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Innate immune defense mechanisms against infection and cancer encompass the modulation of pattern recognition receptor (PRR)‐mediated inflammation, including upregulation of various transcription factors and the activation of pro‐inflammatory pathways important for immune surveillance. Dysfunction of PRRs‐mediated signaling has been implicated in cancer and autoimmune diseases, while the overactivation of PRRs‐driven responses during infection can lead to devastating consequences such as acute lung injury or sepsis. We used crystal structure‐based design to develop immunomodulatory lipopolysaccharide (LPS) mimetics targeting one of the ubiquitous PRRs, Toll‐like Receptor 4 (TLR4). Taking advantage of an exo‐anomeric conformation and specific molecular shape of synthetic nonreducing β,β‐diglucosamine, which was investigated by NMR, we developed two sets of lipid A mimicking glycolipids capable of either potently activating innate immune responses or inhibiting pro‐inflammatory signaling. Stereoselective 1,1′‐glycosylation towards fully orthogonally protected nonreducing GlcNβ(1↔1′)βGlcN followed by stepwise assembly of differently functionalised phosphorylated glycolipids provided biologically active molecules that were evaluated for their ability to trigger or to inhibit cellular innate immune responses. Two LPS mimetics, identified as potent TLR4‐specific inducers of the intracellular signaling pathways, serve as vaccine adjuvant‐ and immunotherapy candidates, while anionic glycolipids with TLR4‐inhibitory potential hold therapeutic promise for the management of acute or chronic inflammation. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) play a crucial role in innate immunity, and a complex network tightly controls their signaling cascades to maintain immune homeostasis. Within the modification network, posttranslational modifications (PTMs) are at the core of signaling cascades. Conventional PTMs, which include phosphorylation and ubiquitination, have been extensively studied. The regulatory role of unconventional PTMs, involving unanchored ubiquitination, ISGylation, SUMOylation, NEDDylation, methylation, acetylation, palmitoylation, glycosylation, and myristylation, in the modulation of innate immune signaling pathways has been increasingly investigated. This comprehensive review delves into the emerging field of unconventional PTMs and highlights their pivotal role in innate immunity. [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]

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]

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]

Crustacean species are among the most valued seafood with socioeconomic and ecological implications in the global fisheries sector. Microbial infections to the farming stock due to continued expansion and aquaculture puts global crustacean production at risk. Understanding and reviewing the complex innate immune system of crustaceans would be pivotal in formulating informed decisions for the control and management of epidemic diseases, thus making the global crustacean aquaculture industry sustainable. Under the purview of innate immunity in crustaceans, pattern recognition receptors (PRRs) represent the sensors capable of discriminating non‐self pathogenic modules and invoking the activation of immune responses. The immunity to infections can be manifested at cellular (via phagocytosis, apoptosis, nodulation and encapsulation) and humoral (effected by prophenoloxidase cascade, lectins, antimicrobial proteins) levels leading to the elimination of pathogens or subversion of the pathogenic implications. In this review, we discuss the participatory role of 12 types of PRRs identified from crustacean species with an exhaustive focus on structural and functional specificities in binding to pathogens and possible execution of the immune activity. Moreover, we have elaborated on the PRRs‐associated or possible signalling cascades (Toll‐NFκB, IMD‐NFκB and JAK‐STAT) in crustacean species that could bridge our understanding of the resistance or susceptibility of the host to varied pathogenic infections thus providing clues to the regulatory mechanisms involved in pathogenesis of infectious diseases and mechanisms of immunity. [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]

Innate immunity is the body’s first line of defense against infections. Innate immune cells express pattern recognition receptors in distinct cellular compartments that are responsible to detect either pathogens-associated molecules or cellular components derived from damaged cells, to trigger intracellular signaling pathways that lead to the activation of inflammatory responses. Inflammation is essential to coordinate immune cell recruitment, pathogen elimination and to keep normal tissue homeostasis. However, uncontrolled, misplaced or aberrant inflammatory responses could lead to tissue damage and drive chronic inflammatory diseases and autoimmunity. In this context, molecular mechanisms that tightly regulate the expression of molecules required for the signaling of innate immune receptors are crucial to prevent pathological immune responses. In this review, we discuss the ubiquitination process and its importance in the regulation of innate immune signaling and inflammation. Then, we summarize the roles of Smurf1, a protein that works on ubiquitination, on the regulation of innate immune signaling and antimicrobial mechanisms, emphasizing its substrates and highlighting its potential as a therapeutic target for infectious and inflammatory conditions. [ABSTRACT FROM AUTHOR]

