Search

Akt is an important kinase in metabolism. Akt also phosphorylates and activates endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS, respectively) expressed in M0 (unpolarized) macrophages. We showed that e/nNOS NO production downstream of bitter taste receptors enhances macrophage phagocytosis. In airway epithelial cells, we also showed that the activation of Akt by a small molecule (SC79) enhances NO production and increases levels of nuclear Nrf2, which reduces IL-8 transcription during concomitant stimulation with Toll-like receptor (TLR) 5 agonist flagellin. We hypothesized that SC79's production of NO in macrophages might likewise enhance phagocytosis and reduce the transcription of some pro-inflammatory cytokines. Using live cell imaging of fluorescent biosensors and indicator dyes, we found that SC79 induces Akt activation, NO production, and downstream cGMP production in primary human M0 macrophages. This was accompanied by a reduction in IL-6, IL-8, and IL-12 production during concomitant stimulation with bacterial lipopolysaccharide, an agonist of pattern recognition receptors including TLR4. Pharmacological inhibitors suggested that this effect was dependent on Akt and Nrf2. Together, these data suggest that several macrophage immune pathways are regulated by SC79 via Akt. A small-molecule Akt activator may be useful in some infection settings, warranting future in vivo studies. [ABSTRACT FROM AUTHOR]

Nucleotide-binding oligomerization domain containing 2 (NOD2), located in the cell cytoplasm, is a pattern recognition receptor belonging to the innate immune receptor family. It mediates the innate immune response by identifying conserved sequences in bacterial peptide glycans and plays an essential role in maintaining immune system homeostasis. Gene mutations of NOD2 lead to the development of autoimmune diseases such as Crohn's disease and Blau syndrome. Recently, NOD2 has been shown to be associated with the pathogenesis of diabetes, cardiac-cerebral diseases, and cancers. However, the function of NOD2 in these non-communicable diseases (CNCDs) is not well summarized in reviews. Our report mainly discusses the primary function and molecular mechanism of NOD2 as well as its potential clinical significance in CNCDs. [ABSTRACT FROM AUTHOR]

The lung is prone to infections from respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A challenge in combating these infections is the difficulty in targeting antiviral activity directly at the lung mucosal tract. Boosting the capability of the respiratory mucosa to trigger a potent immune response at the onset of infection could serve as a potential strategy for managing respiratory infections. This study focused on screening immunomodulators to enhance innate immune response in lung epithelial and immune cell models. Through testing various subfamilies and pathways of pattern recognition receptors (PRRs), the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family was found to selectively activate innate immunity in lung epithelial cells. Activation of NOD1 and dual NOD1/2 by the agonists TriDAP and M-TriDAP, respectively, increased the number of IL-8+ cells by engaging the NF-κB and interferon response pathways. Lung epithelial cells showed a stronger response to NOD1 and dual NOD1/2 agonists compared to control. Interestingly, a less-pronounced response to NOD1 agonists was noted in PBMCs, indicating a tissue-specific effect of NOD1 in lung epithelial cells without inducing widespread systemic activation. The specificity of the NOD agonist pathway was confirmed through gene silencing of NOD1 (siRNA) and selective NOD1 and dual NOD1/2 inhibitors in lung epithelial cells. Ultimately, activation induced by NOD1 and dual NOD1/2 agonists created an antiviral environment that hindered SARS-CoV-2 replication in vitro in lung epithelial cells. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) is a continuing global threat that puts half of the world's population at risk for infection. This mosquito-transmitted virus is endemic in over 100 countries. When a mosquito takes a bloodmeal, virus is deposited into the epidermal and dermal layers of human skin, infecting a variety of permissive cells, including keratinocytes, Langerhans cells, macrophages, dermal dendritic cells, fibroblasts, and mast cells. In response to infection, the skin deploys an array of defense mechanisms to inhibit viral replication and prevent dissemination. Antimicrobial peptides, pattern recognition receptors, and cytokines induce a signaling cascade to increase transcription and translation of pro-inflammatory and antiviral genes. Paradoxically, this inflammatory environment recruits skin-resident mononuclear cells that become infected and migrate out of the skin, spreading virus throughout the host. The details of the viral–host interactions in the cutaneous microenvironment remain unclear, partly due to the limited body of research focusing on DENV in human skin. This review will summarize the functional role of human skin, the cutaneous innate immune response to DENV, the contribution of the arthropod vector, and the models used to study DENV interactions in the cutaneous environment. [ABSTRACT FROM AUTHOR]

Simple Summary: Heat stress is an important stressor in poultry husbandry with the rise in global temperature. Heat stress causes immune dysfunction and inflammatory responses in broiler chickens. Supplementation with plant extracts, which can be used to improve immune function and alleviate inflammatory response, can be an effective nutritional intervention. This study evaluated the effect of peppermint extract on the morphological changes and major pattern recognition receptors (PRRs) related to innate immunity and inflammatory response in the spleen of broiler chickens under chronic heat stress. Dietary peppermint extract inhibits chronic heat stress-induced activation of innate immunity and inflammatory response in the spleen of broiler chickens. Therefore, the supplementation with peppermint extract can be used to regulate innate immunity and inflammatory response in broiler chickens. The aim of this study was to investigate the effect of dietary peppermint extract (PE) on innate immunity and inflammatory responses in the spleen of broiler chickens under chronic heat stress. In order to further study the mechanism of the activation of innate immunity and inflammation induced by chronic heat stress and the regulatory effect of peppermint extract, we examined the spleen's histological change, the mRNA expression of major pattern recognition receptors (PRRs) (TLR2, TLR4, NOD1, MDA5 and DAI) and transcription factors (NF-κB, AP-1 and IRF3) and downstream inflammatory cytokines (IFN-α, IFN-β, IL-1β, IL-6 and TNF-α) of innate immune signaling pathways associated with heat stress in the spleen of broiler chickens. The results indicated that chronic heat stress damaged the spleen tissue. In addition, chronic heat stress induced the activation of innate immunity and inflammatory responses by increasing the mRNA expression of TLR2, TLR4 and DAI, mRNA expression of transcriptional factors (NF-κB, AP-1 and IRF3) and the concentration of downstream inflammatory cytokines in the spleen of broiler chickens. Dietary peppermint extract alleviated the damage of spleen tissue caused by chronic heat stress. In addition, peppermint extract reduced the mRNA expression of DAI, mRNA expression of transcriptional factors NF-κB, AP-1 and IRF3, and the concentration of inflammatory cytokines in the spleen of broiler chickens under chronic heat stress. In conclusion, dietary peppermint extract could have a beneficial effect on regulating inflammatory response and innate immunity via inhibiting the activation of NF-κB, AP-1 and IRF3 signaling pathways mediated by DAI in the spleen of broiler chickens induced by chronic heat stress. [ABSTRACT FROM AUTHOR]

Simple Summary: Outbreaks of white spot disease in Pacific white shrimp pose a significant threat to the major shrimp farming industry. Understanding the mechanisms of the shrimp against the causative virus is crucial. C-type lectins are important pattern recognition receptors that can be involved in the response against viral infections. This study identified the C-type lectin domain family 4 member F in shrimp as an important receptor gene that could promote replication of the causative virus and affect the survival rate of shrimp. This study will provide a theoretical basis for understanding the resistance mechanisms of shrimp against the virus. White spot disease (WSD) outbreaks pose a significant threat to the Pacific white shrimp (Litopenaeus vannamei) farming industry. The causative agent is the white spot syndrome virus (WSSV). There are no effective treatments for WSD so far. Therefore, understanding the resistance mechanisms of L. vannamei against the WSSV is crucial. C-type lectins (CTLs) are important pattern recognition receptors (PRRs) that promote agglutination, phagocytosis, encapsulation, bacteriostasis, and antiviral infections. This study cloned the C-type lectin domain family 4 member F (LvCLEC4F) from L. vannamei. LvCLEC4F contains a 492 bp open reading frame (ORF) encoding a protein of 163 amino acids, including a carbohydrate recognition domain (CRD). Following a challenge with the WSSV, the expression profile of LvCLEC4F was significantly altered. Using RNA interference (RNAi) technology, it was found that LvCLEC4F promotes WSSV replication and affects the expression levels of genes related to the regulation of apoptosis, signaling and cellular stress response, and immune defense. Meanwhile, the hemolymph agglutination phenomenon in vivo was weakened when LvCLEC4F was knocked down. These results indicated that LvCLEC4F may play an important role in the interaction between L. vannamei and WSSV. [ABSTRACT FROM AUTHOR]

