Immune Regulatory Mechanisms Research Articles

Genetic link between gut microbiota, immune cells, and rheumatoid arthritis: Mechanism of action of CD28 proteins

The gut microbiota serves a crucial function in modulating the immune responses of the host, as well as in managing inflammation within the body. In this particular study, the researchers sought to delve deeper into the specific mechanisms through which CD28 interacts with the gut microbiota and influences the functionality of immune cells. The study collected intestinal microbial samples from RA patients and healthy controls, analyzed microbial composition by high-throughput sequencing, and detected CD28 expression in T cells in combination with cellular immunology methods. At the same time, the effects of CD28 deletion on intestinal microbiota changes and inflammatory responses were evaluated using animal models. The findings from this study revealed a notable distinction in the gut microbiota profiles of individuals diagnosed with rheumatoid arthritis (RA) when compared to those of healthy control subjects. Specifically, the abundance of certain microbial species was observed to have a negative correlation with the expression levels of CD28, highlighting a complex interaction between the gut microbiome and the immune regulatory mechanisms involved in RA. Furthermore, experiments conducted on mice lacking CD28 demonstrated considerable alterations in their gut microbiota composition. These Cd28-deficient mice exhibited elevated levels of inflammatory markers, indicating an interplay between CD28 and the regulation of both the microbiota and the immune response.

Study on the physicochemical properties and immune regulatory mechanism of polysaccharide fraction from Aronia Melanocarpa fruit

Study on the physicochemical properties and immune regulatory mechanism of polysaccharide fraction from Aronia Melanocarpa fruit

Mechanisms of Mt.b Ag85B-Fc fusion protein against allergic asthma in mice by intranasal immunization.

Ag85B, the primary component of the Ag85 complex and an early secreted protein by Mycobacterium tuberculosis, has shown potential for the treatment of allergic asthma (AA) when used as a Fc-fusion protein. Administered via nasal immunization, Ag85B-Fc fusion protein significantly alleviated airway inflammation and reduced the proportions of some anaphylaxis related cells in lungs, with no significant histopathological injury to major organs in ovalbumin (OVA)-induced AA model mice. To investigate the underlying immune regulatory mechanisms of Ag85B protein, integrated proteomics and transcriptomics analyses were conducted, identifying the complement and coagulation cascades, and phagosomes as the two significantly enriched pathways at both gene and protein levels. Moreover, C3ar1 (C3aR1), Itgam (CD11b), Itgb2 (CD18), fgg (FGG), Cybb (CYBB), and Ncf4 (NCF4) were identified as core target factors that play a central role in allergic and asthmatic responses. Among them, C3aR1 and CR3 consisting of CD11b and CD18, are main complement receptors, indicating that Ag85B alleviated AA by regulating C3aR1- and CR3-mediated signal transduction. The validation results were consistent with the aforementioned findings. Overall, these results provide valuable insight into the application of mucosal immunotherapy in treatment of AA, positioning Ag85B-Fc fusion protein as a safe mucosal immunotherapeutic agent for AA.

Protective effect of Schistosoma mansoni infection and/or soluble egg antigen on allergic reaction in male mice