Due to the global crisis caused by the dramatic rise of drug resistance among Gram-negative bacteria, there is an urgent need for a thorough understanding of the pathogenesis of infections of such an etiology. In light of the limited availability of new antibiotics, therapies aimed at host–pathogen interactions emerge as potential treatment modalities. Thus, understanding the mechanism of pathogen recognition by the host and immune evasion appear to be the key scientific issues. Until recently, lipopolysaccharide (LPS) was recognized as a major pathogen-associated molecular pattern (PAMP) of Gram-negative bacteria. However, recently, ADP-L-glycero-β-D-manno-heptose (ADP-heptose), an intermediate carbohydrate metabolite of the LPS biosynthesis pathway, was discovered to activate the hosts' innate immunity. Therefore, ADP-heptose is regarded as a novel PAMP of Gram-negative bacteria that is recognized by the cytosolic alpha kinase-1 (ALPK1) protein. The conservative nature of this molecule makes it an intriguing player in host–pathogen interactions, especially in the context of changes in LPS structure or even in its loss by certain resistant pathogens. Here, we present the ADP-heptose metabolism, outline the mechanisms of its recognition and the activation of its immunity, and summarize the role of ADP-heptose in the pathogenesis of infection. Finally, we hypothesize about the routes of the entry of this sugar into cytosol and point to emerging questions that require further research. [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]

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]

Innate immunity serves as the frontline to combat invading pathogens. Oral microbiota is the total collection of microorganisms colonized within the oral cavity. By recognizing the resident microorganisms through pattern recognition receptors, innate immunity is capable of interacting with oral microbiota and maintaining homeostasis. Dysregulation of interaction may lead to the pathogenesis of several oral diseases. Decoding the crosstalk between oral microbiota and innate immunity may be contributory to developing novel therapies for preventing and treating oral diseases. This article reviewed pattern recognition receptors in the recognition of oral microbiota, the reciprocal interaction between innate immunity and oral microbiota, and discussed how the dysregulation of this relationship leads to the pathogenesis and development of oral diseases. Many studies have been conducted to illustrate the relationship between oral microbiota and innate immunity and its role in the occurrence of different oral diseases. The impact and mechanisms of innate immune cells on oral microbiota and the mechanisms of dysbiotic microbiota in altering innate immunity are still needed to be investigated. Altering the oral microbiota might be a possible solution for treating and preventing oral diseases. [ABSTRACT FROM AUTHOR]

Filoviruses are a group of single-stranded negative sense RNA viruses. The most well-known filoviruses that affect humans are ebolaviruses and marburgviruses. During infection, they can cause life-threatening symptoms such as inflammation, tissue damage, and hemorrhagic fever, with case fatality rates as high as 90%. The innate immune system is the first line of defense against pathogenic insults such as filoviruses. Pattern recognition receptors (PRRs), including toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors, AIM2-like receptors, and NOD-like receptors, detect pathogens and activate downstream signaling to induce the production of proinflammatory cytokines and interferons, alert the surrounding cells to the threat, and clear infected and damaged cells through innate immune cell death. However, filoviruses can modulate the host inflammatory response and innate immune cell death, causing an aberrant immune reaction. Here, we discuss how the innate immune system senses invading filoviruses and how these deadly pathogens interfere with the immune response. Furthermore, we highlight the experimental difficulties of studying filoviruses as well as the current state of filovirus-targeting therapeutics. [ABSTRACT FROM AUTHOR]

Lectin–glycan interactions play a crucial role in the immune system. An important class of lectins in the innate immune system is myeloid C-type lectin receptors (CLRs). Myeloid CLRs act as pattern recognition receptors and are predominantly expressed by myeloid cells, such as macrophages, dendritic cells, and neutrophils. In innate immunity, CLRs contribute to self/non-self discrimination. While the recognition of pathogen-associated molecular patterns (PAMPs) by CLRs may contribute to a protective immune response, CLR engagement can also be exploited by pathogens for immune evasion. Since various CLRs act as endocytic receptors and trigger distinct signaling pathways in myeloid cells, CLR targeting has proven useful for drug/antigen delivery into antigen-presenting cells and the modulation of immune responses. This review covers recent discoveries of pathogen/CLR interactions and novel approaches for CLR targeting within the period of the past two years. [Display omitted] • Myeloid C-type lectin receptors (CLRs) are pathogen sensors in innate immunity. • Myeloid CLRs may be exploited by pathogens for immune evasion. • CLR targeting has proven useful for cell-specific antigen/drug delivery. • Multivalent glycan display on carrier systems facilitates CLR targeting. • This review covers recent studies (mainly in the past two years) on CLR research. [ABSTRACT FROM AUTHOR]

