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The soluble urokinase plasminogen activator receptor (suPAR) has been implicated in a wide range of pathological conditions including primary nephrotic syndromes and acute kidney injuries. suPAR can trigger transduction cascades in podocytes by outside-in activation of αVβ3-integrin, but there is evidence that the functional cell surface response element is actually a complex of different types of receptors, which may also include the receptor for advanced glycation end-products (RAGE) and formyl peptide receptors (FPRs). Here we observed that ROS accumulation and Src activation could be evoked by continuous 24 h exposure to either suPAR or the FPR agonist fMLF. Responses to suPAR and fMLF were completely blocked by either the FPR antagonist WRW4 or by the αV-integrin inhibitor cilengitide. Moreover, endogenous podocyte mouse Fpr1 co-immunoprecipitates with β3-integrin, suggesting that these receptors occur as a complex on the cell surface. suPAR- and fMLF-evoked activation of Src and ROS differed in time course. Thus, robust pertussis toxin (PTX)-sensitive responses were evoked by 60 min exposures to fMLF but not to suPAR. By contrast, responses to 24 h exposures to either suPAR or fMLF were PTX-resistant and were instead abolished by knockdown of β-arrestin-1 (BAR1). FPRs, integrins, and RAGE (along with various Toll-like receptors) can all function as pattern-recognition receptors that respond to "danger signals" associated with infections and tissue injury. The fact that podocytes express such a wide array of pattern-recognition receptors suggests that the glomerular filter is designed to change its function under certain conditions, possibly to facilitate clearance of toxic macromolecules. [ABSTRACT FROM AUTHOR]

In the process of long‑term adaptation to environment, plants have evolved a large number of cell surface and intracellular immune receptors to sense various biological and abiotic stimuli, and then trigger receptor‑dependent immune responses. Cell surface Pattern‑ Recognition Receptor(PRR)is able to recognize pathogenic microbial model molecules and activate basic immunity, thereby enabling plants to acquire corresponding tolerance. At present, with the help of efficient research methods, researchers have made some progress in PRR‑mediated plant disease resistance and environmental stress tolerance. Here, we reviewed the recent achievements of plant PRR on types and structures, ligand recognition and binding mechanisms, characteristics and mechanism of innate immunity mediated by PRRs, and identification of novel PRRs. Meanwhile, this review also focused on PRR‑mediated salt resistance. The results will help us further understand the immune basis of plant‑environment interaction, and will provide theoretical basis and guidance for the use of genetic engineering to cultivate excellent disease resistant and stress resistant plant varieties [ABSTRACT FROM AUTHOR]

Plants rely on innate immune systems to defend against a wide variety of biotic attackers. Key components of innate immunity include cell-surface pattern-recognition receptors (PRRs), which recognize pest- and pathogen-associated molecular patterns (PAMPs). Unlike other classes of receptors that often have visible cell-death immune outputs upon activation, PRRs generally lack rapid methods for assessing function. Here, we describe a genetically encoded bioluminescent reporter of immune activation by heterologously expressed PRRs in the model organism Nicotiana benthamiana. We characterized N. benthamiana transcriptome changes in response to Agrobacterium tumefaciens and subsequent PAMP treatment to identify pattern-triggered immunity (PTI)-associated marker genes, which were then used to generate promoter-luciferase fusion fungal bioluminescence pathway (FBP) constructs. A reporter construct termed pFBP_2xNbLYS1::LUZ allows for robust detection of PTI activation by heterologously expressed PRRs. Consistent with known PTI signaling pathways, reporter activation by receptor-like protein (RLP) PRRs is dependent on the known adaptor of RLP PRRs, i.e., SOBIR1. The FBP reporter minimizes the amount of labor, reagents, and time needed to assay function of PRRs and displays robust sensitivity at biologically relevant PAMP concentrations, making it ideal for high throughput screens. The tools described in this paper will be powerful for investigations of PRR function and characterization of the structure-function of plant cell-surface receptors. [Graphic: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2023.

Surgery or radiation therapy is nearly universally applied for pediatric solid tumors. In many cases, in diverse tumor types, distant metastatic disease is present and evades surgery or radiation. The systemic host response to these local control modalities may lead to a suppression of antitumor immunity, with potential negative impact on the clinical outcomes for patients in this scenario. Emerging evidence suggests that the perioperative immune responses to surgery or radiation can be modulated therapeutically to preserve anti-tumor immunity, with the added benefit of preventing these local control approaches from serving as pro-tumorigenic stimuli. To realize the potential benefit of therapeutic modulation of the systemic response to surgery or radiation on distant disease that evades these modalities, a detailed knowledge of the tumor-specific immunology as well as the immune responses to surgery and radiation is imperative. In this Review we highlight the current understanding of the tumor immune microenvironment for the most common peripheral pediatric solid tumors, the immune responses to surgery and radiation, and current evidence that supports the potential use of immune activating agents in the perioperative window. Finally, we define existing knowledge gaps that limit the current translational potential of modulating perioperative immunity to achieve effective anti-tumor outcomes. [ABSTRACT FROM AUTHOR]

