, circumvent pre-existing immunity, and streamline production. Lessons learned from the COVID-19 pandemic and prior outbreaks are guiding the development of platform-based approaches designed for rapid deployment during future public health emergencies. This review provides an exhaustive, in-depth examination of the historical evolution, immunobiological principles, current platforms, manufacturing complexities, regulatory frameworks, known safety issues, and future directions for viral vector-based vaccines.

p53, often referred to as the "guardian of the genome," is a critical regulator of cellular responses to stress. p53 plays a dual role in tumor suppression and immune regulation. In addition to its well-known functions of maintaining genomic stability and inducing apoptosis, p53 orchestrates a complex interaction between innate and adaptive immune responses. This involvement contributes to pathogen clearance, immune surveillance, and immunogenic cell death (ICD). This review explores the influence of p53 on immune dynamics, detailing its effects on macrophages, dendritic cells, natural killer cells (NK), T cells, and B cells. This review explains how mutations in p53 disrupt immune responses, promoting tumor immune evasion, and highlights its regulation of inflammatory cytokines and pattern recognition receptors. Furthermore, p53's role in ICD marks it as a key player in antitumor immunity, which has significant implications for cancer immunotherapy. The review also discusses the role of p53 in inflammation, autoimmune diseases, and chronic infections, revealing its dual function in promoting and suppressing inflammation through interactions with NF-κB signaling. Therapeutically, approaches that target p53, including wild-type p53 reactivation and combination therapies with immune checkpoint inhibitors, show considerable promise. Advances in high-throughput technologies, such as single-cell RNA sequencing and CRISPR screens, provide new insights into the immunological functions of p53, including its role in microbiome-immune interactions and immune senescence. This comprehensive review highlights the importance of incorporating immunological insights from p53 into innovative therapeutic strategies, addressing existing knowledge gaps, and paving the way for personalized medicine.

The human body functions as a complex ecosystem, hosting trillions of microbes that collectively form the microbiome, pivotal in immune system regulation. The host-microbe immunological axis maintains homeostasis and influences key physiological processes, including metabolism, epithelial integrity, and neural function. Recent advancements in microbiome-based therapeutics, including probiotics, prebiotics and fecal microbiota transplantation, offer promising strategies for immune modulation. Microbial therapies leveraging microbial metabolites and engineered bacterial consortia are emerging as novel therapeutic strategies. However, significant challenges remain, including individual microbiome variability, the complexity of host-microbe interactions, and the need for precise mechanistic insights. This review comprehensively examines the host microbiota immunological interactions, elucidating its mechanisms, therapeutic potential, and the future directions of microbiome-based immunomodulation in human health. It will also critically evaluate challenges, limitations, and future directions for microbiome-based precision medicine.

Along with the increasing litter sizes in pig industry, using milk replacer (MR) as a nutrient supplement has been widely practiced, yet the effects of replacing sow milk (SM) with MR on growth and development of piglets remain unclear. This study evaluated the differential effects of MR versus SM on growth performance, body composition, muscle fiber types, and intestinal health of piglets during the neonatal and nursery periods. Forty 2-day-old piglets, selected from 10 healthy sows, were randomly divided into two groups receiving either SM or MR ad libitum until postnatal day 23 (PND 23), then transitioned to be fed with nursery diet until PND 37. Blood, muscle, and intestinal tissues, along with colonic digesta and carcass samples, were collected on PND 12 (n = 10) and PND 37 (n = 10) for analysis of parameters related to intestinal function, microbiota composition and muscular development. The results showed that MR-fed piglets had lower average daily gain (ADG) and higher diarrhea index during the neonatal period. During the nursery period, however, MR-fed piglets had significantly higher average daily feed intake (ADFI) and ADG. Compared to SM-fed piglets, MR-fed piglets had a lower percentage of fast twitch fibers, but a higher percentage of slow twitch fibers on PND 12, along with lower body fat content on both PND 12 and PND 37. In addition, MR-fed piglets had significantly deeper crypt depth, increased mRNA expressions of inflammatory genes, and lower alpha diversity on PND 12. On PND 37, however, MR-fed piglets had higher villus height, increased sucrase activity and alpha diversity. On PND 12, likewise, MR-fed piglets were enriched with Prevotella associated with diarrhea, while SM-fed piglets were enriched with Lachnospiraceae associated with body fat deposition. In contrast, on PND 37, MR-fed piglets were enriched with commonly recognized beneficial bacteria, such as f_Muribaculaceae, g_Prevotellaceae_NK3B31_group, f_Oscillospiraceae and f_Rikenellaceae. These findings indicate that piglets fed MR experienced temporary growth check and intestinal complications in neonatal period, but intriguingly MR piglets had higher feed intake, compensatory growth, and recovery of intestinal function during the nursery period.

Despite the development of effective vaccines against hepatitis A virus (HAV) infection, outbreaks of acute hepatitis A still occur globally, such that HAV remains a major cause of acute viral hepatitis. Most patients with acute hepatitis A recover spontaneously; however, some adult cases result in acute liver failure due to immune-mediated liver damage. Previous studies suggested that HAV evades the innate immune response through strong counteractive mechanisms, and that HAV-specific CD8+ T cells contribute to liver damage in patients with acute hepatitis A. However, recent research findings have led to revisions of old hypotheses. Here we will describe the most current knowledge regarding the innate immune response to HAV and the HAV-mediated counteractions against innate immune responses. Additionally, we will discuss the roles of various types of T cells in viral clearance and liver injury in patients with acute hepatitis A.