The epithelium of the mammary gland (MG) fulfills three major functions: nutrition of progeny, transfer of immunity from mother to newborn, and its own defense against infection. The defense function of the epithelium requires the cooperation of mammary epithelial cells (MECs) with intraepithelial leucocytes, macrophages, DCs, and resident lymphocytes. The MG is characterized by the secretion of a large amount of a nutrient liquid in which certain bacteria can proliferate and reach a considerable bacterial load, which has conditioned how the udder reacts against bacterial invasions. This review presents how the mammary epithelium perceives bacteria, and how it responds to the main bacterial genera associated with mastitis. MECs are able to detect the presence of actively multiplying bacteria in the lumen of the gland: they express pattern recognition receptors (PRRs) that recognize microbe-associated molecular patterns (MAMPs) released by the growing bacteria. Interactions with intraepithelial leucocytes fine-tune MECs responses. Following the onset of inflammation, new interactions are established with lymphocytes and neutrophils recruited from the blood. The mammary epithelium also identifies and responds to antigens, which supposes an antigen-presenting capacity. Its responses can be manipulated with drugs, plant extracts, probiotics, and immune modifiers, in order to increase its defense capacities or reduce the damage related to inflammation. Numerous studies have established that the mammary epithelium is a genuine effector of both innate and adaptive immunity. However, knowledge gaps remain and newly available tools offer the prospect of exciting research to unravel and exploit the multiple capacities of this particular epithelium. [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]

Innate immunity is a primary defense system against microbial infections. Innate immune pattern recognition receptors (PRRs) play pivotal roles in detection of invading pathogens. When pathogens, such as bacteria and viruses, invade our bodies, their components are recognized by PRRs as pathogen-associated molecular patterns (PAMPs), activating the innate immune system. Cellular components such as DNA and RNA, acting as damage-associated molecular patterns (DAMPs), also activate innate immunity through PRRs under certain conditions. Activation of PRRs triggers inflammatory responses, interferon-mediated antiviral responses, and the activation of acquired immunity. Research on innate immune receptors is progressing rapidly. A variety of these receptors has been identified, and their regulatory mechanisms have been elucidated. Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) constitute a major family of intracellular PRRs and are involved in not only combating pathogen invasion but also maintaining normal homeostasis. Some NLRs are known to form multi-protein complexes called inflammasomes, a process that ultimately leads to the production of inflammatory cytokines and induces pyroptosis through the proteolytic cascade. The aberrant activation of NLRs has been found to be associated with autoimmune diseases. Therefore, NLRs are considered targets for drug discovery, such as for antiviral drugs, immunostimulants, antiallergic drugs, and autoimmune disease drugs. This review summarizes our recent understanding of the activation and regulation mechanisms of NLRs, with a particular focus on their structural biology. These include NOD2, neuronal apoptosis inhibitory protein (NAIP)/NLRC4, NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, and NLRP9. NLRs are involved in a variety of diseases, and their detailed activation mechanisms based on structural biology can aid in developing therapeutic agents in the future. [ABSTRACT FROM AUTHOR]

Innate immunity is the first line of defense against invading external pathogens, and pattern recognition receptors (PRRs) are the key receptors that mediate the innate immune response. Nowadays, there are various PRRs in cells that can activate the innate immune response by recognizing pathogen-related molecular patterns (PAMPs). The DNA sensor cGAS, which belongs to the PRRs, plays a crucial role in innate immunity. cGAS detects both foreign and host DNA and generates a second-messenger cGAMP to mediate stimulator of interferon gene (STING)-dependent antiviral responses, thereby exerting an antiviral immune response. However, the process of cGAS/STING signaling is regulated by a wide range of factors. Multiple studies have shown that viruses directly target signal transduction proteins in the cGAS/STING signaling through viral surface proteins to impede innate immunity. It is noteworthy that the virus utilizes these cGAS/STING signaling regulators to evade immune surveillance. Thus, this paper mainly summarized the regulatory mechanism of the cGAS/STING signaling pathway and the immune escape mechanism of the corresponding virus, intending to provide targeted immunotherapy ideas for dealing with specific viral infections in the future. [ABSTRACT FROM AUTHOR]