Innate immunity plays an important role in host defense against microbial infections. It also participates in activation of acquired immunity through cytokine production and antigen presentation. Pattern recognition receptors such as Toll-like receptors and nucleotide oligomerization domain-like receptors sense invading pathogens and associated tissue injury, after which inflammatory mediators such as pro-inflammatory cytokines and nitric oxide are induced. Supersulfides are molecular species possessing catenated sulfur atoms such as persulfide and polysulfide moieties. They have recently been recognized as important regulators in cellular redox homeostasis by acting as potent antioxidants and nucleophiles. In addition, recent studies suggested that supersulfides are critically involved in the regulation of innate immune and inflammatory responses. In this review, we summarize current knowledge of the chemistry and biology of supersulfides, with particular attention to their roles in regulation of innate immune, and inflammatory responses. Studies with animal models of infection and inflammation demonstrated the potent anti-inflammatory functions of supersulfides such as blocking pro-inflammatory signaling cascades, reducing oxidative stresses, and inhibiting replication of microbial pathogens including severe acute respiratory syndrome coronavirus 2. Precise understanding of how supersulfides regulate innate immune responses is the necessary requirement for developing supersulfide-based diagnostic as well as therapeutic strategies against inflammatory disorders. [ABSTRACT FROM AUTHOR]

During the replication of viral genomes, RNA viruses produce double‐stranded RNA (dsRNA), through the activity of their RNA‐dependent RNA polymerases (RdRps) as viral replication intermediates. Recognition of viral dsRNA by host pattern recognition receptors – such as retinoic acid‐induced gene‐I (RIG‐I)‐like receptors and Toll‐like receptor 3 – triggers the production of interferon (IFN)‐β via the activation of IFN regulatory factor (IRF)‐3. It has been proposed that, during the replication of viral genomes, each of RIG‐I and melanoma differentiation‐associated gene 5 (MDA5) form homodimers for the efficient activation of a downstream signalling pathway in host cells. We previously reported that, in the non‐neoplastic human hepatocyte line PH5CH8, the RdRp NS5B derived from hepatitis C virus (HCV) could induce IFN‐β expression by its RdRp activity without the actual replication of viral genomes. However, the exact mechanism by which HCV NS5B produced IFN‐β remained unknown. In the present study, we first showed that NS5B derived from another Flaviviridae family member, GB virus B (GBV‐B), also possessed the ability to induce IFN‐β in PH5CH8 cells. Similarly, HCV NS5B, but not its G317V mutant, which lacks RdRp activity, induced the dimerization of MDA5 and subsequently the activation of IRF‐3. Interestingly, immunofluorescence analysis showed that HCV NS5B produced dsRNA. Like HCV NS5B, GBV‐B NS5B also triggered the production of dsRNA and subsequently the dimerization of MDA5. Taken together, our results show that HCV NS5B triggers an MDA5‐mediated innate immune response by producing dsRNA without the replication of viral genomes in human hepatocytes. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss, characterised by the dysfunction and death of the photoreceptors and retinal pigment epithelium (RPE). Innate immune cell activation and accompanying para-inflammation have been suggested to contribute to the pathogenesis of AMD, although the exact mechanism(s) and signalling pathways remain elusive. Pattern recognition receptors (PRRs) are essential activators of the innate immune system and drivers of para-inflammation. Of these PRRs, the two most prominent are (1) Toll-like receptors (TLR) and (2) NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-inflammasome have been found to modulate the progression of AMD. Mutations in TLR2 have been found to be associated with an increased risk of developing AMD. In animal models of AMD, inhibition of TLR and NLRP3 has been shown to reduce RPE cell death, inflammation and angiogenesis signalling, offering potential novel treatments for advanced AMD. Here, we examine the evidence for PRRs, TLRs2/3/4, and NLRP3-inflammasome pathways in macular degeneration pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Lung ischemia/reperfusion injury (LIRI) is a common occurrence in clinical practice and represents a significant complication following pulmonary transplantation and various diseases. At the core of pulmonary ischemia/reperfusion injury lies sterile inflammation, where the innate immune response plays a pivotal role. This review aims to investigate recent advancements in comprehending the role of innate immunity in LIRI. Methods: A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning lung ischemia/reperfusion injury, cell death, damage-associated molecular pattern molecules (DAMPs), innate immune cells, innate immunity, inflammation. Results: During the process of lung ischemia/reperfusion, cellular injury even death can occur. When cells are injured or undergo cell death, endogenous ligands known as DAMPs are released. These molecules can be recognized and bound by pattern recognition receptors (PRRs), leading to the recruitment and activation of innate immune cells. Subsequently, a cascade of inflammatory responses is triggered, ultimately exacerbating pulmonary injury. These steps are complex and interrelated rather than being in a linear relationship. In recent years, significant progress has been made in understanding the immunological mechanisms of LIRI, involving novel types of cell death, the ability of receptors other than PRRs to recognize DAMPs, and a more detailed mechanism of action of innate immune cells in ischemia/reperfusion injury (IRI), laying the groundwork for the development of novel diagnostic and therapeutic approaches. Conclusions: Various immune components of the innate immune system play critical roles in lung injury after ischemia/reperfusion. Preventing cell death and the release of DAMPs, interrupting DAMPs receptor interactions, disrupting intracellular inflammatory signaling pathways, and minimizing immune cell recruitment are essential for lung protection in LIRI. [ABSTRACT FROM AUTHOR]

Vaccination is a valid strategy to prevent and control newly emerging and reemerging infectious diseases in humans and animals. However, synthetic and recombinant antigens are poor immunogenic to stimulate efficient and protective host immune response. Immunostimulants are indispensable factors of vaccines, which can promote to trigger fast, robust, and long-lasting immune responses. Importantly, immunotherapy with immunostimulants is increasing proved to be an effective and promising treatment of cancer, which could enhance the function of the immune system against tumor cells. Pattern recognition receptors (PRRs) play vital roles in inflammation and are central to innate and adaptive immune responses. Toll-like receptors (TLRs)-targeting immunostimulants have become one of the hotspots in adjuvant research and cancer therapy. Bacterial-origin immunoreactive molecules are usually the ligands of PRRs, which could be fast recognized by PRRs and activate immune response to eliminate pathogens. Varieties of bacterial immunoreactive molecules and bacterial component-mimicking molecules have been successfully used in vaccines and clinical therapy so far. This work provides a comprehensive review of the development, current state, mechanisms, and applications of bacterial-origin immunostimulants. The exploration of bacterial immunoreactive molecules, along with their corresponding mechanisms, holds immense significance in deepening our understanding of bacterial pathogenicity and in the development of promising immunostimulants. [ABSTRACT FROM AUTHOR]

Endogenous double-stranded RNA has emerged as a potent stimulator of innate immunity. Under physiological conditions, endogenous dsRNA is maintained in the cell nucleus or the mitochondria; however, if protective mechanisms are breached, it leaches into the cytoplasm and triggers immune signaling pathways. Ectopic activation of innate immune pathways is associated with various diseases and senescence and can trigger apoptosis. Hereby, the level of cytoplasmic dsRNA is crucial. We have enriched dsRNA from two melanoma cell lines and primary dermal fibroblasts, including a competing probe, and analyzed the dsRNA transcriptome using RNA sequencing. There was a striking difference in read counts between the cell lines and the primary cells, and the effect was confirmed by northern blotting and immunocytochemistry. Both mitochondria (10–20%) and nuclear transcription (80–90%) contributed significantly to the dsRNA transcriptome. The mitochondrial contribution was lower in the cancer cells compared to fibroblasts. The expression of different transposable element families was comparable, suggesting a general up-regulation of transposable element expression rather than stimulation of a specific sub-family. Sequencing of the input control revealed minor differences in dsRNA processing pathways with an upregulation of oligoadenylate synthase and RNP125 that negatively regulates the dsRNA sensors RIG1 and MDA5. Moreover, RT-qPCR, Western blotting, and immunocytochemistry confirmed the relatively minor adaptations to the hugely different dsRNA levels. As a consequence, these transformed cell lines are potentially less tolerant to interventions that increase the formation of endogenous dsRNA. [ABSTRACT FROM AUTHOR]