Vibrio anguillarum serves as a pathogenic organism in aquaculture, leading to a lethal hemolytic septicemia in aquatic species. Whereas little study has evaluated the molecular mechanism of the infection caused by V. anguillarum in Jinhu grouper. In this study, analysis of the transcriptome was conducted on the liver and spleen tissues from Jinhu groupers infected with V. anguillarum infection. We identified 2978 DEGs in the liver group and 2506 DEGs in spleen group, including 1689 and 1502 up-regulated genes and 1289 and 1004 down-regulated genes, respectively. Gene set enrichment analysis revealed a significant reduction in genes associated with metabolism such as carbon metabolism and glycolysis/gluconeogenesis in the liver, while upregulation of genes linked to the above pathways as well as in the citrate cycle in the spleen. In addition, the upregulated genes in the liver and spleen are both enriched in the cell cycle. Subsequent investigation into the principal DEGs implicated in the TLR pathways showed that V. anguillarum infection may activate the TLR pathway by overexpression of the tlr5 and promote the synthesis of proinflammatory cytokines il1β and il-8. Among these, 11 genes related to metabolism, cell cycle and immunity were selected and characterized. Overall, our research indicates that V. anguillarum can affect the metabolism and cell cycle while also triggering immune defense reactions in Jinhu grouper.

Toll-like receptors (TLRs) play a crucial role in the innate immune response, mediating cellular interactions with the microenvironment and influencing periodontal disease progression. This in vitro study aimed to comprehensively characterize the TLR expression profile of periodontal ligament mesenchymal stem/progenitor cells (PDLSCs) and investigate its modulation by inflammatory stimuli associated with periodontal disease. PDLSCs (n = 6) were isolated, selected using anti-STRO-1 antibodies, and cultured to evaluate their colony-forming abilities and stem/progenitor characteristics. Baseline and inflammation-induced TLR expressions were evaluated using RT-PCR and protein analyses following cytokine-mediated stimulation. PDLSCs exhibited the expected stem cell characteristics and expressed multiple TLRs under both conditions. Notably, inflammatory stimulation significantly upregulated TLR1 and TLR2 while downregulating TLR10 (p < 0.05). These findings provide a comprehensive characterization of TLR expression in PDLSCs and demonstrate how inflammation modulates their innate immune profile. The observed shifts in TLR expression may influence PDLSC responses to microbial pathogens and impact their immunomodulatory and regenerative properties in periodontal tissues. Understanding these interactions could contribute to developing targeted strategies for improving PDLSC-based therapies in periodontal disease.

Histone lactylation, a newly glycosis-related histone modification, plays a crucial role in the regulation of gene expression in various immune cells. However, the role of histone lactylation in astrocytes remains unclear. Here, this study showed that the H3K18 lactylation (H3K18la) levels were upregulated in primary astrocytes under unconjugated bilirubin (UCB) stimulation and hippocampus of bilirubin encephalopathy (BE) rats. Inhibition of glycolysis decreased H3K18la and attenuated pyroptosis both in vitro and in vivo. CUT& Tag and RNA-seq results revealed that H3K18la was enriched at the promoter of nucleotide-binding oligomerization domain 2 (NOD2) and promoted its transcription. Moreover, NOD2 boosted the activation of downstream mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, which exacerbated the neuroinflammation of BE. Collectively, this study provides a novel understanding of epigenetic regulation in astrocytes, and interruption of the H3K18la/NOD2 axis may represent a novel therapeutic strategy for treating bilirubin encephalopathy.

Bacterial antiviral STANDs (Avs) are evolutionarily related to the nucleotide-binding oligomerization domain (NOD)-like receptors widely distributed in immune systems across animals and plants. EfAvs5, a type 5 Avs from Escherichia fergusonii, contains an N-terminal SIR2 effector domain, a NOD, and a C-terminal sensor domain, conferring protection against diverse phage invasions. Despite the established roles of SIR2 and STAND in prokaryotic and eukaryotic immunity, the mechanism underlying their collaboration remains unclear. Here we present cryo-EM structures of EfAvs5 filaments, elucidating the mechanisms of dimerization, filamentation, filament bundling, ATP binding, and NAD+ hydrolysis, all of which are crucial for anti-phage defense. The SIR2 and NOD domains engage in intra- and inter-dimer interaction to form an individual filament, while the outward C-terminal sensor domains contribute to bundle formation. Filamentation potentially stabilizes the dimeric SIR2 configuration, thereby activating the NADase activity of EfAvs5. Furthermore, we identify the nucleotide kinase gp1.7 of phage T7 as an activator of EfAvs5, demonstrating its ability to induce filamentation and NADase activity. Together, we uncover the filament assembly of Avs5 as a unique mechanism to switch enzyme activities and perform anti-phage defenses.