BackgroundInnovative treatments are being examined to develop more effective and innocuous protective medications for allergic conditions. In recent times, helminth-based immunotherapy is gaining attention as a potential therapeutic approach that could establish a pathway for controlling anaphylaxis. To the extent of our knowledge, there are no previous studies that examine the protective effect of both Schistosoma mansoni (S. mansoni) and its soluble egg antigen (SEA) together against anaphylaxis. Therefore, the purpose of the current study was to examine and compare the impact of SEA immunization and/or S. mansoni infection on Ovalbumin (OVA)-induced systemic anaphylaxes in mice model.ResultsThe outcome results revealed that S. mansoni infection and SEA immunization were able to improve body weight, reduce the mortality rate, increase plasma IgE and IgG4 levels and decrease histamine levels in broncho-alveolar lavage fluid (BALF). Additionally, they elevated interleukin-(IL)-4, IL-10, interferon-gamma (IFN-γ) and transforming growth factor-beta (ΤGF-β) levels in BALF. They also restored the stabilization of peritoneal mast cells (MCs) membrane in inverted light microscopy results accompanied by amelioration of the lung and liver histology.ConclusionsThe present study provided indication for the prophylactic effects of S. mansoni infection and SEA immunization against OVA-induced systemic anaphylaxes in mice model. Also, it focuses on the possible therapeutic mechanisms of helminth-derived products administration that might be related to upregulation of immune regulatory mechanisms. As a result, S. mansoni-derived products may be used as preventative supplemented treatments to inhibit the development of anaphylaxis which provides us with a new vision for developing pioneering therapy.

Extracellular vesicles in hepatocellular carcinoma: unraveling immunological mechanisms for enhanced diagnosis and overcoming drug resistance.

Current research is focused on utilizing EVs as a biopsy tool to improve the diagnostic accuracy of HCC, reduce surgical risk, and explore their potential in modulating drug resistance and advancing immunotherapeutic strategies. Extracellular vesicles (EVs) have been increasingly recognized as important non-invasive biomarkers in hepatocellular carcinoma (HCC) due to the presence of a variety of biomolecules within them, such as proteins and RNAs, etc. EVs play a key role in the early detection, diagnosis, treatment, and prognostic monitoring of HCC. These vesicles influence the development of HCC and therapeutic response in a variety of ways, including influencing the tumor microenvironment, modulating drug resistance, and participating in immune regulatory mechanisms. In addition, specific molecules such as miRNAs and specific proteins in EVs are regarded as potential markers for monitoring treatment response and recurrence of HCC, which have certain research space and development prospects. In this paper, we summarize the aspects of EVs as HCC diagnostic and drug resistance markers, and also discuss the questions that may be faced in the development of EVs as markers.

Measurement of Four Uterine NK Cell Subtypes Using Multiplexed Fluorescent Immunohistochemical Staining in Women with Repeated Implantation Failure.

Immunohistochemistry (IHC) plays a crucial role in biological research and clinical diagnosis, serving as the most commonly used method for identifying and visualizing tissue antigens. However, traditional IHC staining methods have limitations in distinguishing various subtypes of immune cells. This challenge has driven scientists to explore new technologies and methodologies for precise identification and differentiation of immune cell subtypes. In recent years, multiplex IHC has emerged as a solution, enabling the simultaneous detection of multiple antigens and their visualization within the same tissue sample. Uterine natural killer (uNK) cells play a pivotal role in early pregnancy processes, including decidualization, remodeling of uterine spiral arteries, and embryo implantation. Different subtypes of uNK cells exhibit different functions, allowing them to coordinate various biological events for successful embryo development and pregnancy. Therefore, in-depth research on uNK cell subtypes is essential for elucidating immune regulation mechanisms during pregnancy. Such studies provide valuable insights and novel approaches for addressing related conditions such as infertility and recurrent reproductive failure. This paper introduces a detailed multiplex IHC staining protocol for studying the density of four subtypes of uNK cells in endometrial specimens during the window of implantation (WOI). The protocol includes sample preparation, optimization of subtype markers, microscopic imaging, and data analyses. This multiplex IHC staining protocol offers high specificity and sensitivity, enabling simultaneous detection of different uNK cell subtypes, thus providing researchers with a powerful tool to explore the intricacies and mechanisms of immune regulation during pregnancy.

CXC chemokine receptor 4 - mediated immune modulation and tumor microenvironment heterogeneity in gastric cancer: Utilizing multi-omics approaches to identify potential therapeutic targets.