Breast cancer stands as a primary malignancy among women, ranking second in global cancer-related deaths. Despite treatment advancements, many patients progress to metastatic stages, posing a significant therapeutic challenge. Current therapies primarily target cancer cells, overlooking their intricate interactions with the tumor microenvironment (TME) that fuel progression and treatment resistance. Dysregulated innate immunity in breast cancer triggers chronic inflammation, fostering cancer development and therapy resistance. Innate immune pattern recognition receptors (PRRs) have emerged as crucial regulators of the immune response as well as of several immune-mediated or cancer cell-intrinsic mechanisms that either inhibit or promote tumor progression. In particular, several studies showed that the Toll-like receptor 2 (TLR2) and the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathways play a central role in breast cancer progression. In this review, we present a comprehensive overview of the role of TLR2 and STING in breast cancer, and we explore the potential to target these PRRs for drug development. This information will significantly impact the scientific discussion on the use of PRR agonists or inhibitors in cancer therapy, opening up new and promising avenues for breast cancer treatment. [ABSTRACT FROM AUTHOR]

In innate immunity, the first layer of defense against any microbial infection is triggered by the perception of pathogen-associated molecular patterns by highly specific pattern recognition receptors. The Pseudomonas syringae pv. tomato and Pseudomonas aeruginosa are plant-pathogenic bacterial species that include pathogenic strains in a wide range of different plant species. In the current study, extensive analysis including gene expression of 12 hub genes, gene ontology, protein–protein interaction, and cis-element prediction to dissect the Arabidopsis response to above-mentioned bacteria were performed. Further, we evaluated weighted co-expression network analysis (WGCNA) in the wild-type plants and coi-1 mutant line and determined changes in responsive genes at two time-points (4 and 8 h) of post-treatment with P. syringae and P. aeruginosa. Compared to the wild-type plants, coi-1 mutant showed significant expression in most of the genes involved, indicating that their protein products have important role in innate immunity and RNA silencing pathways. Our findings showed that 12 hub genes were co-expressed in response to P. syringae and P. aeruginosa infections. Based on the network analysis, transcription factors, receptors, protein kinase, and pathogenesis-related protein (PR1) were involved in the immunity system. Gene ontology related to each module was involved in defense response, protein serine kinase activity, and primary miRNA processing. Based on the cis-elements prediction, MYB, MYC, WRE3, W-box, STRE, and ARE contained the most number of cis-elements in co-expressed network genes. Also, in coi-1 mutant, most responsive genes against theses pathogens were up-regulated. The knowledge gained in the gene expression analysis in response to P. syringae and P. aeruginosa in the model plant, i.e., Arabidopsis, is essential to allow us to gain more insight about the innate immunity in other crops. [ABSTRACT FROM AUTHOR]

Innate immunity is the first line of defense against infections, which functions as a significant role in resisting pathogen invasion. Rapid immune response is initiated by pattern recognition receptors (PRRs) quickly distinguishing "self" and "non‐self." Upon evolutionarily conserved pathogen‐associated molecular pattern (PAMP) is recognized by PRRs, innate immune response against infection is triggered via an orchestration of molecular interaction, cytokines cascades, and immune cells. RIG‐I plays a critical role in type I interferon (IFN‐I) production by direct recognition of cytoplasmic double‐stranded viral RNA. However, the activation mechanism of RIG‐I is incompletely understood. In this study, we reported RNA‐binding protein ZFP36 as a positive regulator of RIG‐I‐mediated IFN‐I production. ZFP36 is a member of Zinc finger proteins (ZFPs) characterized by the zinc finger (ZnF) motif, which broadly involved gene transcription and signal transduction. However, its role in regulating antiviral innate immune signaling is still unclear. We found that ZFP36 associates with RIG‐I and potentiates the FN‐β production induced by SeV. Mechanistically, ZFP36 promotes K63‐linked polyubiquitination of RIG‐I, mostly at K154/K164/K172, thereby facilitating the activation of RIG‐I during infection. While the mutant ZFP36 (C118S/C162S) failed to increase polyubiquitination of RIG‐I and SeV induced FN‐β. Our findings collectively demonstrated that ZFP36 acts as a positive regulator in antiviral innate immunity by targeting RIG‐I for K63‐linked ubiquitination, thus improving our understanding of the activation mechanism of RIG‐I. [ABSTRACT FROM AUTHOR]

Guanylate-binding proteins (GBPs) have newly identified functions, including pattern-recognition capabilities and pathogen-selective antimicrobial activities against bacteria, viruses, and parasites. Human GBP1 binds directly to the cytoplasmic lipopolysaccharide (LPS) of Gram-negative bacteria and activates caspase-4, redefining this GBP as a pattern-recognition receptor and inspiring the search for ligands of other human GBPs. Mouse GBPs kill certain Gram-negative bacteria and activate inflammasomes, but the ligands targeted by mouse GBPs are not known. Harnessing the antimicrobial power of GBPs is an emerging concept which could lead to novel therapeutics, such as drugs used to treat multidrug-resistant infections. Guanylate-binding proteins (GBPs) are a family of intracellular proteins which have diverse biological functions, including pathogen sensing and host defense against infectious disease. These proteins are expressed in response to interferon (IFN) stimulation and can localize and target intracellular microbes (e.g., bacteria and viruses) by protein trafficking and membrane binding. These properties contribute to the ability of GBPs to induce inflammasome activation, inflammation, and cell death, and to directly disrupt pathogen membranes. Recent biochemical studies have revealed that human GBP1, GBP2, and GBP3 can directly bind to the lipopolysaccharide (LPS) of Gram-negative bacteria. In this review we discuss emerging data highlighting the functional versatility of GBPs, with a focus on their molecular mechanisms of pattern recognition and antimicrobial activity. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cause of cancer worldwide and is the leading cause of mortality for women across most of the world. Immunotherapy is a burgeoning area of cancer treatment, including for breast cancer; these are therapies that harness the power of the immune system to clear cancerous cells. Toll-like receptor 3 (TLR3) is an RNA receptor found in the endosome, and ligands that bind to TLR3 are currently being tested for their efficacy as breast cancer immunotherapeutics. The current review introduces TLR3 and the role of this receptor in breast cancer, and summarizes data on the potential use of TLR3 ligands, mainly polyinosinic:polycytidylic acid and its derivatives, as breast cancer monot [ABSTRACT FROM AUTHOR]

Hematopoietic stem/progenitor cells (HSPCs) express receptors for complement cascade (ComC) cleavage fragments C3a and C5a and may respond to inflammation-related cues by sensing pathogen-associated molecular pattern molecules (PAMPs) released by pathogens as well as non-infectious danger associated molecular pattern molecules (DAMPs) or alarmin generated during stress/tissue damage sterile inflammation. To facilitate this HSPCs are equipped with C3a and C5a receptors, C3aR and C5aR, respectively, and express on the outer cell membrane and in cytosol pattern recognition receptors (PPRs) that sense PAMPs and DAMPs. Overall, danger-sensing mechanisms in HSPCs mimic those seen in immune cells, which should not surprise as hematopoiesis and the immune system develop from the same common stem cell precursor. This review will focus on the role of ComC-derived C3a and C5a that trigger nitric oxide synthetase-2 (Nox2) complex to release reactive oxygen species (ROS) that activate important cytosolic PRRs—Nlrp3 inflammasome, which orchestrates responsiveness of HSPCs to stress. Moreover, recent data indicate that in addition to circulating in peripheral blood (PB) activated liver-derived ComC proteins, a similar role plays ComC expressed and intrinsically activated in HSPCs known as "complosome". We postulate that ComC triggered Nox2-ROS-Nlrp3 inflammasome responses, if they occur within non-toxic to cells' "hormetic range of activation", positively regulate HSCs migration, metabolism, and proliferation. This sheds a new light on the immune-metabolic regulation of hematopoiesis. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are critical cellular mediators of host immunity, notably by expressing a broad panel of pattern recognition receptors. One of those receptors, the C-type lectin receptor DC-SIGN, was previously reported as a regulator of endo/lysosomal targeting through functional connections with the autophagy pathway. Here, we confirmed that DC-SIGN internalization intersects with LC3+ autophagy structures in primary human monocyte-derived dendritic cells (MoDC). DC-SIGN engagement promoted autophagy flux which coincided with the recruitment of ATG-related factors. As such, the autophagy initiation factor ATG9 was found to be associated with DC-SIGN very early upon receptor engagement and required for an optimal DC-SIGN-mediated autophagy flux. The autophagy flux activation upon DC-SIGN engagement was recapitulated using engineered DC-SIGN-expressing epithelial cells in which ATG9 association with the receptor was also confirmed. Finally, Stimulated emission depletion (STED) microscopy performed in primary human MoDC revealed DC-SIGN-dependent submembrane nanoclusters formed with ATG9, which was required to degrade incoming viruses and further limit DC-mediated transmission of HIV-1 infection to CD4+ T lymphocytes. Our study unveils a physical association between the Pattern Recognition Receptor DC-SIGN and essential components of the autophagy pathway contributing to early endocytic events and the host's antiviral immune response. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a chronic infectious disease mainly caused by Mycobacterium tuberculosis (M. tuberculosis). The structures of polysaccharides and glycolipids at M. tuberculosis cell wall vary among different strains, which affect the physiology and pathogenesis of mycobacteria by activating or inhibiting innate and acquired immunity. Among them, some components such as lipomannan (LM) and lipoarabinomannan (LAM) activate innate immunity by recognizing some kinds of pattern recognition receptors (PRRs) like Toll‐like receptors, while other components like mannose‐capped lipoarabinomannan (ManLAM) could prevent innate immune responses by inhibiting the secretion of pro‐inflammatory cytokines and maturation of phagosomes. In addition, many glycolipids can activate natural killer T (NKT) cells and CD1‐restricted T cells to produce interferon‐γ (IFN‐γ). Furthermore, humoral immunity against cell wall components, such as antibodies against LAM, plays a role in immunity against M. tuberculosis infection. Cell wall polysaccharides and glycolipids of M. tuberculosis have potential applications as antigens and adjuvants for novel TB subunit vaccines. [ABSTRACT FROM AUTHOR]