Toll-like receptors (TLR), the key players of the innate immune system, contribute to the pathogenesis of atopic dermatitis (AD) through multiple pathways. TLRs play a crucial role in delaying barrier repair, promoting Th2-mediated dermatitis, shifting the response toward Th1 in the chronic phase, and contributing to the establishment of the itch-scratch cycle, as well as mediating the effects of UV radiation. The dysregulation of proinflammatory and immunomodulatory effects of TLRs can be attributed to their ligand structures, receptor heterodimerization, the relative frequency of each TLR, interactions with other receptors/signalling pathways, cytokine milieu, and genetic polymorphisms. Current AD treatments like vitamin-D analogs, tacrolimus, and cyclosporine partially work through TLR modulation. Direct TLR stimulation using different compounds has shown therapeutic benefits in preclinical studies. However, significant challenges exist, including off-target effects due to ubiquitous TLR expression and complex roles in immune responses. Future directions include CRISPR-based gene editing to understand TLR functions, development of specific TLR modulators for targeted therapy, and machine learning applications to predict drug responses and identify novel ligands. Patient heterogeneity, including the presence or absence of polymorphisms, variations in TLR expression levels, and differences in immune responses, underscores the need for personalized therapeutic approaches.

Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1). STING activation enhanced lysosome biogenesis through inducing the nuclear translocation of transcription factor EB (TFEB) as well as its paralogs transcription factor E3 (TFE3) and microphthalmia-associated transcription factor (MITF). STING-induced lipidation of GABA type A receptor-associated protein (GABARAP), an autophagy-related protein, on STING vesicles was responsible for TFEB activation. Membrane-bound GABARAP sequestered the GTPase-activating protein folliculin (FLCN) and FLCN-interacting protein (FNIP) complex to block its function toward the Rag GTPases Ras-related GTP-binding C and D (RagC and RagD), abolishing mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent phosphorylation and inactivation of TFEB. Functionally, STING-induced lysosome biogenesis within cells facilitated the clearance of cytoplasmic DNA and invading pathogens. Thus, our findings reveal that induction of lysosome biogenesis is another important function of the cGAS-STING pathway.

It has recently been recognized that the physical characteristics of biomaterials - such as size, structure, shape, charge, mechanical strength, hydrophobicity, and multivalency - regulate immunological functions in innate immune cells. In immuno-oncology applications, biomaterials are engineered with distinct physical properties to achieve desired innate immune responses. In this review, we discuss how physical characteristics influence effector functions and innate immune signaling pathways in distinct innate immune cell subtypes. We highlight how physical properties of biomaterials impact phagocytosis regulation, biodistribution, and innate immune cell targeting. We outline the recent advances in physical engineering of biomaterials that directly or indirectly induce desired innate immune responses for cancer immunotherapy. Lastly, we discuss the challenges in current biomaterial approaches that need to be addressed to improve clinical applicability.

Occupational exposure to crystalline silica (CS) is known to induce silicosis, a chronic lung disease characterized by the formation of granulomas and severe lung fibrosis. Specifically, individuals exposed to low doses of CS may develop silicosis after a decade or more of exposure. Similarly, in rat silicosis models exposed to occupationally relevant doses of α-quartz, there is an initial phase characterized by minimal and well-controlled pulmonary inflammation, followed by the development of robust and persistent inflammation. During the initial phase, the inflammation provoked by α-quartz is subdued by two mechanisms. Firstly, α-quartz particles are engulfed by alveolar macrophages (AMs) of the alternatively activated (M2) subtype and interstitial macrophages (IMs), limiting their interaction with other lung cells. Secondly, the anti-inflammatory cytokine, interleukin (IL)-10, is constitutively expressed by these macrophages, further dampening the inflammatory response. In the later inflammatory phase, IL-10-dependent anti-inflammatory state is disrupted by Type I interferons (IFNs), leading to the production of pro-inflammatory cytokines in response to α-quartz, aided by lipopolysaccharides (LPS). This review delves into the complex pathways involving IL-10, LPS, and Type I IFNs in α-quartz-induced pulmonary inflammation, offering a detailed analysis of the underlying mechanisms and identifying areas for future research.

The single nucleotide polymorphism in NOD2 (rs2066847) is associated with conditions that may predispose to the development of gastrointestinal disorders, as well as the known BRCA1 and BRCA2 variants classified as risk factors in many cancers. In our study, we analyzed these variants in a group of patients with pancreatitis and pancreatic cancer to clarify their role in pancreatic disease development. The DNA was isolated from whole blood samples of 553 patients with pancreatitis, 83 patients with pancreatic cancer, 44 cases of other pancreatic diseases, and 116 healthy volunteers. The NOD2 (rs2066847), BRCA1 (rs80357914) and BRCA2 (rs276174813) were genotyped. The statistically significant 3-fold increased risk of pancreatic cancer was detected among the patients with rs2066847 polymorphism (OR = 2.77, p-value = 0.019). We did not find the studied polymorphisms in BRCA1 (rs80357914) and BRCA2 (rs276174813). However, the adjacent polymorphisms have been detected only in patients with pancreatic diseases. The studied variant in NOD2 occurs more frequently in pancreatic patients and significantly increases the risk of pancreatic cancer. It can be considered as a genetic risk factor that predisposes to cancer development. The analyzed regions in BRCA1 and BRCA2 may be a potential target in further search for a genetic marker of pancreatic diseases.