G-protein-coupled receptors (GPRs) are critical regulators of various biological behaviors, and their role in gastric cancer (GC) progression is gaining increasing attention. Among them, the immune regulatory mechanisms mediated by chemokine receptor 4 (CXCR4) remain insufficiently understood. This study aims to explore the immune regulatory functions of CXCR4 and the heterogeneity of the tumor microenvironment (TME) by examining GPR-related gene expression in GC. Through multi-omics approaches, including spatial transcriptomics and single-cell RNA sequencing, we investigated the oncogenic mechanisms of CXCR4, particularly its role in T cell immune exhaustion. In vitro experiments, including ELISA, PCR, CCK8 assays, cell scratch assays, and colony formation assays, were used to validate the role of CXCR4 in the migration and invasion of AGS and SNU-1 cell lines. CXCR4 silencing using siRNA further demonstrated its regulatory effects on these cellular processes. Our results revealed a strong correlation between elevated CXCR4 expression and increased exhaustion of regulatory T cells (Tregs) in the TME. Furthermore, heightened CXCR4 expression was linked to increased TME heterogeneity, driven by oxidative stress and activation of the NF-κB pathway, promoting immune evasion and tumor progression. Silencing CXCR4 significantly inhibited the invasive and proliferative abilities of AGS and SNU-1 cells, while also reducing the expression of pro-inflammatory cytokines IL-1β and interleukin-6, thus alleviating chronic inflammation and improving TME conditions. In conclusion, our comprehensive investigation highlights CXCR4 as a key mediator of TME dynamics and immune modulation in GC. Targeting CXCR4 presents a promising therapeutic strategy to slow tumor progression by reducing Tregs-mediated immune exhaustion and TME heterogeneity, positioning it as a novel therapeutic target in GC treatment.

Increased PRP19 in Hepatocyte Impedes B Cell Function to Promote Hepatocarcinogenesis.

Tumor immune microenvironment is strongly associated with the malignancy behavior of hepatocellular carcinoma (HCC). However, the immune function and regulatory mechanisms of B cells in HCC remain unclear. The expression differences between B cell high- and low-infiltration HCC samples are explored to identify the key regulator. Pre-mRNA processing factor 19 (PRP19) expression is increased in B cell low-infiltrated tissues and negatively correlated with the B cell marker, CD20. Inhibition of PRP19 expression promoted B cell infiltration in tumor tissue and impeded HCC growth. Mechanically, the co-immunoprecipitation (Co-IP) assay revealed that PRP19 interacts with DEAD-box helicase 5 (DDX5), leading to ubiquitination and degradation of the DDX5 protein. The attenuated DDX5 impairs CXCL12 mRNA stability to suppress B cell recruitment and plasma cell differentiation via CXCL12/CXCR4 axis. Moreover, the adoptive transfer of CXCR4+ B cells combined with CXCL12 treatment in mice models effectively inhibits HCC development by reshaping the immune response. The expression of PRP19, DDX5, and infiltrating B cells are recognized as clinical prognosis indicators for HCC patients. Overall, this study provides valuable insights into the clinical benefits of HCC immunotherapy by targeting PRP19 and modulating tumor-infiltrating B cell immune function.

Bioinformatics analysis of immune infiltration in human diabetic retinopathy and identification of immune-related hub genes and their ceRNA networks