Invading pathogens have developed weapons that subvert physiological conditions to weaken the host and permit the spread of infection. Cells, on their side, have thus developed countermeasures to maintain cellular physiology and counteract pathogenesis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) is a pattern recognition receptor that recognizes viral DNA present in the cytosol, activating the stimulator of interferon genes (STING) protein and leading to the production of type I interferons (IFN-I). Given its role in innate immunity activation, STING is considered an interesting and innovative target for the development of broad-spectrum antivirals. In this review, we discuss the function of STING; its modulation by the cellular stimuli; the molecular mechanisms developed by viruses, through which they escape this defense system; and the therapeutical strategies that have been developed to date to inhibit viral replication restoring STING functionality. [ABSTRACT FROM AUTHOR]

Human mitochondria contain a circular genome that encodes 13 subunits of the oxidative phosphorylation system. In addition to their role as powerhouses of the cells, mitochondria are also involved in innate immunity as the mitochondrial genome generates long double-stranded RNAs (dsRNAs) that can activate the dsRNA-sensing pattern recognition receptors. Recent evidence shows that these mitochondrial dsRNAs (mt-dsRNAs) are closely associated with the pathogenesis of human diseases that accompany inflammation and aberrant immune activation, such as Huntington's disease, osteoarthritis, and autoimmune Sjögren's syndrome. Yet, small chemicals that can protect cells from a mt-dsRNA-mediated immune response remain largely unexplored. Here, we investigate the potential of resveratrol (RES), a plant-derived polyphenol with antioxidant properties, on suppressing mt-dsRNA-mediated immune activation. We show that RES can revert the downstream response to immunogenic stressors that elevate mitochondrial RNA expressions, such as stimulation by exogenous dsRNAs or inhibition of ATP synthase. Through high-throughput sequencing, we find that RES can regulate mt-dsRNA expression, interferon response, and other cellular responses induced by these stressors. Notably, RES treatment fails to counter the effect of an endoplasmic reticulum stressor that does not affect the expression of mitochondrial RNAs. Overall, our study demonstrates the potential usage of RES to alleviate the mt-dsRNA-mediated immunogenic stress response. [ABSTRACT FROM AUTHOR]

Simple Summary: The cellular and humoral mechanisms of natural immunity are at the beginning of all the defence processes of an organism. Their defence function is based on the ability to recognize pathogen-associated molecular patterns and damage (danger)-associated molecular patterns using pattern recognition receptors. Recognition of pathogen-associated molecular patterns and/or damage (danger)-associated molecular patterns has a crucial role in the activation of the innate immune defence mechanisms. An inflammatory response, as a basic event in early defence occurs, which is the complex, developmentally acquired ability of living organisms to react to various damages. If it is not strictly regulated, it turns into damaging inflammation. This is common both in some infectious diseases, such as prolonged COVID-19, and in precancerous tissue preceding the development of tumors. This short review presents a vision of an integration of innate immune recognition, cell-autonomous stress response, infection, and tumorigenesis. Engagement of PRRs in recognition of PAMPs or DAMPs is one of the processes that initiates cellular stress. These sensors are involved in signaling pathways leading to induction of innate immune processes. Signaling initiated by PRRs is associated with the activation of MyD88-dependent signaling pathways and myddosome formation. MyD88 downstream signaling depends upon the context of signaling initiation, the cell (sub)type and the microenvironment of signal initiation. Recognition of PAMPs or DAMPs through PRRs activates the cellular autonomous defence mechanism, which orchestrates the cell responses to resolve specific insults at the single cell level. In general, stressed endoplasmic reticulum is directly linked with the induction of autophagy and initiation of mitochondrial stress. These processes are regulated by the release of Ca2+ from ER stores accepted by mitochondria, which respond through membrane depolarization and the production of reactive oxygen species generating signals leading to inflammasome activation. In parallel, signaling from PRRs initiates the accumulation of misfolded or inappropriately post-translationally modified proteins in the ER and triggers a group of conserved emergency rescue pathways known as unfolded protein response. The cell-autonomous effector mechanisms have evolutionarily ancient roots and were gradually specialized for the defence of specific cell (sub)types. All of these processes are common to the innate immune recognition of microbial pathogens and tumorigenesis as well. PRRs are active in both cases. Downstream are activated signaling pathways initiated by myddosomes, translated by the cellular autonomous defence mechanism, and finalized by inflammasomes. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract of all animals, including insects, is colonized by a remarkable array of microorganisms which are referred to collectively as the gut microbiota. The hosts establish mutually beneficial interactions with the gut microbiota. However, the mechanisms shaping these interactions remain to be better understood. Here, we investigated the roles of Musca domestica peptidoglycan recognition protein SC (MdPGRP‐SC), a secreted pattern recognition receptor, in shaping the gut microbial community structure by using biochemical and high‐throughput sequencing approaches. The recombinant MdPGRP‐SC (rMdPGRP‐SC) could strongly bind various pathogen‐associated molecular patterns (PAMPs) including peptidoglycan, lipopolysaccharide and D‐galactose, and exhibited mild affinity to β‐1, 3‐glucan and D‐mannose. Meanwhile, rMdPGRP‐SC could also bind different kinds of microorganisms, including gram‐positive bacteria (Bacillus subtilis and Staphylococcus aureus), gram‐negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and yeast (Pichia pastoris). rMdPGRP‐SC also exhibited weak antibacterial activity against Bacillus subtilis. Knockdown of MdPGRP‐SC by RNAi reduced the persistence of ingested E. coli and a load of indigenous microbiota in the larval gut significantly. In addition, depleted MdPGRP‐SC also altered the gut microbiota composition and led to increased ratios of Gram‐negative bacteria. We hypothesize that MdPGRP‐SC is involved in maintaining gut homeostasis by modulating the immune intensity of the gut through multiple mechanisms, including degrading or neutralizing various PAMPs and selectively suppressing the growth of some bacteria. Considering the functional conservation of the peptidoglycan recognition protein (PGRP) family in insects, the catalytic PGRPs might be promising candidate targets not only for pest and vector control but also for the treatment of bacterial infection in insect farming. [ABSTRACT FROM AUTHOR]

The mucociliary airway epithelium lines the human airways and is the primary site of host-environmental interactions in the lung. Following virus infection, airway epithelial cells initiate an innate immune response to suppress virus replication. Therefore, defining the virus-host interactions of the mucociliary airway epithelium is critical for understanding the mechanisms that regulate virus infection, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Non-human primates (NHP) are closely related to humans and provide a model to study human disease. However, ethical considerations and high costs can restrict the use of in vivo NHP models. Therefore, there is a need to develop in vitro NHP models of human respiratory virus infection that would allow for rapidly characterizing virus tropism and the suitability of specific NHP species to model human infection. Using the olive baboon (Papio anubis), we have developed methodologies for the isolation, in vitro expansion, cryopreservation, and mucociliary differentiation of primary fetal baboon tracheal epithelial cells (FBTECs). Furthermore, we demonstrate that in vitro differentiated FBTECs are permissive to SARS-CoV-2 infection and produce a potent host innate-immune response. In summary, we have developed an in vitro NHP model that provides a platform for the study of SARS-CoV-2 infection and other human respiratory viruses. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) are estimated to comprise ∼8% of the entire human genome, but the vast majority of them remain transcriptionally silent in most normal tissues due to accumulated mutations. However, HERVs can be frequently activated and detected in various tissues under certain conditions. Nucleic acids or proteins produced by HERVs can bind to pattern recognition receptors of immune cells or other cells and initiate an innate immune response, which may be involved in some pathogenesis of diseases, especially cancer and autoimmune diseases. In this review, we collect studies of the interaction between HERV elements and Toll-like receptors and attempt to provide an overview of their role in the immunopathological mechanisms of inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Plastic pollution is a significant problem worldwide because of the risks it poses to the equilibrium and health of the environment as well as to human beings. Discarded plastic released into the environment can degrade into microplastics (MPs) due to various factors, such as sunlight, seawater flow, and temperature. MP surfaces can act as solid scaffolds for microorganisms, viruses, and various biomolecules (such as LPS, allergens, and antibiotics), depending on the MP characteristics of size/surface area, chemical composition, and surface charge. The immune system has efficient recognition and elimination mechanisms for pathogens, foreign agents, and anomalous molecules, including pattern recognition receptors and phagocytosis. However, associations with MPs can modify the physical, structural, and functional characteristics of microbes and biomolecules, thereby changing their interactions with the host immune system (in particular with innate immune cells) and, most likely, the features of the subsequent innate/inflammatory response. Thus, exploring differences in the immune response to microbial agents that have been modified by interactions with MPs is meaningful in terms of identifying new possible risks to human health posed by anomalous stimulation of immune reactivities. [ABSTRACT FROM AUTHOR]