Surgery or radiation therapy is nearly universally applied for pediatric solid tumors. In many cases, in diverse tumor types, distant metastatic disease is present and evades surgery or radiation. The systemic host response to these local control modalities may lead to a suppression of antitumor immunity, with potential negative impact on the clinical outcomes for patients in this scenario. Emerging evidence suggests that the perioperative immune responses to surgery or radiation can be modulated therapeutically to preserve anti-tumor immunity, with the added benefit of preventing these local control approaches from serving as pro-tumorigenic stimuli. To realize the potential benefit of therapeutic modulation of the systemic response to surgery or radiation on distant disease that evades these modalities, a detailed knowledge of the tumor-specific immunology as well as the immune responses to surgery and radiation is imperative. In this Review we highlight the current understanding of the tumor immune microenvironment for the most common peripheral pediatric solid tumors, the immune responses to surgery and radiation, and current evidence that supports the potential use of immune activating agents in the perioperative window. Finally, we define existing knowledge gaps that limit the current translational potential of modulating perioperative immunity to achieve effective anti-tumor outcomes.

Bystander activation of T cells is defined as induction of effector responses by innate cytokines in the absence of cognate antigens and independent of T cell receptor (TCR) signaling. Here we show that C-reactive protein (CRP), a soluble pattern-recognition receptor assembled noncovalently by five identical subunits, can instead trigger bystander activation of CD4 + T cells by evoking allosteric activation and spontaneous signaling of TCR in the absence of cognate antigens. The actions of CRP depend on pattern ligand-binding induced conformational changes that result in the generation of monomeric CRP (mCRP). mCRP binds cholesterol in plasma membranes of CD4 + T cells, thereby shifting the conformational equilibrium of TCR to the cholesterol-unbound, primed state. The spontaneous signaling of primed TCR leads to productive effector responses manifested by upregulation of surface activation markers and release of IFN-γ. Our results thus identify a novel mode of bystander T cell activation triggered by allosteric TCR signaling, and reveal an interesting paradigm wherein innate immune recognition of CRP transforms it to a direct activator that evokes immediate adaptive immune responses. • A novel mode of bystander activation in CD4+ T cells is identified. • This mode depends on spontaneous signaling of TCR triggered by mCRP. • mCRP acts via binging to membrane cholesterol to shift the conformational equilibrium of TCR. [ABSTRACT FROM AUTHOR]

Humoral immunity plays a defensive role against invading microbes. However, it has been largely overlooked with respect to Aspergillus fumigatus, an airborne fungal pathogen. Previously, we have demonstrated that surfactant protein D (SP-D), a major humoral component in human lung-alveoli, recognizes A. fumigatus conidial surface exposed melanin pigment. Through binding to melanin, SP-D opsonizes conidia, facilitates conidial phagocytosis, and induces the expression of protective pro-inflammatory cytokines in the phagocytic cells. In addition to melanin, SP-D also interacts with galactomannan (GM) and galactosaminogalactan (GAG), the cell wall polysaccharides exposed on germinating conidial surfaces. Therefore, we aimed at unravelling the biological significance of SP-D during the germination process. Here, we demonstrate that SP-D exerts direct fungistatic activity by restricting A. fumigatus hyphal growth. Conidial germination in the presence of SP-D significantly increased the exposure of cell wall polysaccharides chitin, α-1,3-glucan and GAG, and decreased β-1,3-glucan exposure on hyphae, but that of GM was unaltered. Hyphae grown in presence of SP-D showed positive immunolabelling for SP-D. Additionally, SP-D treated hyphae induced lower levels of pro-inflammatory cytokine, but increased IL-10 (anti-inflammatory cytokine) and IL-8 (a chemokine) secretion by human peripheral blood mononuclear cells (PBMCs), compared to control hyphae. Moreover, germ tube surface modifications due to SP-D treatment resulted in an increased hyphal susceptibility to voriconazole, an antifungal drug. It appears that SP-D exerts its anti-A. fumigatus functions via a range of mechanisms including hyphal growth-restriction, hyphal surface modification, masking of hyphal surface polysaccharides and thus altering hyphal immunostimulatory properties.

The innate immune response constitutes the cell's first line of defense against viruses and culminates in the expression of type I interferon (IFN) and IFN-stimulated genes, inducing an antiviral state in infected and neighboring cells. Efficient signal transduction is a key factor for strong but controlled type I IFN expression and depends on the compartmentalization of different steps of the signaling cascade and dynamic events between the involved compartments or organelles. This compartmentalization of the innate immune players not only relies on their association with membranous organelles but also includes the formation of supramolecular organizing centers (SMOCs) and effector concentration by liquid–liquid phase separation. For their successful replication, viruses need to evade innate defenses and evolve a multitude of strategies to impair type I IFN induction, one of which is the disruption of spatial immune signaling dynamics. This review focuses on the role of compartmentalization in ensuring an adequate innate immune response to viral pathogens, drawing attention to crucial translocation events occurring downstream of pattern recognition and leading to the expression of type I IFN. Furthermore, it intends to highlight concise examples of viral countermeasures interfering with this spatial organization to alleviate the innate immune response. [ABSTRACT FROM AUTHOR]