Diabetic retinopathy (DR) is the most common microvascular complication in diabetic patients, and recent studies have shown that immune regulatory mechanisms are closely associated with retinal damage in DR. Therefore, this study focused on exploring immune cells and immune-related genes (IRGs) in DR and gaining insight into the ceRNA mechanisms by which IRGs regulate DR progression. Four datasets from human DR model retinal tissues were obtained from the Gene Expression Omnibus (GEO) database. R software was first used to identify differentially expressed mRNAs (DE-mRNAs) in the dataset GSE160306-mRNAs, then the distribution of immune cells in the gene matrix was analyzed by xCell and ImmuCellAI, ImmPort and InnateDB database were used to obtain immune-related hub genes (IRHGs) in the DR, and finally the STRING online tool and Cytoscape to construct the immune-related ceRNA network. The datasets GSE102485, GSE160308 and GSE160306-lncRNAs were used to validate the results of the ceRNA network further. The results of immune cell infiltration analysis showed that macrophages are important immune cells in DR; immune-related gene screening showed that FCGR2B is an IRHG in DR, and 2 immune-related ceRNA networks of IRHG were obtained: DDN-AS1/miR-10a-5p/FCGR2B and LINC01515/miR-10a-5p/FCGR2B. Our study suggests that infiltration of immune cells, especially the immune role of macrophages, is an important component of DR progression; the immune-related hub gene FCGR2B and its ceRNA network may be a key regulatory network for DR progression. The discovery of key immune cells, IRHG and ceRNA networks in this study may provide new prospects for early intervention and targeted treatment of DR.

Machine vision-assisted genomic prediction and genome-wide association of spleen-related traits in large yellow croaker infected with visceral white-nodules disease

High-resolution and high-throughput genotype-to-phenotype studies in fish are rapidly advancing, driven by innovative technologies that aim to address the challenges of modern breeding models. In recent years, machine vision and deep learning techniques, particularly convolutional neural networks (CNNs), have achieved significant success in image recognition and segmentation. Moreover, qualitative and quantitative analysis of disease resistance has always been a crucial field of research in genetics. This motivation has led us to investigate the potential of large yellow croaker visceral white-nodules disease (VWND) in encoding information on disease resistance for the task of accession classification. In this study, we proposed an image segmentation framework for the feature extraction of the spleen after VWND infection based on machine vision. We utilized deep CNNs and threshold segmentation for automatic feature learning and object segmentation. This approach eliminates subjectivity and enhances work efficiency compared to using hand-crafted features. Additionally, we employed spleen-related traits to conduct genome-wide association analysis (GWAS), which led to the identification of 24 significant SNPs and 10 major quantitative trait loci. The results of function enrichment analysis on candidate genes also indicated potential relationships with immune regulation mechanisms. Furthermore, we explored the use of genomic selection (GS) technology for phenotype prediction of extreme individuals, which further supports the predictability of spleen-related phenotypes for VWND resistance in large yellow croakers. Our findings demonstrate that artificial intelligence (AI)-based phenotyping approaches can deliver state-of-the-art performance for genetics research. We hope this work will provide a paradigm for applying deep learning and machine vision to phenotyping in aquaculture species.

Adaptive Imune Fuzzy Quasi-Sliding Mode Formation Tracking Control for Wheeled Mobile Robots with Obstacle Avoidance Under Incidence of Uncertainties and Disturbances: An Artificial Immune Systems Inspired Approach

This paper presents an adaptive immune fuzzy quasi-sliding mode kinematic control integrated with a PD dynamic control for the trajectory tracking and the leader-follower formation control by nonholonomic differential-drive wheeled mobile robots under incidence of uncertainties and disturbances. An immune regulation mechanism bio-inspired approach with reaction effect established by novel fuzzy rules set to adjust the control effort adaptively is designed, also using a fuzzy boundary layer and introducing an adaptation law for the immune portion gain online adjustment in such a way that they can also avert parameter drift, dealing with the drawbacks of a classic first-order sliding mode control, suppressing chattering and still maintaining the robustness with no a priori knowledge of the bounds of the disturbances. An obstacle avoidance strategy with a reactive method and variable avoidance radius is also proposed. The stability analysis is performed based on the Lyapunov theory. Simulation results demonstrate the proposed control effectiveness.

Distinct soluble immune checkpoint profiles characterize COVID-19 severity, mortality and SARS-CoV-2 variant infections.