Simple Summary: Mastitis is one of the most challenging diseases of dairy animals, with a high impact on animal production and welfare. The development of mastitis vaccines requires deep understanding of host–pathogen interaction mechanisms in the mammary gland. In the present study, we investigated the immunomodulatory effect of selected Toll-like receptor (TLR) ligands, representing gram-positive and gram-negative bacterial mastitis pathogens, on the phenotype and function of milk immune cells in a whole milk stimulation assay. The analysis of stimulation-induced shape change, change in the expression of cell surface markers, phagocytosis, apoptosis, ROS production, and NETosis revealed selective modulating effects of the TLR ligands LPS and Pam3CSK4 on camel milk immune cells. These results may have implications for the use of synthetic TLR agonists as immunomodulatory adjuvants of the immune response to intra-mammary vaccines against mastitis pathogens. (1) Toll-like receptors (TLR) are a family of pattern recognition receptors that sense distinct molecular patterns of microbial origin. Although the immune cell composition of camel milk has been recently described, host–pathogen interaction studies in the camel mammary gland are still scarce. The present study aimed to use a whole milk stimulation assay for investigating the modulatory effect of selected Toll-like receptor (TLR) ligands on the phenotype and function of milk immune cells. (2) Methods—camel milk samples (n = 7) were stimulated in vitro with the TLR4 ligand LPS or the TLR2/1 ligand Pam3CSK4, and separated milk cells were evaluated for stimulation-induced shape change, the expression of cell surface markers, phagocytosis, apoptosis, ROS production, and NETosis. Stimulation with PMA was used as a control stimulation. (3) Results—all stimulants induced shape change in milk cells, change in the expression of several cell markers, and increased cell apoptosis and NETosis. In addition, stimulation with Pam3CSK4 and PMA was associated with enhanced ROS production, while only PMA stimulation resulted in enhanced bacterial phagocytosis by milk immune cells. (4) Conclusions—our data indicates selective modulating effects of the TLR ligands LPS and Pam3CSK4 on camel milk phagocytes. These results may have implications for the use of synthetic TLR agonists as immunomodulatory adjuvants of the immune response to intra-mammary vaccines against mastitis pathogens. [ABSTRACT FROM AUTHOR]

Toll-like receptor 7 (TLR7) is a class of pattern recognition receptors (PRRs) recognizing the pathogen-associated elements and damage and as such is a major player in the innate immune system. TLR7 triggers the release of pro-inflammatory cytokines or type-I interferons (IFN), which is essential for immunoregulation. Increasing reports also highlight that the abnormal activation of endosomal TLR7 is implicated in various immune-related diseases, carcinogenesis as well as the proliferation of human immunodeficiency virus (HIV). Hence, the design and development of potent and selective TLR7 antagonists based on small molecules or oligonucleotides may offer new tools for the prevention and management of such diseases. In this review, we offer an updated overview of the main structural features and therapeutic potential of small-molecule antagonists of TLR7. Various heterocyclic scaffolds targeting TLR7 binding sites are presented: pyrazoloquinoxaline, quinazoline, purine, imidazopyridine, pyridone, benzanilide, pyrazolopyrimidine/pyridine, benzoxazole, indazole, indole, and quinoline. Additionally, their structure-activity relationships (SAR) studies associated with biological activities and protein binding modes are introduced. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an immune-mediated disorder triggered by dietary gluten intake in some genetically predisposed individuals; however, the additional non-HLA-related genetic factors implicated in CD immunopathogenesis are not well-defined. The role of the innate immune system in autoimmunity has emerged in the last few years. Genetic polymorphisms of some pattern-recognition receptors, including toll-like receptors (TLRs), have been associated with several autoimmune disorders. In this review, we summarize and discuss the evidence from basic research and clinical studies as regards the potential role of TLRs in CD immunopathogenesis. The evidence supporting the role of TLRs in CD immunopathogenesis is limited, especially in terms of basic research. However, differences in the expression and activation of TLRs between active CD patients from one side, and controls and treated CD patients from the other side, have been described in some clinical studies. Therefore, TLRs may be part of those non-HLA-related genetic factors implicated in CD etiopathogenesis, considering their potential role in the interaction between the host immune system and some environmental factors (including viral infections and gut microbiota), which are included in the list of candidate agents potentially contributing to the determination of CD risk in genetically predisposed individuals exposed to dietary gluten intake. Further basic research and clinical studies focused on TLRs in the context of CD and other gluten-related disorders are needed. [ABSTRACT FROM AUTHOR]

Early innate viral recognition by the host is critical for the rapid response and subsequent clearance of an infection. Innate immune cells patrol sites of infection to detect and respond to invading microorganisms including viruses. Surface Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) that can be activated by viruses even before the host cell becomes infected. However, the early activation of surface TLRs by viruses can lead to viral clearance by the host or promote pathogenesis. Thus, a plethora of research has attempted to identify specific viral ligands that bind to surface TLRs and mediate progression of viral infection. Herein, we will discuss the past two decades of research that have identified specific viral proteins recognized by cell surface-associated TLRs, how these viral proteins and host surface TLR interactions affect the host inflammatory response and outcome of infection, and address why controversy remains regarding host surface TLR recognition of viral proteins. [ABSTRACT FROM AUTHOR]

Summary: Heterodimeric complexes incorporating the lipase‐like proteins EDS1 with PAD4 or SAG101 are central hubs in plant innate immunity. EDS1 functions encompass signal relay from TIR domain‐containing intracellular NLR‐type immune receptors (TNLs) towards RPW8‐type helper NLRs (RNLs) and, in Arabidopsis thaliana, bolstering of signaling and resistance mediated by cell‐surface pattern recognition receptors (PRRs). Increasing evidence points to the activation of EDS1 complexes by small molecule binding.We used CRISPR/Cas‐generated mutant lines and agroinfiltration‐based complementation assays to interrogate functions of EDS1 complexes in Nicotiana benthamiana.We did not detect impaired PRR signaling in N. benthamiana lines deficient in EDS1 complexes or RNLs. Intriguingly, in assays monitoring functions of SlEDS1‐NbEDS1 complexes in N. benthamiana, mutations within the SlEDS1 catalytic triad could abolish or enhance TNL immunity. Furthermore, nuclear EDS1 accumulation was sufficient for N. benthamiana TNL (Roq1) immunity.Reinforcing PRR signaling in Arabidopsis might be a derived function of the TNL/EDS1 immune sector. Although Solanaceae EDS1 functionally depends on catalytic triad residues in some contexts, our data do not support binding of a TNL‐derived small molecule in the triad environment. Whether and how nuclear EDS1 activity connects to membrane pore‐forming RNLs remains unknown. [ABSTRACT FROM AUTHOR]

Infections caused by human respiratory syncytial virus (RSV) are associated with substantial rates of morbidity and mortality. Treatment options are limited, and there is urgent need for the development of efficient antivirals. Pattern recognition receptors such as the cytoplasmic helicase retinoic acid–inducible gene (RIG) I can be activated by viral nucleic acids, leading to activation of interferon-stimulated genes and generation of an "antiviral state." In the current study, we activated RIG-I with synthetic RNA agonists (3pRNA) to induce resistance to RSV infection in vitro and in vivo. In vitro, pretreatment of human, mouse, and ferret airway cell lines with RIG-I agonist before RSV exposure inhibited virus infection and replication. Moreover, a single intravenous injection of 3pRNA 1 day before RSV infection resulted in potent inhibition of virus replication in the lungs of mice and ferrets, but not in nasal tissues. These studies provide evidence that RIG-I agonists represent a promising antiviral drug for RSV prophylaxis. [ABSTRACT FROM AUTHOR]