The Arabidopsis PEN3 ABC transporter accumulates at sites of pathogen detection, where it is involved in defense against a number of pathogens. Perception of PAMPs by pattern recognition receptors initiates recruitment of PEN3 and also leads to PEN3 phosphorylation at multiple amino acid residues. Whether PAMP-induced phosphorylation of PEN3 is important for its defense function or focal recruitment has not been addressed. In this study, we evaluated the role of PEN3 phosphorylation in modulating the localization and defense function of the transporter. We report that PEN3 phosphorylation is critical for its function in defense, but dispensable for recruitment to powdery mildew penetration sites. These results indicate that PAMP-induced phosphorylation is likely to regulate the transport activity of PEN3.

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in unprecedented morbidity and mortality worldwide. The host cells use a number of pattern recognition receptors (PRRs) for early detection of coronavirus infection, and timely interferon secretion is highly effective against SARS-CoV-2 infection. However, the virus has developed many strategies to delay interferon secretion and disarm cellular defense by intervening in interferon-associated signaling pathways on multiple levels. As a result, some COVID-19 patients suffered dramatic susceptibility to SARS-CoV-2 infection, while another part of the population showed only mild or no symptoms. One hypothesis suggests that functional differences in innate immune integrity could be the key to such variability. This review tries to decipher possible interactions between SARS-CoV-2 proteins and human antiviral interferon sensors. We found that SARS-CoV-2 actively interacts with PRR sensors and antiviral pathways by avoiding interferon suppression, which could result in severe COVID-19 pathogenesis. Finally, we summarize data on available antiviral pharmaceutical options that have shown potential to reduce COVID-19 morbidity and mortality in recent clinical trials. [ABSTRACT FROM AUTHOR]

Summary: Fusarium wilt caused by the ascomycete fungus Fusarium oxysporum is a devastating disease of many economically important crops. The mechanisms underlying plant responses to F. oxysporum infections remain largely unknown.We demonstrate here that a water‐soluble, heat‐resistant and nonproteinaceous F. oxysporum cell wall extract (FoCWE) component from multiple F. oxysporum isolates functions as a race‐nonspecific elicitor, also termed pathogen‐associated molecular pattern (PAMP). FoCWE triggers several demonstrated immune responses, including mitogen‐activated protein (MAP) kinase phosphorylation, reactive oxygen species (ROS) burst, ethylene production, and stomatal closure, in cotton and Arabidopsis.Pretreated FoCWE protects cotton seeds against infections by virulent F. oxysporum f. sp. vasinfectum (Fov), and Arabidopsis plants against the virulent bacterium, Pseudomonas syringae, suggesting the potential application of FoCWEs in crop protection. Host‐mediated responses to FoCWE do not appear to require LYKs/CERK1, BAK1 or SOBIR1, which are commonly involved in PAMP perception and/or signalling. However, FoCWE responses and Fusarium resistance in cotton partially require two receptor‐like proteins, GhRLP20 and GhRLP31.Transcriptome analysis suggests that FoCWE preferentially activates cell wall‐mediated defence, and Fov has evolved virulence mechanisms to suppress FoCWE‐induced defence. These findings suggest that FoCWE is a classical PAMP that is potentially recognised by a novel pattern‐recognition receptor to regulate cotton resistance to Fusarium infections. [ABSTRACT FROM AUTHOR]

Summary: Fusarium spp. cause severe economic damage in many crops, exemplified by Panama disease of banana or Fusarium head blight of wheat. Plants sense immunogenic patterns (termed elicitors) at the cell surface to initiate pattern‐triggered immunity (PTI). Knowledge of fungal elicitors and corresponding plant immune‐signaling is incomplete but could yield valuable sources of resistance.We characterized Arabidopsis thaliana PTI responses to a peptide elicitor fraction present in several Fusarium spp. and employed a forward‐genetic screen using plants containing a cytosolic calcium reporter to isolate fusarium elicitor reduced elicitation (fere) mutants.We mapped the causal mutation in fere1 to the leucine‐rich repeat receptor‐like kinase MDIS1‐INTERACTING RECEPTOR‐LIKE KINASE 2 (MIK2) and confirmed a crucial role of MIK2 in fungal elicitor perception. MIK2‐dependent elicitor responses depend on known signaling components and transfer of AtMIK2 is sufficient to confer elicitor sensitivity to Nicotiana benthamiana.Arabidopsis senses Fusarium elicitors by a novel receptor complex at the cell surface that feeds into common PTI pathways. These data increase mechanistic understanding of PTI to Fusarium and place MIK2 at a central position in Arabidopsis elicitor responses. [ABSTRACT FROM AUTHOR]