Radiotherapy is one of the most effective and frequently used treatments for a wide range of cancers. In addition to its direct anti-cancer cytotoxic effects, ionising radiation can augment the anti-tumour immune response by triggering proinflammatory signals, DNA damage-induced immunogenic cell death and innate immune activation. Anti-tumour innate immunity can result from recruitment and stimulation of dendritic cells (DCs) which leads to tumour-specific adaptive T-cell priming and immunostimulatory cell infiltration. Conversely, radiotherapy can also induce immunosuppressive and anti-inflammatory mediators that can confer radioresistance. Targeting the DNA damage response (DDR) concomitantly with radiotherapy is an attractive strategy for overcoming radioresistance, both by enhancing the radiosensitivity of tumour relative to normal tissues, and tipping the scales in favour of an immunostimulatory tumour microenvironment. This twopronged approach exploits genomic instability to circumvent immune evasion, targeting both hallmarks of cancer. In this review, we describe targetable DDR proteins (PARP (poly[ADP-ribose] polymerase); ATM/ATR (ataxia–telangiectasia mutated and Rad3-related), DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) and Wee1 (Wee1-like protein kinase) and their potential intersections with druggable immunomodulatory signalling pathways, including nucleic acid-sensing mechanisms (Toll-like receptors (TLR); cyclic GMP–AMP synthase (cGAS)– stimulator of interferon genes (STING) and retinoic acid-inducible gene-I (RIG-I)- like receptors), and how these might be exploited to enhance radiation therapy. We summarise current preclinical advances, recent and ongoing clinical trials and the challenges of therapeutic combinations with existing treatments such as immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Hemorrhagic shock (HS) is a shock result of hypovolemic injury, in which the innate immune response plays a central role in the pathophysiology of the severe complications and organ injury in surviving patients. During the development of HS, innate immunity acts as the first line of defense, mediating a rapid response to pathogens or danger signals through pattern recognition receptors. The early and exaggerated activation of innate immunity, which is widespread in patients with HS, results in systemic inflammation, cytokine storm, and excessive activation of complement factors and innate immune cells, comprised of type II innate lymphoid cells, CD4+ T cells, natural killer cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. Recently, compelling evidence focusing on the innate immune regulation in preclinical and clinical studies promises new treatment avenues to reverse or minimize HS-induced tissue injury, organ dysfunction, and ultimately mortality. In this review, we first discuss the innate immune response involved in HS injury, and then systematically detail the cutting-edge therapeutic strategies in the past decade regarding the innate immune regulation in this field; these strategies include the use of mesenchymal stem cells, exosomes, genetic approaches, antibody therapy, small molecule inhibitors, natural medicine, mesenteric lymph drainage, vagus nerve stimulation, hormones, glycoproteins, and others. We also reviewed the available clinical studies on immune regulation for treating HS and assessed the potential of immune regulation concerning a translation from basic research to clinical practice. Combining therapeutic strategies with an improved understanding of how the innate immune system responds to HS could help to identify and develop targeted therapeutic modalities that mitigate severe organ dysfunction, improve patient outcomes, and reduce mortality due to HS injury. [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]

Extensive crosstalk exists between autophagy and innate immune signalling pathways. The stimuli that induce pattern recognition receptor (PRR)‐mediated innate immune signalling pathways, also upregulate autophagy. The purpose of this increased autophagy is to eliminate the stimuli and/or suppress the inflammatory pathways by targeted degradation of PRRs or intermediary proteins (termed 'inflammophagy'). By executing these functions, autophagy dampens excess inflammation triggered by the innate immune signalling pathways. Thus, autophagy helps in the maintenance of the body's innate immune homeostasis to protect from inflammatory and autoimmune diseases. Many autophagy‐dependent mechanisms that could control innate immune signalling have been studied over the last few years. However, still, the understanding is incomplete, and studies that are more systematic should be undertaken to delineate the mechanisms of inflammophagy. Here, we discuss the available knowledge of crosstalk between autophagy and PRR signalling pathways. [ABSTRACT FROM AUTHOR]