Because invertebrates lack acquired immunity, they rely primarily on the innate immune system to defend themselves against viral and bacterial infections. SVWC, also called Vago, is a class of small-molecule proteins characterized by a single von Willebrand factor C-domain and appears to be restricted to arthropods. It has been reported that SVWC is involved in antiviral immunity in invertebrates, but whether it is involved in antimicrobial immunity and the mechanism of its involvement in antimicrobial immunity remains unclear. In this study, we identified a novel SVWC gene in Eriocheir sinensis and named it EsSVWC. EsSVWC was found to respond positively to bacterial stimulation and to regulate the expression of related antimicrobial peptides (AMPs). The EsSVWC protein recognized and bound to a variety of pathogen-associated molecular patterns (PAMPs) but did not exhibit direct bactericidal effects. Thus, the EsSVWC protein in crabs helps resist bacterial infection and improve survival rates. In summary, EsSVWC may regulate the innate immune system of crabs in response to microbial invasion in an indirect manner. • We identified and characterized a new SVWC gene, EsSVWC , in Eriocheir sinensis. • EsSVWC regulates antimicrobial peptide expression in response to bacterial stress. • EsSVWC binds to bacteria by recognizing pathogen-associated molecular patterns. • EsSVWC does not have a direct bactericidal or bacterial growth inhibitory effect. • EsSVWC is indirectly involved in the innate antibacterial response in E. sinensis. [ABSTRACT FROM AUTHOR]

Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of double-stranded RNA (dsRNA) that activates anti-infective innate immunity. The underlying mechanisms are identified as targeting pattern recognition receptors and Th1-inducing. However, whether poly I:C manipulates metabolism to implement this anti-infective function is unknown. Here, GC-MS based metabolomics was used to characterize metabolic profiles induced by different doses of poly I:C. Analysis on the dose-dependent metabolomes shows that elevation of the TCA cycle and malate with the increasing dose of ploy I:C forms the most characteristic feature of the poly I:C stimulation. Exogenous malate activates the TCA cycle and elevates survival of zebrafish infected with Vibrio alginolyticus , which is related to the elevated expression of il-1b, il-6, il-8, tnf-a , and c3b. These results reveal a previously unknown regulation of poly I:C that boosts the TCA cycle to enhance innate immunity against bacterial infection. • Metabolic profiles induced by different doses of poly I:C. was characterized. • Elevated TCA cycle and malate forms the most characteristic feature. • Malate boosts TCA cycle and elevates zebrafish survival post bacterial infection. • This is related to the elevated expression of il-1b, il-6, il-8, tnf-a , and c3b. • These reveal a metabolic modulation of poly I:C against bacterial infection. [ABSTRACT FROM AUTHOR]

We postulated that mobilization, homing, and engraftment of hematopoietic stem/progenitor cells (HSCPs) is facilitated by a state of sterile inflammation induced in bone marrow (BM) after administration of pro-mobilizing drugs or in response to pre-transplant myeloablative conditioning. An important role in this phenomenon plays purinergic signaling that by the release of extracellular adenosine triphosphate (eATP) activates in HSPCs and in cells in the hematopoietic microenvironment an intracellular pattern recognition receptor (PPR) known as Nlrp3 inflammasome. We reported recently that its deficiency results in defective trafficking of HSPCs. Moreover, it is known that eATP after release into extracellular space is processed by cell surface expressed ectonucleotidases CD39 and CD73 to extracellular adenosine (eAdo) that in contrast to eATP shows an anti-inflammatory effect. Based on data that the state of sterile inflammation promotes trafficking of HSPCs, and since eAdo is endowed with anti-inflammatory properties we become interested in how eAdo will affect the mobilization, homing, and engraftment of HSPCs and which of eAdo receptors are involved in these processes. As expected, eAdo impaired HSPCs trafficking and this occurred in autocrine- and paracrine-dependent manner by direct stimulation of these cells or by affecting cells in the BM microenvironment. We report herein for the first time that this defect is mediated by activation of the A2B receptor and a specific inhibitor of this receptor improves eAdo-aggravated trafficking of HSPCs. To explain this at the molecular level eAdo-A2B receptor interaction upregulates in HSPCs in NF-kB-, NRF2- and cAMP-dependent manner heme oxygenase-1 (HO-1), that is Nlrp3 inflammasome inhibitor. This corroborated with our analysis of proteomics signature in murine HSPCs exposed to eAdo that revealed that A2B inhibition promotes cell migration and proliferation. Based on this we postulate that blockage of A2B receptor may accelerate the mobilization of HSPCs as well as their hematopoietic reconstitution and this approach could be potentially considered in the future to be tested in the clinic. [ABSTRACT FROM AUTHOR]

Ficolins, belonging to the fibrinogen-related protein superfamily, are important pattern recognition receptors in innate immunity. Here, a ficolin gene Ptficolin was characterized from the swimming crab Portunus trituberculatus. The completed cDNA sequence of Ptficolin encoded a signal peptide, a coiled-coil region and a fibrinogen-like domain but without the typical collagen region of vertebrate ficolins. Ptficolin showed higher expression in stomach and hepatopancreas, and presented a time-dependent response after pathogen challenge and injury stimulation. The recombinant Ptficolin (rPtficolin) could bind to various PAMPs and microorganisms, and agglutinate microorganisms and rabbit erythrocytes in a Ca2+-dependent manner, with strong binding ability to N -acetyl sugars. Meanwhile, rPtficolin promoted the hemocyte phagocytosis and clearance activity of Vibrio , while Ptficolin knockdown impaired the bacterial phagocytosis and clearance ability, suggesting the opsonin activity of Ptficolin. Knockdown of Ptficolin could downregulate the transcription of most complement-like genes and AMPs, but enhance the expression of most proPO system-related genes and key genes of Toll, IMD and JNK pathways. Moreover, knockdown of Ptficolin led to the increased hemolymph clotting time and the decreased expression of clotting-related genes. Our results indicate that Ptficolin could recognize and eliminate invading pathogens, and might be a prominent component in hemolymph coagulation of crab. • Ptficolin was a novel ficolin isolated from Portunus trituberculatus. • Ptficolin exhibited strong binding, agglutinating and antibacterial activity. • Ptficolin showed opsonic activity that promote phagocytosis and bacterial clearance. • Knockdown of Ptficolin downregulated the expression of complement-like genes, AMPs and clotting-related genes. • Ptficolin might be a prominent component in hemolymph coagulation of crab. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat (LRR)-only proteins have been proved to be involved in the innate immune responses as they could mediate protein-protein or protein-ligand interactions. In the present study, a novel LRR-only protein (Lv LRRop-1) was identified and characterized from Pacific white shrimp Litopenaeus vannamei. The complete cDNA sequence of Lv LRRop-1 contains an open reading frame (ORF) of 1488 bp, which encoded a polypeptide of 495 amino acids with a predicted molecular mass of 55.67 kDa and a calculated theoretical isoelectric point of 6.435. There are five LRR motifs, six LRR_TYP motifs in the protein sequence of Lv LRRop-1 with consensus signature sequences of LxxLxxLxLxxNxL. The Lv LRRop-1 mRNA transcripts could be detected in all the tested tissues, including eyestalk, gill, gonad, heart, hemocytes, hepatopancreas, intestine, muscle, nerve and stomach, especially highest in hemocytes and hepatopancreas. The mRNA transcripts of Lv LRRop-1 increased within the first 6 h in hemocytes and hepatopancreas after Vibrio parahaemolyticus or white spot syndrome virus (WSSV) challenges. The recombinant Lv LRRop-1 could bind four typical pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS), peptidoglycan (PGN), glucan (GLU) and polycytidine-polycytidylic acid (poly IC), in a dose-dependent manner, and inhibit the growth of bacteria Micrococcus luteu s. These data indicated that Lv LRRop-1 could play a pivotal role in the innate immune response of shrimps as a kind of pattern recognition receptor (PRR). • Molecular characterization of a novel LRR-only protein in Litopenaeus vannamei • Its expression profiles and pattern recognition ligands spectrum were investigated • It could inhibit the growth of bacteria Micrococcus luteu s [ABSTRACT FROM AUTHOR]