Antigen-presenting cells (APCs) are present throughout the human body—in tissues, at barrier sites and in the circulation. They are critical for processing external signals to instruct both local and systemic responses toward immune tolerance or immune defense. APCs express an extensive repertoire of pattern-recognition receptors (PRRs) to detect and transduce these signals. C-type lectin receptors (CLRs) comprise a subfamily of PRRs dedicated to sensing glycans, including those expressed by commensal and pathogenic bacteria. This review summarizes recent findings on the recognition of and responses to bacteria by membrane-expressed CLRs on different APC subsets, which are discussed according to the primary site of infection. Many CLR-bacterial interactions promote bacterial clearance, whereas other interactions are exploited by bacteria to enhance their pathogenic potential. The discrimination between protective and virulence-enhancing interactions is essential to understand which interactions to target with new prophylactic or treatment strategies. CLRs are also densely concentrated at APC dendrites that sample the environment across intact barrier sites. This suggests an–as yet–underappreciated role for CLR-mediated recognition of microbiota-produced glycans in maintaining tolerance at barrier sites. In addition to providing a concise overview of identified CLR-bacteria interactions, we discuss the main challenges and potential solutions for the identification of new CLR-bacterial interactions, including those with commensal bacteria, and for in-depth structure-function studies on CLR-bacterial glycan interactions. Finally, we highlight the necessity for more relevant tissue-specific in vitro, in vivo and ex vivo models to develop therapeutic applications in this area. [ABSTRACT FROM AUTHOR]

C-type lectins are Ca2+-dependent carbohydrate-binding proteins containing one or more carbohydrate-recognition domains (CRDs). C-type lectins play crucial roles in innate immunity, including nonself-recognition and pathogen elimination. In the present study, two C-type lectins (designated ReCTL-1 and ReCTL-2) were identified from the shrimp Rimicaris exoculata which dwells in deep-sea hydrothermal vents. The open reading frames of ReCTL-1 and ReCTL-2 encoded polypeptides of 171 and 166 amino acids respectively, which were both composed of a signal peptide and a single CRD. The key motifs determining the carbohydrate binding specificity of ReCTL-1 and ReCTL-2 were respectively Glu–Pro–Ala (EPA) and Gln–Pro–Asn (QPN), which were firstly discovered in R. exoculata. ReCTL-1 and ReCTL-2 displayed similar pathogen-associated molecular pattern (PAMP) binding features and they bound three PAMPs—β-glucan, lipopolysaccharide and peptidoglycan—with relatively high affinity. In addition, both could efficiently recognize and bind Gram-positive bacteria, Gram-negative bacteria and fungi. However, ReCTL-1 and ReCTL-2 exhibited different microbial agglutination activities: ReCTL-1 agglutinated Staphylococcus aureus and Saccharomyces cerevisiae , while ReCTL-2 agglutinated Micrococcus luteus , Vibrio parahaemolyticus and V. fluvialis. Both ReCTL-1 and ReCTL-2 inhibited the growth of V. fluvialis. All these results illustrated that ReCTL-1 and ReCTL-2 could function as important pattern-recognition receptors with broad nonself-recognition spectra and be involved in immune defense against invaders, but their specificities are not the same. In addition, the two ReCTLs possessed different carbohydrate binding specificities from each other and from the classical pattern: ReCTL-1 with an EPA motif bound d -galactose and l -mannose, while ReCTL-2 with a QPN motif bound d -fucose and N-acetylglucosamine. • ReCTL-1, -2 could act as PRRs to recognize, bind and eliminate specific pathogens. • ReCTL-1 with EPA motif was identified to bind d -galactose and l -mannose. • ReCTL-2 with QPN motif could specifically bind d -fucose and N-GlcNAc. [ABSTRACT FROM AUTHOR]

Innate immune signaling of plants is initiated by pattern recognition receptors (PRRs) at the plasma membrane. Upon pathogen attack, PRRs recognize pathogen-associated molecular patterns (PAMPs) via ectodomain and lead to signaling cascade via cytoplasmic kinase domain. PAMP-triggered immunity (PTI) activates basal defense responses sufficient to confer broad-spectrum disease resistance by inhibiting pathogen entry and growth. On the other hand, one of the major virulence factors in plant-pathogenic bacteria is type III secretion system, which can deliver effector proteins into the host cell and modulate host cellular processes. Most type III effectors are implicated in PTI suppression, and PRRs have been identified as targets of multiple type III effectors. Mutants defective in T3SS lack pathogenicity in many bacterial species, revealing that T3SS-mediated PTI suppression is critical for host colonization and subsequent disease development. This review summarizes molecular basis of bacterial pathogen perception by plant PRRs and also interaction between PRRs and type III effectors during early stages of plant-pathogen interaction. [ABSTRACT FROM AUTHOR]