Over the past four years, the COVID-19 pandemic has posed serious global health challenges. The severe form of disease and death resulted from the failure of immune regulatory mechanisms, closely highlighted by the dual proinflammatory cytokine and soluble immune checkpoint (sICP) storm. Identifying the individual factors impacting on disease severity, evolution and outcome, as well as any additional interconnections, have become of high scientific interest. In this study, we evaluated a novel panel composed of ten sICPs for the predictive values of COVID-19 disease severity, mortality and Delta vs. Omicron variant infections in relation to hyperinflammatory biomarkers. The serum levels of sICPs from confirmed SARS-CoV-2 infected patients at hospital admission were determined by Luminex, and artificial neural network analysis was applied for defining the distinct patterns of molecular associations with each form of disease: mild, moderate, and severe. Notably, distinct sICP profiles characterized various stages of disease and Delta infections: while sCD40 played a central role in all defined diagrams, the differences emerged from the distribution levels of four molecules recently found and relatively less investigated (sCD30, s4-1BB, sTIM-1, sB7-H3), and their associations with various hematological and biochemical inflammatory biomarkers. The artificial neural network analysis revealed the prominent role of serum sTIM-1 and Galectin-9 levels at hospital admission in discriminating between survivors and non-survivors, as well as the role of specific anti-interleukin therapy (Tocilizumab, Anakinra) in improving survival for patients with initially high sTIM-1 levels. Furthermore, strong associations between sCD40 and Galectin-9 with suPAR defined the Omicron variant infections, while the positive match of sCD40 with sTREM-1 serum levels characterized the Delta-infected patients. Of importance, this study provides a comprehensive analysis of circulatory immune factors governing the COVID-19 pathology, and identifies key roles of sCD40, sTIM-1, and Galectin-9 in predicting mortality.

Integrated microRNA study and pathological analysis provides new insights into the immune response of Ruditapes philippinarum under Vibrio anguillarum challenge

Manila clam (Ruditapes philippenarum) is an important shellfish aquaculture product. The large-scale breeding of clams is often affected by V. anguillarum and causes large-scale death. However, the pathogenesis, immune response and metabolic pathway of V. anguillarum are still unclear. In this study, we found that the bacterial load in the hepatopancreas of R. philippinarum peaked at 48 h after V. anguillarum infection, and then gradually decreased, while the activity of lysozyme reached the peak at 12 h. Tissue section observation reveals that the infected hepatopancreas cells lost normal structure or necrosis. Additionally, six small RNA libraries were constructed using hepatopancreas of clams. A total of 15 differentially expressed (DE) microRNA (miRNA) were identified at 48 h after V. anguillarum infection, including 8 upregulated and 7 downregulated miRNAs. GO and KEGG enrichment results indicated the prediction of 48 known miRNAs and 127 new miRNAs, with functional annotation suggests that endocytosis pathway and bacterial recognition proteins may play key roles in immune response. The sequencing results were basically consistent with the qRT-PCR validation, indicating the accuracy of the data. This study provides a new idea to explore the immune regulation mechanism of shellfish after V. anguillarum infection, which brings important reference significance for modern immunological research.

Physical, chemical, and biological property of silk reinforced polycaprolactone composites for bone tissue engineering