Lectins are important pattern recognition receptors (PRRs) and their immunological action is related to the recognition of glycans present in the pathogen cells surface. The lectins described for Litopenaeus vannamei are divided into C-type, L-type and galectin, which are mainly expressed in hepatopancreas and hemocytes. They are involved in several immune response pathways, such as phagocytosis, hemocytes recruitment, prophenoloxidase activation, and gene regulation. Although lectins have multiple immune functions, most experimental challenges focus only on WSSV and Vibrio sp. This article is a detailed review on the role of lectins in L. vannamei immune system, bringing together information on molecular structure, temporal and special expression and immune function, highlighting the wide participation of these molecules in shrimp innate immune system. • All known Litopenaeus vannamei lectins can be classified into three categories. • L. vannamei lectins are mainly expressed in hepatopancreas, gills and hemolymph. • Many L. vannamei lectins are upregulated after pathogen challenges. • L. vannamei lectins are involved in several immune pathways. • L. vannamei lectins are involved in response against bacteria and viruses. [ABSTRACT FROM AUTHOR]

Otitis media (OM) is the most common disease among young children and one of the most frequent reasons to visit the pediatrician. Development of OM requires nasopharyngeal colonization by a pathogen which must gain access to the tympanic cavity through the eustachian tube (ET) along with being able to overcome the defense mechanisms of the immune system and middle ear mucosa. OM can be caused by viral or bacterial infection. The three main bacterial pathogens are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis. Innate immunity is important in OM resolution as the disease occurs in very young children before the development of specific immunity. Elements of innate immunity include natural barriers and pattern recognition receptors such as Toll like receptors (TLRs), and Nod like receptors (NLRs). Surfactant proteins A (SP-A) and D (SP-D) act as pattern recognition receptors and are found in the lung and many other tissues including the ET and the middle ear where they probably function in host defense. Surfactant has a potential for use in the treatment of OM due to surface tension lowering function in the ET, and the possible immune functions of SP-D and SP-A in the middle ear and ET. [ABSTRACT FROM AUTHOR]

The LGP2 (Laboratory of Genetics and Physiology 2) protein is a member of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLRs) family, which is a class of antiviral pattern recognition receptors located in the cytoplasm. However, few studies have investigated the function of LGP2 in invertebrates. In this study, the complete coding sequence of the LGP2 gene of the Pacific oyster , Crassostrea gigas, was obtained and named CgLGP2-like. Sequence analysis revealed that CgLGP2-like encodes 803 amino acids, and the encoded protein contains a DEXDc, HELICc, and C-terminal regulatory domains. Multiple sequence alignment demonstrated that the sequences of these key protein functional domains were relatively conserved. Phylogenetic analysis revealed that CgLGP2-like was a new member of the animal LGP2 family. Quantitative real-time PCR results showed that CgLGP2-like mRNA was expressed in all tested oyster tissues, with the highest expression observed in the labial palpus and digestive glands. CgLGP2-like expression in gill tissues was significantly induced after the poly(I:C) challenge. Furthermore, multiple IRF and NF-κB binding sites were identified in the CgLGP2-like promoter region, which may be one of the reasons why CgLGP2-like responds to poly(I:C) stimulation. Finally, the results of dual-luciferase reporter gene assays revealed that overexpression of CgLGP2-like may have a regulatory effect on the human IFN , AP-1 , and oyster CgIL-17 genes in HEK293T cells. Overall, our results preliminarily elucidate the immune functions of invertebrate LGP2 protein and provide valuable information for the development of comparative immunology. • CgLGP2-like was identified and characterized in the Pacific oyster. • CgLGP2-like expression was induced by poly(I:C) challenge. • CgLGP2-like may have a regulatory effect on the human IFN , AP-1 , and oyster CgIL-17 genes. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) and M-ficolin are the pattern recognition proteins of the innate immune system. In this report, a mixture of CRP and M-ficolin reversibly co-aggregated in a calcium-dependent manner. This coaggregation was enhanced at low pH (6.5) or low salt (35 mM NaCl) concentrations. The co-aggregate was dissolved by adding EDTA and reformed by adding calcium. The M-ficolin fibrinogen-like domain (FD1), the ligand-binding domain of M-ficolin, also showed calcium-dependent coaggregation with CRP, indicating that reversible coaggregation is caused by CRP interacting with FD1. Interestingly, adding phosphocholine (PC), the ligand of CRP, to a CRP-FD1 mixture abolished the reversible coaggregation activity. PC also inhibited the interaction between CRP and FD1. These results indicate that CRP retains PC-binding activity in the coaggregation state and that FD1 binds specifically to the PC-binding site on CRP but does not fully occupy the five PC-binding sites on a CRP pentamer as judged by SDS-PAGE analysis of precipitates. Coaggregation analysis using FD1 mutants showed that FD1 also retains ligand-binding activity in the coaggregation state and that coaggregation requires the trimeric form of FD1. It was also found that modifications to the ligand-binding site of FD1 affect coaggregation efficiency. Although the biological functions of the coaggregation activity of CRP and M-ficolin remain unresolved, the co-aggregates may function as bacteria-trapping particles with affinities for ligands of CRP and M-ficolin. In addition, coaggregation may be involved in CRP deposition in the lesions of several arterial diseases, such as atherosclerosis. • CRP and M-ficolin co-aggregate depending on calcium. • Reduced pH or salt-concentration enhances the coaggregation activity. • Both proteins retain their ligand-binding activity in co-aggregates. • Co-aggregates may act as bacteria-trapping particles under acidosis conditions. • Coaggregation may be involved in CRP deposition in the lesions of atherosclerosis. [ABSTRACT FROM AUTHOR]

Innate immunity is the first line of defense against invading pathogens. Innate immune cells can recognize invading pathogens through recognizing pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). The recognition of PAMPs by PRRs triggers immune defense mechanisms and the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. However, sustained and overwhelming activation of immune system may disrupt immune homeostasis and contribute to inflammatory disorders. Immunomodulators targeting PRRs may be beneficial to treat infectious diseases and their associated complications. However, therapeutic performances of immunomodulators can be negatively affected by (1) high immune-mediated toxicity, (2) poor solubility and (3) bioactivity loss after long circulation. Recently, nanocarriers have emerged as a very promising tool to overcome these obstacles owning to their unique properties such as sustained circulation, desired bio-distribution, and preferred pharmacokinetic and pharmacodynamic profiles. In this review, we aim to provide an up-to-date overview on the strategies and applications of nanocarrier-assisted innate immune modulation for the management of infections and their associated complications. We first summarize examples of important innate immune modulators. The types of nanomaterials available for drug delivery, as well as their applications for the delivery of immunomodulatory drugs and vaccine adjuvants are also discussed. [ABSTRACT FROM AUTHOR]

The environmental conditions and isolation in the Antarctic have driven the evolution of a unique biodiversity at a macro to microorganism scale. Here, we investigated the possible adaptation of the teleost Nototheniacoriiceps immune system to the cold environment and unique microbial community of the Southern Ocean. The fish immune system was stimulated through an intraperitoneal injection of lipopolysaccharide (LPS 0111:B4 from E. coli) and the tissue transcriptomic response and plasma biochemistry were analyzed 7 days later and compared to a sham injected control. Gene transcription in the head-kidney, intestine and skin was significantly modified by LPS, although tissues showed different responsiveness, with the duodenum most modified and the skin the least modified. The most modified processes in head-kidney, duodenum and skin were related to cell metabolism (up-regulated) and the immune system (comprising 30% of differentially expressed genes). The immune processes identified were mostly down-regulated, particularly interleukins and pattern recognition receptors (PRRs), nucleotide-binding oligomerization domain-like receptors and mannose receptors, unlike the toll-like receptors response commonly described in other teleost fish. The modified transcriptional response was not mirrored by a modified systemic response, as the circulating levels of enzymes of innate immunity, lysozyme and antiproteases, were not significantly different from the untreated and sham control fish. In conclusion, while the N.coriiceps immune system shares many features with other teleosts there are also some specificities. Further studies should better characterize the PRRs and their role in Antarctic teleosts, as well as the importance of the LPS source and its consequences for immune activation in teleosts. [ABSTRACT FROM AUTHOR]