The initial defense against invading pathogenic microbes is the activation of innate immunity by binding of pattern recognition receptors (PRRs) to pathogen associated molecular patterns (PAMPs). To explain the action of PRRs from hagfish, one of the extant jawless vertebrates , we purified the GlcNAc recognition complex (GRC) from serum using GlcNAc-agarose. The GRC comprises four proteins of varying molecular masses: 19 kDa, 26 kDa, 27 kDa, and 31 kDa. Exposure of Escherichia coli to the GRC led to the phagocytic activation of macrophages, revealing the opsonic function of the GRC. The GRC in serum formed a large complex with a molecular mass of approximately 1200 kDa. The GRC bound to Escherichia coli but not to rabbit red blood cells, despite both having GlcNAc on their surface. These structural and binding properties are similar to those of mannose-binding lectin (MBL). The amino acid sequence of a portion of the 31 kDa protein in the GRC matched the amino acid sequence of variable lymphocyte receptor (VLR)-B in some place. According to the Western blot analysis, the 31 kDa protein was recognized by the anti-hagfish VLR-B antiserum. Based on the results, it appears that the GRC functions as a PRR like MBL and that its 31 kDa protein has a structure similar to that of VLR-B. • GlcNAc recognition complex (GRC) in hagfish serum acted as an opsonin. • The GRC acted as a pattern recognition receptor. • The 31 kDa protein in the GRC had the similar structure to VLR-B. [ABSTRACT FROM AUTHOR]

Main conclusion: The overexpression of RXam1 leads to a reduction in bacterial growth of XamCIO136, suggesting that RXam1 might be implicated in strain-specific resistance.Cassava bacterial blight (CBB) caused by Xanthomonas axonopodis pv. manihotis (Xam) is a prevalent disease in all regions, where cassava is cultivated. CBB is a foliar and vascular disease usually controlled through host resistance. Previous studies have found QTLs explaining resistance to several Xam strains. Interestingly, one QTL called XM5 that explained 13% of resistance to XamCIO136 was associated with a similar fragment of the rice Xa21-resistance gene called PCR250. In this study, we aimed to further identify and characterize this fragment and its role in resistance to CBB. Screening and hybridization of a BAC library using the molecular marker PCR250 as a probe led to the identification of a receptor-like kinase similar to Xa21 and were called RXam1 (Resistance toXam 1). Here, we report the functional characterization of susceptible cassava plants overexpressing RXam1. Our results indicated that the overexpression of RXam1 leads to a reduction in bacterial growth of XamCIO136. This suggests that RXAM1 might be implicated in strain-specific resistance to XamCIO136. [ABSTRACT FROM AUTHOR]

Detection of pathogens by all living organisms is the primary step needed to implement a coherent and efficient immune response. This implies a mediation by different soluble and/or membrane-anchored proteins related to innate immune receptors called PRRs (pattern-recognition receptors) to trigger immune signaling pathways. In most invertebrates, their roles have been inferred by analogy to those already characterized in vertebrate homologs. Despite the induction of their gene expression upon challenge and the presence of structural domains associated with the detection of pathogen-associated molecular patterns in their sequence, their exact role in the induction of immune response and their binding capacity still remain to be demonstrated. To this purpose, we developed a fast interactome approach, usable on any host–pathogen couple, to identify soluble proteins capable of directly or indirectly detecting the presence of pathogens. To investigate the molecular basis of immune recognition specificity, different pathogens (Gram-positive bacterium, Micrococcus luteus; Gram-negative, Escherichia coli; yeast, Saccharomyces cerevisiae; and metazoan parasites, Echinostoma caproni or Schistosoma mansoni) were exposed to hemocyte-free hemolymph from the gastropod Biomphalaria glabrata. Twenty-three different proteins bound to pathogens were identified and grouped into three different categories based on their primary function. Each pathogen was recognized by a specific but overlapping set of circulating proteins in mollusk’s hemolymph. While known PRRs such as C-type lectins were identified, other proteins not known to be primarily involved in pathogen recognition were found, including actin, tubulin, collagen, and hemoglobin. Confocal microscopy and specific fluorescent labeling revealed that extracellular actin present in snail hemolymph was able to bind to yeasts and induce their clotting, a preliminary step for their elimination by the snail immune system. Aerolysin-like proteins (named biomphalysins) were the only ones involved in the recognition of all the five pathogens tested, suggesting a sentinel role of these horizontally acquired toxins. These findings highlight the diversity and complexity of a highly specific innate immune sensing system. It paves the way for the use of such approach on a wide range of host–pathogen systems to provide new insights into the specificity and diversity of immune recognition by innate immune systems.

Bovine herpesvirus-4 (BoHV-4) and bovine viral diarrhea virus (BVDV) infect the uterus of cattle, often resulting in reduced fertility, or abortion of the fetus, respectively. Here, exposure of primary bovine endometrial cells to BoHV-4 or BVDV modulated the production of inflammatory mediators. Viral pathogen-associated molecular patterns (PAMPs) are detected via pattern-recognition receptors (PRRs). However, the relative contribution of specific PRRs to innate immunity, during viral infection of the uterus, is unclear. Endometrial epithelial and stromal cells constitutively express the PRR Toll-like receptor (TLR)-3, but, the status of retinoic acid-inducible gene I (RIG-I), a sensor of cytosolic nucleic acids, is unknown. Primary endometrial epithelial and stromal cells had low expression of RIG-I, which was increased in stromal cells after 12 h transfection with the TLR3 ligand Poly(I:C), a synthetic analog of double-stranded RNA. Furthermore, short interfering RNA targeting TLR3, or interferon (IFN) regulatory transcription factor 3, an inducer of type I IFN transcription, reduced Poly(I:C)-induced RIG-I protein expression and reduced inflammatory mediator secretion from stromal cells. We conclude that antiviral defense of endometrial stromal cells requires coordinated recognition of PAMPs, initially via TLR3 and later via inducible RIG-I.