Sepsis-induced cardiomyopathy (SIC), as a common complication in the intensive care unit, not only increases the complexity of patient care but also greatly enhances the risk of death. Currently, clinical management of SIC remains challenging, mainly due to the complexity of its pathogenesis and the lack of targeted therapies. Although the specific etiology of SIC is not yet fully understood, existing studies have revealed several vital pathological processes that are intertwined and contribute to the progression of the disease. This narrative review summarizes the existing pathogenesis of SIC, which involves multiple aspects including the inflammatory response, mitochondrial dysfunction, cell death mechanisms, immune regulation, and calcium homeostasis imbalance. Given the multifactorial pathogenesis of SIC, future studies need to explore the interactions between these mechanisms and how to intervene to develop more precise and effective therapeutic strategies to reduce mortality and improve prognosis in patients with SIC.

Aeromonas hydrophila causes motile Aeromonas septicemia (MAS) in freshwater fish. In recent years, MAS outbreaks due to virulent Aeromonas hydrophila (vAh) have been responsible for large-scale losses within commercial catfish farms in Mississippi and Alabama. The aim of this study was to evaluate immune gene expression in catfish immune-competent tissues during infection with vAh strain ML09-119. Specific pathogen-free catfish fingerlings were intraperitoneally infected with vAh strain ML09-119, and relative expression of thirteen immune-related genes was evaluated from head kidney, spleen, and liver. Our results revealed that vAh was detected 2 h post-infection (hpi) in the head kidney, liver, and spleen. The highest concentration of vAh was detected at 12 hpi, from which point concentrations decreased until clearance at 5 days post-infection (dpi). Gene expression analysis revealed upregulation of pro-inflammatory cytokines and innate immune response (TLR 4 and 5) in the first 24 hpi. Adaptive immune-related genes were upregulated at 7 dpi in the spleen and 14 dpi in the head kidney. Furthermore, immunoglobulin M showed significant upregulation at 14 dpi in the head kidney and 21 dpi in the spleen. In summary, vAh ML09-119 infection induced a strong inflammatory response involving multiple innate immunity genes, proinflammatory cytokines, and chemokines. Surviving catfish were able to clear the infection and produce antibodies and memory cells. Assessment of the immunological response to vAh infection is critical for understanding the pathogen's mechanisms of pathogenesis and developing means for MAS control, including vaccine development and improved treatments.

Arboviruses are a significant threat to global public health, with outbreaks occurring worldwide. Toll-like receptors (TLRs) play a crucial role in the innate immune response against these viruses by recognizing pathogen-associated molecular patterns and initiating an inflammatory response. Significantly, TLRs commonly implicated in the immune response against viral infections include TLR2, TLR4, TLR6, TLR3, TLR7, and TLR8; limiting or allowing them to replicate and spread within the host. Modulating TLRs has emerged as a promising approach to combat arbovirus infections. This review summarizes recent advances in TLR modulation as a therapeutic target in arbovirus infections. Studies have shown that the activation of TLRs can enhance the immune response against arbovirus infections, leading to increased viral clearance and protection against disease. Conversely, inhibition of TLRs can reduce the excessive inflammation and tissue damage associated with arbovirus infection. Modulating TLRs represents a potential therapeutic strategy to combat arbovirus infections.

Bacterial cyclic dinucleotides (CDNs), cyclic di-guanosine monophosphate (c-di-GMP), and cyclic di-adenosine monophosphate (c-di-AMP) upregulate interferon signaling proteins of human gingival fibroblasts (HGFs). However, the simultaneous effect of bacterial CDNs and lipopolysaccharides (LPS) on the HGF proteome is unknown.

The aim was to apply an unbiased proteomics approach to evaluate how simultaneous exposure to CDNs and Porphyromonas gingivalis (Pg) LPS affect the global proteome of HGFs.

The proteomic responses of HGFs were examined under three different treatment conditions (c-di-AMP+Pg LPS, c-di-GMP+Pg LPS, and Pg LPS alone) by label-free quantitative mass spectrometry analysis.

Simultaneous exposure to CDNs and Pg LPS significantly upregulated innate immunity-related and interferon signaling-related proteins, such as ubiquitin-like protein ISG15 (ISG15), deoxynucleoside triphosphate triphosphohydrolase (SAMHD1), interferon regulatory factor 9 (IRF-9), interferon-induced GTP-binding protein Mx (MX)1, and MX2. Interferon signaling pathway was the most significantly regulated canonical pathway in both CDN treatment groups.

Simultaneous exposure to CDNs and Pg LPS stimulates the periodontal immune response by activating the anti-microbial cellular responses of HGFs with some notable differences from individual exposures.