C-type lectins (CTLs) are glycan-binding pattern recognition receptors (PRRs) that can bind to carbohydrates on pathogen surfaces, triggering immune responses in shrimp innate immunity. In this study, a unique Ca2+-inhibited CTL named Fc Lec was identified and characterized in Chinese shrimp Fenneropenaeus chinensis. The full-length cDNA sequence of Fc Lec was 976 bp (GenBank accession number KU361826), with a 615 bp open reading frame (ORF) encoding 204 amino acids. Fc Lec possesses a C-type lectin-like domain (CTLD) containing four conserved cysteines (Cys105, Cys174, Cys192, and Cys200) and two sugar-binding site structures (QPD and LNP). The tertiary structure of Fc Lec deduced revealed three α-helices and eight β-pleated sheets. The mRNA expression levels of Fc Lec in hemocytes and the hepatopancreas were markedly elevated after stimulation with Vibrio anguillarum and white spot syndrome virus (WSSV). The recombinant Fc Lec protein exhibited Ca2+-independent hemagglutination and bacterial agglutination, but these activities were observed only in the presence of EDTA to chelate metal ions. These findings suggest that Fc Lec plays important and functionally distinct roles in the shrimp's innate immune response to bacteria and viruses, enriching the current understanding of the relationship between CTL activity and Ca2+ in invertebrates. [Display omitted] • A novel CTL, Fc Lec, were identified from F. chinensis. • Fc Lec plays distinct and significant roles in the innate immune system's reaction to microbial assaults. • Fc Lec exhibits Ca2+-independent and even Ca2+-inhibited activity. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a unique breast cancer subtype characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Since TNBC lacks ER, PR, and HER2, there are currently no drugs that specifically target TNBC. Therefore, the development of new drugs or effective treatment strategies to target TNBC has become an urgent clinical need. Research has shown that the application of histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors leads to genomic and epigenomic instability. This, in turn, triggers the activation of pattern recognition receptors (PRRs) and subsequently activates downstream interferon (IFN) signalling pathways. In this study, the bifunctional HDAC and DNMT inhibitor J208 exhibited antitumour activity in TNBC cell lines. J208 effectively induced apoptosis and cell cycle arrest at the G0/G1 phase, inhibiting cell migration and invasion in TNBC. Moreover, this bifunctional inhibitor induced the expression of endogenous retroviruses (ERVs) and elicited a viral mimicry response, which increased the intracellular levels of double-stranded RNA (dsRNA) to activate the innate immune signalling pathway in TNBC. In summary, we demonstrated that the bifunctional inhibitor J208, which is designed to inhibit HDAC and DNMT, has potent anticancer effects, providing a new research basis for reactivating antitumour immunity by triggering innate immune signalling and offering a promising strategy for TNBC treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

The innate and adaptive immune systems are the two key branches that determine host protection at all mucosal surfaces in human body, including the female reproductive tract. The pattern recognition receptors within the host that recognize pathogen-associated molecular patterns are expressed on the cells of the innate immune system. Rapidly reactive, theinnate immune system, responds immediately to the presence of infectious or other non-self agents, thereby launching an inflammatory response to protect the host until the activation of slower adaptive immune system. Macrophages, dendritic cells, and toll-like receptors are integral components of the innate immune system. In contrast, T-helper (Th1/Th2/Th17) cells and regulatory T (Treg) cells are the primary components of adaptive immune system. Studies showed that the growth and progression of endometriosis continue even in unilateral ovariectomized animal suggesting that besides ovarian steroid hormones, the growth of endometriosis could be regulated by innate/adaptive immune systems in pelvic environment. Recent reports demonstrated a potential role of Th1/Th2/Th17/Treg cells either individually or collectively in the initiation, maintenance, and progression of endometriosis. Herewe review the fundamental knowledge of innate and adaptive immunity and elaborate the role of innate and adaptive immunity in endometriosis based on both human and experimental data. • Endometriosis is a multifactorial condition with multiple theories of pathogenesis. • The LPS/TLR4/NF-κB cascade may be involved in promoting the growth of endometriosis. • A competition between Tregs and effector immune cells in pelvis may determine the fate of lesions. • Manipulation of Tregs to suppress Th17 cells could be the therapeutic target. [ABSTRACT FROM AUTHOR]

In China, Procambarus clarkii has grown to be one of the most important cultivated crustacean species due to its excellent resistance ability against viral and bacterial infection. However, this broad-spectrum mechanism of disease resistance is less well known. In this study, a new LGBP known as Pc LGBP was cloned and described. Its full-length cDNA is 1200 bp with an open reading frame (ORF) of 1086 bp, encoding a 361 amino acid polypeptide. The transcripts of Pc LGBP were widely dispersed in P. clarkii tissues, with particularly elevated expression levels in hemocytes. Furthermore, Aeromonas hydrophila and white spot syndrome virus (WSSV) challenge dramatically increased its mRNA expression in hemocytes and gills. The purified recombinant Pc LGBP protein could bind to different kinds of pathogenic microorganisms, demonstrating a broad-spectrum pathogen recognition ability. Besides, Pc LGBP knockdown by RNA interference and r Pc LGBP injection experiments confirmed that the protein could apparently accelerate the bacterial clearance and inhibit the WSSV proliferation in vivo , thus increase the survival rate of A. hydrophila or WSSV infected P. clarkii. Further studies revealed that silencing of Pc LGBP resulted in inactivation of prophenoloxidase (proPO) system, decreased the expression levels of Toll/IMD pathway components, as well as some antimicrobial peptides (AMPs). Taken together, Pc LGBP may protect P. clarkii from diverse invading pathogens through activating the proPO system, NF-κB pathway and the expression of AMPs. These findings would contribute to the exploration of the crustacean immunity regulatory mechanisms and hold potential for the disease resistance breeding of P. clarkii. • A novel member of LGBP family named Pc LGBP was identified in Procambarus clarkii. • Pc LGBP was involved in both anti-bacterial and anti-viral immune response. • Pc LGBP exhibited broad-spectrum resistance ability in vivo. • Pc LGBP participate in the activation of the proPO system and NF-κB pathway. [ABSTRACT FROM AUTHOR]

The signal transducer and activator of transcription 2 (STAT2), a downstream factor of type I interferons (IFNs), is a key component of the cellular antiviral immunity response. However, the role of STAT2 in the upstream of IFN signaling, such as the regulation of pattern recognition receptors (PRRs), remains unknown. In this study, STAT2 homologue of black carp (Mylopharyngodon piceus) has been cloned and characterized. The open reading frame (ORF) of bcSTAT2 comprises 2523 nucleotides and encodes 841 amino acids, which presents the conserved structure to that of mammalian STAT2. The dual-luciferase reporter assay and the plaque assay showed that bcSTAT2 possessed certain IFN-inducing ability and antiviral ability against both spring viremia of carp virus (SVCV) and grass carp reovirus (GCRV). Interestingly, we detected the association between bcSTAT2 and bcRIG-I through co-immunoprecipitation (co-IP) assay. Moreover, when bcSTAT2 was co-expressed with bcRIG-I, bcSTAT2 obviously suppressed bcRIG-I-induced IFN expression and antiviral activity. The subsequent co-IP assay and immunoblotting (IB) assay further demonstrated that bcSTAT2 inhibited K63-linked polyubiquitination but not K48-linked polyubiquitination of bcRIG-I, however, did not affect the oligomerization of bcRIG-I. Thus, our data conclude that black carp STAT2 negatively regulates RIG-I through attenuates its K63-linked ubiquitination, which sheds a new light on the regulation of the antiviral innate immunity cascade in vertebrates. • bcSTAT2 possesses certain IFN-inducing ability and antiviral ability. • bcSTAT2 obviously inhibits bcRIG-I-induced IFN expression and antiviral activity. • bcSTAT2 restrains K63-linked polyubiquitination but not K48-linked polyubiquitination of bcRIG-I. [ABSTRACT FROM AUTHOR]

Diseases caused by pathogens contribute to molecular adaptations in host immunity. Variety of viral pathogens challenging animal immunity can drive positive selection diversifying receptors recognising the infections. However, whether distinct virus sensing systems differ across animals in their evolutionary modes remains unclear. Our review provides a comparative overview of natural selection shaping molecular evolution in vertebrate viral-binding pattern recognition receptors (PRRs). Despite prevailing negative selection arising from the functional constraints, multiple lines of evidence now suggest diversifying selection in the Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs) and oligoadenylate synthetases (OASs). In several cases, location of the positively selected sites in the ligand-binding regions suggests effects on viral detection although experimental support is lacking. Unfortunately, in most other PRR families including the AIM2-like receptor family, C-type lectin receptors (CLRs), and cyclic GMP-AMP synthetase studies characterising their molecular evolution are rare, preventing comparative insight. We indicate shared characteristics of the viral sensor evolution and highlight priorities for future research. • We review natural selection acting on vertebrate receptors recognising viruses. • Positive selection targets both ligand-binding and signalling domains. • Receptors binding viral nucleic acids show less positive selection than others. • To majority of receptor genes we have limited information on molecular evolution. • Molecular adaptations clarify evolution of diversity in animal immunity. [ABSTRACT FROM AUTHOR]