Nanotechnology-based strategies can dramatically impact the treatment, prevention and diagnosis of a wide range of diseases. Despite the unprecedented success achieved with the use of nanomaterials to address unmet biomedical needs and their particular suitability for the effective application of a personalized medicine, the clinical translation of those nanoparticulate systems has still been impaired by the limited understanding on their interaction with complex biological systems. As a result, unexpected effects due to unpredicted interactions at biomaterial and biological interfaces have been underlying the biosafety concerns raised by the use of nanomaterials. This review explores the current knowledge on how nanoparticle (NP) physicochemical and surface properties determine their interactions with innate immune cells, with particular attention on the activation of pattern-recognition receptors and inflammasome. A critical perspective will additionally address the impact of biological systems on the effect of NP on immune cell activity at the molecular level. We will discuss how the understanding of the NP-innate immune cell interactions can significantly add into the clinical translation by guiding the design of nanomedicines with particular effect on targeted cells, thus improving their clinical efficacy while minimizing undesired but predictable toxicological effects. [ABSTRACT FROM AUTHOR]

Bovine herpesvirus-4 (BoHV-4) and bovine viral diarrhea virus (BVDV) infect the uterus of cattle, often resulting in reduced fertility, or abortion of the fetus, respectively. Here, exposure of primary bovine endometrial cells to BoHV-4 or BVDV modulated the production of inflammatory mediators. Viral pathogen-associated molecular patterns (PAMPs) are detected via pattern-recognition receptors (PRRs). However, the relative contribution of specific PRRs to innate immunity, during viral infection of the uterus, is unclear. Endometrial epithelial and stromal cells constitutively express the PRR Toll-like receptor (TLR)-3, but, the status of retinoic acid-inducible gene I (RIG-I), a sensor of cytosolic nucleic acids, is unknown. Primary endometrial epithelial and stromal cells had low expression of RIG-I, which was increased in stromal cells after 12 h transfection with the TLR3 ligand Poly(I:C), a synthetic analog of double-stranded RNA. Furthermore, short interfering RNA targeting TLR3, or interferon (IFN) regulatory transcription factor 3, an inducer of type I IFN transcription, reduced Poly(I:C)-induced RIG-I protein expression and reduced inflammatory mediator secretion from stromal cells. We conclude that antiviral defense of endometrial stromal cells requires coordinated recognition of PAMPs, initially via TLR3 and later via inducible RIG-I. [ABSTRACT FROM AUTHOR]

Summary Toll-like receptor 7 (TLR7) is a single-stranded RNA (ssRNA) sensor in innate immunity and also responds to guanosine and chemical ligands, such as imidazoquinoline compounds. However, TLR7 activation mechanism by these ligands remain largely unknown. Here, we generated crystal structures of three TLR7 complexes, and found that all formed an activated m-shaped dimer with two ligand-binding sites. The first site conserved in TLR7 and TLR8 was used for small ligand-binding essential for its activation. The second site spatially distinct from that of TLR8 was used for a ssRNA-binding that enhanced the affinity of the first-site ligands. The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. Our structural, biochemical, and mutagenesis studies indicated that TLR7 is a dual receptor for guanosine and uridine-containing ssRNA. Our findings have important implications for understanding of TLR7 function, as well as for therapeutic manipulation of TLR7 activation. [ABSTRACT FROM AUTHOR]

This study evaluated the effect of yeast-derived products on growth performance, gut lesion score, intestinal population ofClostridium perfringens, and local innate immunity of broiler chickens challenged withC. perfringens. One-day-old broiler chickens were randomly assigned to eight dietary treatments providing six replicate pens of 55 birds each per treatment. Dietary treatments consisted of Control diets without and withC. perfringenschallenge, and diets containing bacitracin methylene disalicylate (BMD, 55 g/tonne), nucleotides (150 g/tonne), yeast cell wall (YCW, 300 g/tonne), and a commercial product Maxi-Gen Plus (1 kg/tonne) fed to chickens challenged withC. perfringens. Diets containing 10% distillers dried grains with solubles without and withC. perfringenschallenge were also used. Birds were orally challenged withC. perfringens(108 colony-forming units (cfu)/bird) on day 14. On day 21, intestinal samples were collected for gene expression analysis. Pathogen challenge significantly (P < 0.05) impaired feed intake, body weight gain, and feed conversion ratio (FCR) shortly after the challenge (14–21 days). IncreasedC. perfringenscounts and intestinal lesion scores were observed for challenged birds except the BMD-containing diet. Over the entire trial (1–35 days), no difference in growth performance was observed except the BMD diet which improved FCR over the Control, challenged group. Birds receiving nucleotides showed increased expression of toll-like receptors and cytokines interleukin (IL)-4 and IL-18 compared to the Control, challenged group. Expression of macrophage mannose receptor and IL-18 was upregulated in birds receiving YCW. Increased expression of cytokines and receptors involved in innate immunity in broilers receiving nucleotides and YCW suggests the immunomodulatory properties of these products under pathogen challenge conditions. [ABSTRACT FROM PUBLISHER]