To develop a biodegradable implantable bone material with compatible mechanics with the bone tissue, providing a new biomaterial for clinical bone repair and regeneration. Silk reinforced polycaprolactone composites (SPC) containing 20%, 40%, and 60% silk were prepared by layer-by-layer assembly and hot-pressing technology. Macroscopic morphology was observed and microstructure were observed by scanning electron microscopy, compressive mechanical properties were detected by compression test, surface wettability was detected by surface contact angle test, degradation of materials was observed after soaking in PBS for 180 days, and proliferation of MC3T3-E1 cells was detected by cell counting kit 8 assay. Six Sprague Dawley rats were subcutaneously implanted with polycaprolactone (PCL) and 20%-SPC, respectively. Masson staining was used to analyze the in vivo degradation behavior and vascularization effect within 180 days. The pore defects of the three SPC sections were relatively few. In the range of 20% to 60%, as the silk content increased and the PCL content decreased, the interlayer spacing of silk fabric decreased, and the fibers almost covered the entire cross-section. The compressive modulus and compressive strength of SPC showed an increasing trend, and the compressive modulus of 60%-SPC was slightly lower than that of 40%-SPC. There were significant differences in compressive modulus and compressive strength between the materials ( P<0.05). In vitro simulated fluid degradation experiments showed that the mass loss of the three types of SPC after 180 days of degradation was within 5%, with the highest mass loss observed in 60%-SPC. The differences in mass loss between the materials were significant ( P<0.05). As the silk content increased, the static water contact angle of each material gradually decreased, and all could promote the proliferation of MC3T3-E1 cells. The subcutaneous degradation experiment in rats showed that 20%-SPC began to degrade at 30 days after implantation, and material degradation and vascularization were significant at 180 days, which was in sharp contrast to PCL. SPC has the mechanical and hydrophilic properties that are compatible with bone tissue. It maintains its mechanical strength for a long time in a simulated body fluid environment in vitro, and achieves dynamic synchronization of material degradation, tissue regeneration, and vascularization through the body's immune regulation mechanism in vivo. It is expected to provide a new type of implant material for clinical bone repair.

Metallothionein-1 mitigates the advancement of osteoarthritis by regulating Th17/Treg balance

Osteoarthritis (OA) is a chronic inflammatory joint disorder characterized by cartilage degradation and bone remodeling. This study investigated the regulatory role of metallothionein 1 (MT1) in modulating immune responses and the balance between regulatory T cells (Treg) and T helper 17 cells (Th17) in OA. Peripheral blood mononuclear cells (PBMCs) from healthy individuals and OA patients were assessed for cytokine expression linked to Treg/Th17 homeostasis. OA was induced in wild-type (WT) and Mt1 knockout (MT1KO) mice via surgical destabilization of the medial meniscus. Clinical scores, pathological features, inflammatory cytokines, and Treg/Th17 balance were evaluated. MT1KO mice showed significantly elevated Mt1, pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and exacerbated OA progression, characterized by increased knee joint diameter, inflammatory infiltration, and cartilage destruction. Mechanistically, disrupted Treg/Th17 balance played a pivotal role in OA exacerbation, with MT1KO promoting Th17 differentiation and reducing Treg populations. Additionally, the compensatory elevation of anti-inflammatory interleukin-10 (IL-10) in OA patients hinted at a nuanced immune regulatory mechanism. The study illuminates intricate interactions involving MT1, Treg/Th17 cells, and pro-inflammatory cytokines in OA pathogenesis, suggesting MT1′s potential as a pivotal regulatory factor and a therapeutic target for mitigating immune dysregulation in OA.

Myeloid differentiation protein 2 regulates the innate immunity and the disease resistant against Vibrio alginolyticus in Scylla paramamosain

Myeloid differentiation protein 2 (MD2), generally functions as a coreceptor of Toll-like receptor 4 (TLR4), facilitating the activation of TLR4 and the recognition of lipopolysaccharides (LPS) in host organisms. While the role of MD2 in immune activation is well-documented across various species, the specific role of the MD2 homolog in Scylla paramamosain (SpMD2) remains unidentified. In this study, we applied RNA interference to reduce SpMD2 expression, aiming to elucidate its role in immune system of mud crabs. Notably, SpMD2 interference leded to decrease in the hemocyte counts and phagocytic activity, along with increase in apoptosis rates and level of reactive oxygen species (ROS). Furthermore, the activities of key enzymes related to immune, such as superoxide dismutase (SOD), catalase (CAT), phenoloxidase (PO), peroxidase (POD), lysozyme (LZM), and acid phosphatase (ACP), were reduced by SpMD2 knockdown. Following infection with Vibrio alginolyticus, increase of SpMD2 expression level was observed. This was accompanied by alterations in the expression levels of genes related to immune in mud crabs. Challenge experiment with Vibrio alginolyticus showed a higher mortality rate after SpMD2 interference. Our study underscore the critical role of SpMD2 in enhancing the innate immunity and disease resistant in S. paramamosain, advancing our understanding of the innate immune regulatory mechanisms in crustaceans.