The Echiura worm Urechis unicinctus refers to a common benthic invertebrate found in the intertidal zone of Huanghai as well as Bohai Bay. U. unicinctus is known to contain various physiologically active substances, making it highly valuable in terms of its edibility, medicinal properties, and economic potential. Nonetheless, the limited study on the immune system of U. unicinctus poses difficulties for its aquaculture and artificial reproduction. Marine invertebrates, including shellfish and U. unicinctus, are thought to primarily depend on their innate immune system for disease protection, owing to the severalinnate immune molecules they possess. Herein, we employed PacBio single-molecule real-time (SMRT) sequencing technology to perform the full-length transcriptome analysis of U. unicinctus individuals under five different conditions (room temperature (RT), low temperature (LT), high temperature (HT), without water (DRY), ultraviolet irradiation (UV)). Concequently, we identified 59,371 unigenes that had a 2,779 bp average length, 2,613 long non-coding RNAs (lncRNAs), 59,190 coding sequences (CDSs), 35,166 simple sequence repeats (SSRs), and 1,733 transcription factors (TFs), successfully annotating 90.58 % (53,778) of the unigenes. Subsequently, key factors associated with immune-related processes, such as non-self-recognition, cellular immune defenses, and humoral immune defenses, were searched. Our study also identified pattern recognition receptors (PRRs) that included 17 peptidoglycan recognition proteins (PGRPs), 13 Gram-negative binding proteins (GNBPs), 18 scavenger receptors (SRs), 74 toll-like receptors (TLRs), and 89 C-type lectins (CLTs). Altogether, the high-quality transcriptome obtained data will offer valuable insights for further investigations into U. unicinctus innate immune response, laying the foundation for subsequent molecular biology studies and aquaculture.

Antiviral STANDs (Avs) are bacterial anti-phage proteins evolutionarily related to immune pattern recognition receptors of the NLR family. Type 2 Avs proteins (Avs2) were suggested to recognize the phage large terminase subunit as a signature of phage infection. Here, we show that Avs2 from Klebsiella pneumoniae (KpAvs2) can recognize several different phage proteins as signature for infection. While KpAvs2 recognizes the large terminase subunit of Seuratvirus phages, we find that to protect against Dhillonvirus phages, KpAvs2 recognizes a different phage protein named KpAvs2-stimulating protein 1 (Ksap1). KpAvs2 directly binds Ksap1 to become activated, and phages mutated in Ksap1 escape KpAvs2 defense despite encoding an intact terminase. We further show that KpAvs2 protects against a third group of phages by recognizing another protein, Ksap2. Our results exemplify the evolutionary diversification of molecular pattern recognition in bacterial Avs2, and show that a single pattern recognition receptor evolved to recognize different phage-encoded proteins.

In recent years, significant advancements have been made in utilizing nanoparticles (NPs) to modulate immune responses within the central nervous system (CNS), offering new opportunities for nanotherapeutic interventions in neurological disorders. NPs can serve as carriers for immunomodulatory agents or platforms for delivering nucleic acid-based therapeutics to regulate gene expression and modulate immune responses. Several studies have demonstrated the efficacy of NP-mediated immune modulation in preclinical models of neurological diseases, including multiple sclerosis, stroke, Alzheimer's disease, and Parkinson's disease. While challenges remain, advancements in NPs engineering and design have led to the development of NPs using diverse strategies to overcome these challenges. The nano-bio interface with the immune system is key in the conceptualization of NPs to efficiently act as nanotherapeutics in the CNS. The biomolecular corona plays a pivotal role in dictating NPs behavior and immune recognition within the CNS, giving researchers the opportunity to optimize NPs design and surface modifications to minimize immunogenicity and enhance biocompatibility. Here, we review how NPs interact with the CNS immune system, focusing on immunosurveillance of NPs, NP-induced immune reprogramming and the impact of the biomolecular corona on NPs behavior in CNS immune responses. The integration of NPs into CNS nanotherapeutics offers promising opportunities for addressing the complex challenges of acute and chronic neurological conditions and pathologies, also in the context of preventive and rehabilitative medicine. By harnessing the nano-bio immune interface and understanding the significance of the biomolecular corona, researchers can develop targeted, safe, and effective nanotherapeutic interventions for a wide range of CNS disorders to improve treatment and rehabilitation. These advancements have the potential to revolutionize the treatment landscape of neurological diseases, offering promising solutions for improved patient care and quality of life in the future.

Influenza A virus (IAV) remains a significant global public health threat, causing substantial illness and economic burden. Despite existing antiviral drugs, the emergence of resistant strains necessitates alternative therapeutic strategies. This review explores the complex interplay between the ubiquitin proteasome system (UPS) and IAV pathogenesis. We discuss how IAV manipulates the UPS to promote its lifecycle, while also highlighting how host cells utilise the UPS to counteract viral infection. Recent research on deubiquitinases as potential regulators of IAV infection is also addressed. By elucidating the multifaceted role of the UPS in IAV pathogenesis, this review aims to identify potential targets for novel therapeutic interventions.

Koala retrovirus (KoRV), a major pathogen of koalas, exists in both endogenous (KoRV-A) and exogenous forms (KoRV-A to I and K to M) and causes multiple disease phenotypes, including carcinomas and immunosuppression. However, the direct association between the different KoRV subtypes and carcinogenesis remains unknown. Differentially expressed gene (DEG) analysis of peripheral blood mononuclear cells (PBMCs) of koalas carrying both endogenous (KoRV-A) and exogenous (KoRV-A, B, and C) subtypes was performed using a high-throughput RNA-seq approach. PBMCs were obtained from three healthy koalas: one infected with endogenous (KoRV-A; Group I) and two infected with exogenous (KoRV-B and/or KoRV-C; Group II) subtypes. Additionally, spleen samples (n = 6) from six KoRV-infected deceased koalas (K1- K6) and blood samples (n = 1) from a live koala (K7) were collected and examined to validate the findings.