This study evaluated the effect of yeast-derived products on innate and antibody mediated immune response in broiler chickens following immunization with sheep red blood cells (SRBC) and bovine serum albumin (BSA). One-day-old male broiler chickens (Ross-308) were randomly assigned to 6 dietary treatments of 9 replicate cages of 5 birds each per treatment. Dietary treatments consisted of a Control diet without antibiotic, and diets containing 11 mg/kg of virginiamycin, 0.25% of yeast cell wall (YCW), 0.2% of a commercial product Maxi-Gen Plus containing processed yeast and nucleotides, 0.05% of nucleotides, or a diet containing 10% of DDGS. On days 21 and 28 post-hatching, 5 birds per treatment were immunized intramuscularly with both SRBC and BSA. One week after each immunization, blood samples were collected. Serum samples were analyzed by hemagglutination test for antibody response to SRBC, and by ELISA for serum IgM and IgG response to BSA. On d 35, 5 birds per treatment were euthanized and the tissue samples from the cecal tonsils were collected to assess the gene expression of toll-like receptors TLR2b, TLR4, and TLR21, monocyte mannose receptor (MMR), and cytokines IL-10, IL-13, IL-4, IL-12p35, and IFN-γ. The results for gene expression analysis demonstrated that the diet supplemented with YCW increased the expression of TLR2b and T-helper type 2 cytokines IL-10, IL-4, and IL-13 relative to the Control; and the expression of TLR4 and IL-13 was upregulated in the nucleotidecontaining diet. However, the diets containing antibiotics or Maxi-Gen Plus downregulated the expression of IFN-γ compared to the control. The primary antibody response to SRBC was not affected by diets. However, the diet containing YCW increased the secondary antibody response to SRBC compared to the antibiotic treatment. Neither primary nor secondary IgG and IgM response against BSA were affected by diets. In conclusion, supplementation of the diet with YCW stimulated Th2 cell-mediated immune response indicating the immunomodulatory activities of these products following immunization with non-inflammatory antigens. [ABSTRACT FROM AUTHOR]

C-type lectins (CTLs) play important roles in invertebrate innate immunity by recognizing and eliminating pathogens. In the present study, a low-density lipoprotein receptor class A (LDLa) domain-containing CTL was identified from the oriental river prawn Macrobrachium nipponense , designated as MnCTLDcp1. The full-length cDNA of MnCTLDcp1 was composed of 1462 bp, with a 999-bp ORF encoding a 332-aa protein. An LDLa and a single C-type lectin-like domain (CTLD) were found. The mRNA transcripts of MnCTLDcp1 was expressed the highest in heart. After the prawns were challenged by Aeromonas hydrophila and Staphylococcus aureus , the expression level of MnCTLDcp1 in heart and hemocytes were all significantly up-regulated. Sugar binding assay revealed that the MnCTLDcp1 could bind to the glycoconjugates of bacteria surface, such as LPS, PGN and they can compete with bacterial as competitors. The recombinant MnCTLDcp1 agglutinates Gram-positive ( S. aureus and Bacillus subtilis ) and Gram-negative bacteria ( A. hydrophila , Vibrio parahaemolyticus, Escherichia coli and Pseudomonas aeruginosa ) in the presence of calcium and also could bind to these bacteria. These results clearly suggested that MnCTLDcp1 functions as a pattern-recognition receptor involved in the innate immunity of M. nipponense . [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Tripterygium wilfordii (lei gong teng; Thunder of God Vine), which belongs to the Celastraceae family, has long been used in traditional Chinese medicine to treat inflammation and rheumatoid arthritis. Celastrol is a bioactive compound isolated from T. wilfordii. Aim of the study We investigated whether celastrol suppressed binding of lipopolysaccharides (LPS) to myeloid differentiation factor 2 (MD2), thereby downregulating Toll-like receptor4 (TLR4) activation in mouse primary macrophages. Materials and methods Cytokine expression was determined by polymerase chain reaction analysis and enzyme-linked immunosorbent assay in bone marrow-derived primary macrophages (BMDMs). The kinase activity of tank-binding kinase 1 (TBK1) was examined by a luciferase reporter assay and an in vitro kinase assay. LPS binding to MD2 was examined by an in vitro binding assay and confocal microscopy analysis. Results Celastrol reduced LPS-induced expression of inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12, and IL-1β, at both the mRNA and protein levels in BMDMs. Celastrol suppressed LPS binding to MD2, as shown by the in vitro binding assay, whereas it did not inhibit TBK1. In addition, co-localization of LPS with MD2 in BMDMs was blocked by celastrol. The inhibitory effects of celastrol on LPS binding to MD2 were reversed by thiol donors (N-acetyl- L -cysteine and dithiothreitol), suggesting that the thiol reactivity of celastrol contributes to its inhibitory effects on TLR4 activation in macrophages. Conclusion Our results demonstrate that celastrol suppresses TLR4 activation through the inhibition of LPS binding to the TLR4/MD2 complex. These results provide a novel mechanism of action by which celastrol contributes to the anti-inflammatory activity of T. wilfordii . [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that type I interferon (IFN) mediates the host protective response to RNA viruses. However, the anti-viral effector molecules involved in this response have not been fully identified. Here, we show that zinc-finger anti-viral protein (ZAP), an IFN-inducible gene, plays a critical role in the elimination of Sindbis virus (SINV) in vitro and in vivo. The loss of ZAP greatly enhances the replication of SINV but does not inhibit type I IFN production in primary mouse embryonic fibroblasts (MEFs). ZAP binds and destabilizes SINV RNA, thereby suppressing the replication of SINV. Type I IFN fails to suppress SINV replication in ZAP-deficient MEFs, whereas the ectopic expression of ZAP is sufficient to suppress the replication of SINV in MEFs lacking the expression of type I IFN and the IFN-inducible genes. ZAP-deficient mice are highly susceptible to SINV infection, although they produce sufficient amounts of type I IFN. Therefore, ZAP is an RNAsensing anti-viral effector molecule that mediates the type-I-IFN-dependent host defense against SINV. [ABSTRACT FROM AUTHOR]