Versatile whey acidic protein four-disulfide core domain proteins: biology and role in diseases.

The Whey acidic protein four-disulfide core (WFDC) protein family consists of proteins with one or more WFDC domains which are ubiquitously expressed throughout the body of human and perform a wide range of functions, including antiprotease, antibacterial, and immunomodulatory functions. Aberrant expression of WFDC proteins is associated with human diseases. However, review on the WFDC protein family is limited and insufficient. Furthermore, a systematic summary of the underlying mechanisms of WFDC protein activity is lacking. In this review, we give a summary of the structural basis and molecular function of these proteins and review the immune regulatory mechanisms and signaling pathways of WFDC proteins in the development of certain diseases. Furthermore, we discuss the diagnostic and prognostic potential of multiple WFDC proteins in the aforementioned conditions, as well as their prospective use. At last, we also discuss the progress of WFDC protein in clinical trials and put forward some research difficulties and the directions of follow-up research. Our review highlights the functional diversity and clinical significance of WFDC proteins family, while providing potential targets for drug development and innovative therapeutic strategies, this review lays the foundation and direction for future research on WFDC proteins.

Harnessing the potential of the NALT and BALT as targets for immunomodulation using engineering strategies to enhance mucosal uptake.

Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.

Single-cell transcriptome landscape of the kidney reveals potential innate immune regulation mechanisms in hybrid yellow catfish after Aeromonas hydrophila infection

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.

Effects of Vibrio harveyi infection on the biochemistry, histology and transcriptome in the hepatopancreas of ivory shell (Babylonia areolata)

The ivory shell (Babylonia areolata) is one of the most promising high quality marine products. However, ivory shell is susceptible to Vibrio harveyi infection during the culture period. In this study, we investigated the biochemical indicators, histological changes and transcriptomic response in the hepatopancreas of ivory shells from the PBS control group (PC) and infection group (A3) with 1 × 109 CFU/mL V. harveyi after 24 h. Results showed that compared to the PC group, biochemical indicators, including malondialdehyde (MDA), reactive oxygen species (ROS), acid phosphatase (ACP), and Caspase 3 (Casp-3) were significantly increased (p < 0.05) in A3 group after V. harveyi infection for 24 h. Compared with the PC group, the hepatopancreas of A3 group were seriously damaged, the columnar epithelial cells of the tissue were enlarged, the space of digestive cells was increased, and vacuolar cavities appeared. A total of 95,581 unigenes were obtained and 2949 (1787 up-regulated and 1162 down-regulated) differential expressed genes (DEGs) were identified in the A3 group. GO and KEGG enrichment analysis showed that DEGs were mainly enriched in immune system process (GO:0002376), antioxidant activity (GO:0016209), lysosome (ko04142), toll and IMD signaling pathway (ko04624), and etc. These biological functions and pathways are associated with immune and inflammatory responses and apoptosis. 12 DEGs were randomly selected for real-time quantitative PCR (RT-qPCR) validation, and the expression profiles of these DEGs were consistent with the transcriptome data, confirming the accuracy and reliability of the transcriptome results. In summary, V. harveyi infection of ivory shells inducing oxidative stress, leading to severe hepatopancreatic damage, stimulating glutathione production to neutralize excessive ROS, and stimulating antimicrobial peptides production to counteract the deleterious effects of bacterial infection, which in turn modifying the immune and inflammatory response, ultimately resulting in apoptosis. This study provided valuable information to explore the immune regulation mechanism after V. harveyi infection and established molecular basis to support the prevention of V. harveyi infection.