All koalas were positive for the endogenous KoRV-A subtype, and eight koalas were positive for KoRV-B and/or KoRV-C. Transcription of KoRV gag, pol, and env genes was detected in all koalas. Upregulation of cytokine and immunosuppressive genes was observed in koalas infected with KoRV-B or KoRV-B and -C subtypes, compared to koalas infected with only KoRV-A. We found 550 DEG signatures with significant (absolute p < 0.05, and absolute log2 Fold Change (FC) > 1.5) dysregulation, out of which 77.6% and 22.4% DEGs were upregulated (log2FC > 1.5) and downregulated (log2FC <  - 1.5), and downregulated (log2 FC <  - 1), respectively. We identified 17 unique hub genes (82.3% upregulated and 17.7% down-regulated), with KIF23, CCNB2, POLR3F, and RSL24D1 detected as the potential hub genes modified with KoRV infection. Real-time RT-qPCR was performed on seven koalas to ascertain the expression levels of four potential hub genes, which were subsequently normalized to actin copies. Notably, all seven koalas exhibited distinct expression signatures for the hub genes, especially, KIF23 and CCNB2 show the highest expression in healthy koala PBMC, and POLR3F shows the highest expression in koala with lymphoma (K1).

Thus, it can be concluded that multiple KoRV subtypes affect disease progression in koalas and that the predicted hub genes could be promising prognostic biomarkers for pathogenesis.

In the past, we demonstrated that oligodeoxynucleotides containing CpG motifs (CpG-ODN) mimicking bacterial DNA, stimulate the innate immune system of neonatal broiler chickens and protect them against Escherichia coli and Salmonella Typhimurium (S. Typhimurium) septicemia. The first line of innate immune defense mechanism is formed by heterophils and plays a critical protective role against bacterial septicemia in avian species. Therefore, the objectives of this study were 1) to explore the kinetics of CpG-ODN mediated antibacterial mechanisms of heterophils following single or twice administration of CpG-ODN in neonatal broiler chickens and 2) to investigate the kinetics of the immunoprotective efficacy of single versus twice administration of CpG-ODN against S. Typhimurium septicemia. In this study, we successfully developed and optimized flow cytometry-based assays to measure phagocytosis, oxidative burst, and degranulation activity of heterophils. Birds that received CpG-ODN had significantly increased (p < 0.05) phagocytosis, oxidative burst, and degranulation activity of heterophils as early as 24 h following CpG-ODN administration. Twice administration of CpG-ODN significantly increased the phagocytosis activity of heterophils. In addition, our newly developed CD107a based flow cytometry assay demonstrated a significantly higher degranulation activity of heterophils following twice than single administration of CpG-ODN. However, the oxidative burst activity of heterophils was not significantly different between birds that received CpG-ODN only once or twice. Furthermore, delivery of CpG-ODN twice increased immunoprotection against S. Typhimurium septicemia compared to once but the difference was not statistically significant. In conclusion, we demonstrated enhanced bactericidal activity of heterophils after administration of CpG-ODN to neonatal broiler chickens. Further investigations will be required to identify other activated innate immune cells and the specific molecular pathways associated with the CpG-ODN mediated activation of heterophils.

Immunomodulatory therapies are beneficial strategies for the improvement of immune system function. Today, due to the increasing prevalence of immune disorders, cancer, and new viral diseases, there is a greater need to introduce immunomodulatory compounds with more efficiency and fewer side effects. Microbial derivatives are fertile and attractive grounds for discovering lots of novel compounds with various medical properties. The discovery of many natural compounds derived from bacterial sources, such as secondary metabolites with promising immunomodulating activities, represents the importance of this topic in drug discovery and emphasizes the necessity for a coherent source of study in this area. Considering this need, in this review, we aim to focus on the current information about the immunomodulatory effects of bacterial secondary metabolites and natural immunomodulators derived from microorganisms.

Aeromonas hydrophila, the pathogen that is the causative agent of motile Aeromonas septicemia (MAS) disease, commonly attacks freshwater fishes, including yellow catfish (Pelteobagrus fulvidraco). Although the kidney is one of the most important organs involved in immunity in fish, its role in disease progression has not been fully elucidated. Understanding the cellular composition and innate immune regulation mechanisms of the kidney of yellow catfish is important for the treatment of MAS. In this study, single-cell RNA sequencing (scRNA-seq) was performed on the kidney of hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × Pelteobagrus vachelli ♂) after A. hydrophila infection. Nine types of kidney cells were identified using marker genes, and a transcription module of marker genes in the main immune cells of hybrid yellow catfish kidney tissue was constructed using in-situ hybridization. In addition, the single-cell transcriptome data showed that the differentially expressed genes of macrophages were primarily enriched in the Toll-like receptor and Nod-like receptor signaling pathways. The expression levels of genes involved in these pathways were upregulated in macrophages following A. hydrophila infection. Transmission electron microscopy and TUNEL analysis revealed the cellular characteristics of macrophages before and after A. hydrophila infection. These data provide empirical support for in-depth research on the role of the kidney in the innate immune response of hybrid yellow catfish.