Post-transcriptional control determines the fate of cellular RNA molecules. Nonsense-mediated decay (NMD) provides quality control of mRNA, targeting faulty cellular transcripts for degradation by multiple nucleases including the RNA exosome. Recent findings have revealed a role for NMD in targeting viral RNA molecules, thereby restricting virus infection. Interestingly, NMD is also linked to immune responses at another level: mutations affecting the NMD or RNA exosome machineries cause chronic activation of defence programmes, resulting in autoimmune phenotypes. Here we place these observations in the context of other links between innate antiviral immunity and type I interferon mediated disease and examine two models: one in which expression or function of pathogen sensors is perturbed and one wherein host-derived RNA molecules with a propensity to activate such sensors accumulate. [ABSTRACT FROM AUTHOR]

Retinoic acid-inducible gene I ( RIG-I) is a cytosolic pattern-recognition receptor that recognizes viruses and triggers anti-viral immune responses. Activation of intracellular RIG-I signalling is mediated through interferon- β ( IFN- β) promoter stimulator-1 ( IPS-1), an adaptor of RIG-I, which induces IFN regulatory factor ( IRF) 3 activation and type I IFN expression. The phosphatidylinositol-3-kinase ( PI3K) and Akt pathway is activated in host immune cells upon viral infection. However, the mechanism as to how they work in RIG-I signalling has not been fully elucidated. Therefore, we investigated the role of PI3K and Akt in the regulation of RIG-I-mediated IRF3 activation and type I IFN expression in macrophages. Our results show that Sendai virus infection, which is recognized by RIG-I, led to IRF3 activation and IFN- β expression and these responses were attenuated by the PI3K inhibitor ( LY294002) and an Akt dominant-negative mutant in the macrophage cell line( RAW264.7). IRF3 phosphorylation and dimerization as well as IFN- β expression induced by a synthetic RIG-I agonist, short poly(I:C), were suppressed by LY294002 or si RNA-Akt in bone marrow-derived macrophages. Suppression of PI3K and Akt using a dominant-negative mutant and si RNA knockdown resulted in attenuation of IRF3 activation and IFN- β expression induced by RIG-I itself or its adaptor, IPS-1. Association of Akt with IPS-1 increased with short poly(I:C) stimulation and required the pleckstrin homology domain of Akt and caspase-recruitment domain in IPS-1. Collectively, our results show that PI3K and Akt are required downstream of IPS-1 for RIG-I-mediated anti-viral immune responses. The results describe a novel, interactive relationship between RIG-I downstream signalling molecules resulting in efficient anti-viral immunity. [ABSTRACT FROM AUTHOR]

• Plants recognize conserved peptides derived from pathogens by pattern recognition receptors (PRRs). • Various types of plant-derived peptides are recognized by PRRs. • Perception of peptides by PRRs involves dynamic association with co-receptors. • Peptide perception by PRRs rapidly activates immune signaling cascades. Plants are constantly exposed to pathogens in their immediate environment. Plants sense the invasion of pathogens by recognizing the components including peptide fragments derived from pathogens, known as pathogen-associated molecular patterns (PAMPs). Plants also produce immunogenic peptides called phytocytokines that regulate immune responses. These molecules are recognized by pattern recognition receptors (PRRs) at plasma membrane. Activated PRRs induce a variety of immune responses including production of reactive oxygen species (ROS), induction of Ca2+ influx and activation of mitogen activated protein kinases (MAPKs). Pattern-triggered immunity (PTI) wards off microbes and pests. In this review, we summarize recent our advances in understanding how the peptide fragments are generated and perceived by plant PRRs at cell surface, and the activated PRRs transduce the downstream immune signaling. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.