Detection of stereoisomers of carbohydrates with molecular resolution, a challenging goal analysts desire to achieve, is key to the full development of glycosciences. Despite the promise that analytical techniques made, including widely used nuclear magnetic resonance and mass spectrometry, high throughput de novo carbohydrate sequencing remains an unsolved issue. Notably, while next-generation sequencing technologies are readily available for DNA and proteins, they are conspicuously absent for carbohydrates due to the immense stereochemical and structural complexity inherent in these molecules. In this work, we report a novel computational technique that employs quantum tunneling coupled with artificial intelligence to detect complex carbohydrate anomers and stereoisomers with excellent sensitivity. The quantum tunneling footprints of carbohydrate isomers show high distinguishability with an in-depth analysis of underlying chemistry. Our findings open up a new route for carbohydrate sensing, which can be seamlessly integrated with next-generation sequencing technology for real-time analysis.

Legionella pneumophila is a pathogen which can lead to a severe form of pneumonia in humans known as Legionnaires disease after replication in alveolar macrophages. Viable L. pneumophila actively secrete effector molecules to modulate the host's immune response. Here, we report that L. pneumophila-derived factors reprogram macrophages into a tolerogenic state, a process to which the C-type lectin receptor Mincle (CLEC4E) markedly contributes. The underlying epigenetic state is characterized by increases of the closing mark H3K9me3 and decreases of the opening mark H3K4me3, subsequently leading to the reduced secretion of the cytokines TNF, IL-6, IL-12, the production of reactive oxygen species, and cell-surface expression of MHC-II and CD80 upon re-stimulation. In summary, these findings provide important implications for our understanding of Legionellosis and the contribution of Mincle to reprogramming of macrophages by L. pneumophila.

Acute kidney injury (AKI) is characterized by a sudden decline in renal function. The inflammatory response is the fundamental pathologic alteration throughout AKI, regardless of the various causal factors. Macrophages are the main immune cells involved in the inflammatory microenvironment in AKI. Consequently, targeting macrophages might become a novel strategy for the treatment of AKI. In this study, we demonstrated that pseudoginsenoside-F11 (PF11), a distinctive component of Panax quinquefolius L., regulated macrophage function and protected renal tubular epithelial cells TCMK-1 from lipopolysaccharide (LPS) in vitro. PF11 also alleviated renal injuries in an LPS-induced AKI mouse model, decreased the levels of inflammatory cytokines, reduced macrophage inflammatory infiltration, and promoted the polarization of M1 macrophages to M2c macrophages with suppression of the nuclear factor-κB/NOD-like receptor thermal protein domain-associated protein 3/interleukin-1β (NF-κB/NLRP3/IL-1β) signaling pathway. To further investigate whether this nephroprotective effect of PF11 is mediated by macrophages, we performed macrophage depletion by injection of clodronate liposomes in mice. Macrophage depletion abolished PF11's ability to protect against LPS-induced kidney damage with downregulating the NF-κB/NLRP3/IL-1β signaling pathway. In summary, this is the first study providing data on the efficacy and mechanism of PF11 in the treatment of AKI by regulating macrophage function.

The innate immune system is the first responder to infectious agents, cellular debris, and cancerous growths. This system plays critical roles in the antitumor immune responses by boosting and priming T cell-mediated cytotoxicity but is understudied due to the complexity and redundancy of its various downstream signaling cascades. We utilized a mathematical tool to holistically quantify innate immune signaling cascades and immunophenotype over 8,000 tumors from The Cancer Genome Atlas (TCGA). We found that innate immune activation was predictive of patient mortality in a subset of cancers. Further analysis identified PHF genes as transcripts that were associated with genomic stability and innate activation. Knockdown of PHF gene transcripts in vitro led to an increase in cell death and IFNB1 expression in a cGAS-dependent manner, validating PHF genes as potential anti-tumor targets. We also found an association between innate immune activation and both tumor immunogenicity and intratumor microbes, which highlights the versatility of this model. In conclusion, interrogating activation of innate immune signaling cascades demonstrated the importance of studying innate signaling in cancer and broadened the search for new therapeutic adjuvants.

The order Bunyavirales belongs to the class of Ellioviricetes and is classified into fourteen families. Some species of the order Bunyavirales pose potential threats to human health. The continuously increasing research reveals that various viruses within this order achieve immune evasion in the host through suppressing interferon (IFN) response. As the types and nodes of the interferon response pathway are continually updated or enriched, the IFN suppression mechanisms and target points of different virus species within this order are also constantly enriched and exhibit variations. For instance, Puumala virus (PUUV) and Tula virus (TULV) can inhibit IFN response through their functional NSs inhibiting downstream factor IRF3 activity. Nevertheless, the IFN suppression mechanisms of Dabie bandavirus (DBV) and Guertu virus (GTV) are mostly mediated by viral inclusion bodies (IBs) or filamentous structures (FSs). Currently, there are no effective drugs against several viruses belonging to this order that pose significant threats to society and human health. While the discovery, development, and application of antiviral drugs constitute a lengthy process, our focus on key targets in the IFN response suppression process of the virus leads to potential antiviral strategies, which provide references for both basic research and practical applications.

Viral hepatitis is a major cause of liver illness worldwide. Despite advances in the understanding of these infections, the pathogenesis of hepatitis remains a complex process driven by intricate interactions between hepatitis viruses and host cells at the molecular level. This paper will examine in detail the dynamics of these host-pathogen interactions, highlighting the key mechanisms that regulate virus entry into the hepatocyte, their replication, evasion of immune responses, and induction of hepatocellular damage. The unique strategies employed by different hepatitis viruses, such as hepatitis B, C, D, and E viruses, to exploit metabolic and cell signaling pathways to their advantage will be discussed. At the same time, the innate and adaptive immune responses put in place by the host to counter viral infection will be analyzed. Special attention will be paid to genetic, epigenetic, and environmental factors that modulate individual susceptibility to different forms of viral hepatitis. In addition, this work will highlight the latest findings on the mechanisms of viral persistence leading to the chronic hepatitis state and the potential implications for the development of new therapeutic strategies. Fully understanding the complex host-pathogen interactions in viral hepatitis is crucial to identifying new therapeutic targets, developing more effective approaches for treatment, and shedding light on the mechanisms underlying progression to more advanced stages of liver damage.

Influenza B virus (IBV) stands as a paradox, often overshadowed by its more notorious counterpart, influenza A virus (IAV). Yet, it remains a captivating and elusive subject of scientific inquiry. Influenza B is important because it causes seasonal flu outbreaks that can lead to severe respiratory illnesses, including bronchitis, pneumonia, and exacerbations of chronic conditions like asthma. Limitations in the influenza B virus's epidemiological, immunological, and etiological evolution must be addressed promptly. This comprehensive review covers evolutionary epidemiology and pathogenesis, host-virus interactions, viral isolation and propagation, advanced molecular detection assays, vaccine composition and no animal reservoir for influenza B virus. Complex viral etiology begins with intranasal transmission of influenza B virus with the release of a segmented RNA genome that attacks host cell machinery for transcription and translation within the nucleus and the release of viral progeny. Influenza B virus prevalence in domesticated and wild canines, sea mammals, and birds is frequent, yet there is no zoonosis. The periodic circulation of influenza B virus indicates a 1-3-year cycle for monophyletic strain replacement within the Victoria strain due to frequent antigenic drift in the HA near the receptor-binding site (RBS), while the antigenic stability of Yamagata viruses portrays a more conservative evolutionary pattern. Additionally, this article outlines contemporary antiviral strategies, including pharmacological interventions and vaccination efforts. This article serves as a resource for researchers, healthcare professionals, and anyone interested in the mysterious nature of the influenza B virus. It provides valuable insights and knowledge essential for comprehending and effectively countering this viral foe, which continues to pose a significant public health threat.

Bifidobacterium bifidum strain BB1 causes a strain-specific enhancement in intestinal epithelial tight junction (TJ) barrier. Tumor necrosis factor (TNF)-α induces an increase in intestinal epithelial TJ permeability and promotes intestinal inflammation. The major purpose of this study was to delineate the protective effect of BB1 against the TNF-α-induced increase in intestinal TJ permeability and to unravel the intracellular mechanisms involved. TNF-α produces an increase in intestinal epithelial TJ permeability in Caco-2 monolayers and in mice. Herein, the addition of BB1 inhibited the TNF-α increase in Caco-2 intestinal TJ permeability and mouse intestinal permeability in a strain-specific manner. BB1 inhibited the TNF-α-induced increase in intestinal TJ permeability by interfering with TNF-α-induced enterocyte NF-κB p50/p65 and myosin light chain kinase (MLCK) gene activation. The BB1 protective effect against the TNF-α-induced increase in intestinal permeability was mediated by toll-like receptor-2/toll-like receptor-6 heterodimer complex activation of peroxisome proliferator-activated receptor γ (PPAR-γ) and PPAR-γ pathway inhibition of TNF-α-induced inhibitory kappa B kinase α (IKK-α) activation, which, in turn, resulted in a step-wise inhibition of NF-κB p50/p65, MLCK gene, MLCK kinase activity, and MLCK-induced opening of the TJ barrier. In conclusion, these studies unraveled novel intracellular mechanisms of BB1 protection against the TNF-α-induced increase in intestinal TJ permeability. The current data show that BB1 protects against the TNF-α-induced increase in intestinal epithelial TJ permeability via a PPAR-γ-dependent inhibition of NF-κB p50/p65 and MLCK gene activation.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating infectious diseases of pigs globally. The pathogen, porcine reproductive and respiratory syndrome virus (PRRSV), is an enveloped positive-stranded RNA virus, which is considered to be the key triggers for the activation of effective innate immunity through pattern recognition receptor (PRR)-dependent signaling pathways. Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs) and Cytoplasmic DNA receptors (CDRs) are used as PRRs to identify distinct but overlapping microbial components. The innate immune system has evolved to recognize RNA or DNA molecules from microbes through pattern recognition receptors (PRRs) and to induce defense response against infections, including the production of type I interferon (IFN-I) and inflammatory cytokines. However, PRRSV is capable of continuous evolution through gene mutation and recombination to evade host immune defenses and exploit host cell mechanisms to synthesize and transport its components, thereby facilitating successful infection and replication. This review presents the research progress made in recent years in the study of these PRRs and their associated adapters during PRRSV infection.

Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a Toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the antitumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of patients with advanced PDAC.

Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunologic factors on survival outcomes was assessed through univariate Cox proportional hazards models.

Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+ XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronouncedDCand T-cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1.

This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunologic tolerance by enhancing antitumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes. See related commentary by Martínez-Riaño et al., p. 3355.