Epilepsy is a common chronic brain disease. There are many clinical methods to control epileptic seizures, such as anti-seizure medications (ASMs) or surgical removal of epileptogenic lesions. However, the pathophysiology of epilepsy is still unknown, making it difficult to control or prevent it. The host's immune system monitors gut microbes, interacts with microbes through pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) expressed by innate immune cells, and activates immune responses in the body to kill pathogens and balance the relationship between microbes and host. In addition, inflammatory responses induced by the innate immune system are seen in animal models of epilepsy and temporal lobe epilepsy brain tissue to combat pathogens or injuries. This review summarizes the potential relationship between gut microbes, innate immunity, and epilepsy based on recent research to provide more hints for researchers to explore this field further. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS) is a chronic autoimmune disease that affects exocrine glands, primarily the salivary and lachrymal glands. It is characterized by lymphoplasmacytic infiltration of the glandular tissues, ultimately leading to their dysfunction and destruction. Besides classic dry eyes and dry mouth defined as sicca syndrome, patients affected by the disease also typically display symptoms such as fatigue, pain and in more than 50% of cases, systemic manifestations such as arthritis, interstitial lung involvement, neurological involvement and an increased risk of lymphoma. The pathophysiological mechanisms underlying SS still remain elusive. The crucial role of innate immunity has been advocated in recent years regarding the pathogenesis of pSS, especially in the initiation and progression toward autoimmunity. Alarmins are endogenous molecules that belong to the large family of damage associated molecular pattern (DAMP). Alarmins are rapidly released, ensuing cell injury and interacting with pattern recognition receptors (PRR) such as toll-like receptors (TLR) to recruit and activate cells of the innate immune system and to promote adaptive immunity responses. This review highlights the current knowledge of various alarmins and their role in the pathogenesis of pSS. [ABSTRACT FROM AUTHOR]

As important pattern recognition receptors (PRRs), C‐type lectins play crucial roles in the crustacean innate immune system. In this study, a novel C‐type lectin, designated as MnLec1, was obtained from the exoskeleton of the oriental river prawn Macrobrachium nipponense for the first time. The full‐length cDNA of MnLec1 was 1329 bp with an open reading frame of 774 bp. The predicted MnLec1 protein contains a single carbohydrate‐recognition domain with an EPN/LND motif and one Ca2+ binding site‐2. MnLec1 transcripts were widely detected in the tested tissues of M. nipponense and significantly up‐regulated after Aeromonas hydrophila challenge. The recombinant MnLec1 protein was found to have a wide spectrum of binding activities towards various microorganisms, agglutinate two kinds of Gram‐negative bacteria (Escherichia coli and A. hydrophila) in a Ca2+‐independent manner. What's more, the survivability of prawns was significantly down‐regulated after RNAi of MnLec1 when infected with A. hydrophila. Collectively, these findings suggest that MnLec1 from the exoskeleton might function as a PRR and play a crucial role in immune defense against invading pathogens in M. nipponense. [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]

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]

Inflammasomes are important multiprotein regulatory complexes of innate immunity and have recently emerged as playing divergent roles in numerous inflammation-associated cancers. Among these include gastric cancer (GC), the third leading cause of cancer-associated death worldwide, and we have previously discovered a pro-tumorigenic role for the key inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) in the spontaneous genetic gp130 F/F mouse model for GC. However, the identity of the specific pattern recognition receptors (PRRs) that activate tumor-promoting inflammasomes during GC is unknown. Here, we investigated the role of the best-characterized inflammasome-associated PRR, nucleotide-binding domain, and leucine-rich repeat containing receptor, pyrin domain-containing (NLRP) 3, in GC. In gastric tumors of gp130 F/F mice, although NLRP3 expression was elevated at the mRNA (qPCR) and protein (immunohistochemistry) levels, genetic ablation of NLRP3 in gp130 F/F: Nlrp3 -/- mice did not alleviate the development of gastric tumors. Similarly, cellular processes associated with tumorigenesis in the gastric mucosa, namely, proliferation, apoptosis, and inflammation, were comparable between gp130 F/F and gp130 F/F: Nlrp3 -/- mice. Furthermore, inflammasome activation levels, determined by immunoblotting and immunohistochemistry for cleaved Caspase-1, which along with ASC is another integral component of inflammasome complexes, were unchanged in gp130 F/F and gp130 F/F: Nlrp3 -/- gastric tumors. We also observed variable NLRP3 expression levels (mRNA and protein) among independent GC patient cohorts, and NLRP3 was not prognostic for survival outcomes. Taken together, these data suggest that NLRP3 does not play a major role in promoting inflammasome-driven gastric tumorigenesis, and thus pave the way for further investigations to uncover the key inflammasome-associated PRR implicated in GC. [ABSTRACT FROM AUTHOR]

The widespread nature and economic importance of Infectious bronchitis virus (IBV) and interactions between IBV and the host immune response remain poorly understood. Understanding the mechanism of virus recognition via innate immunity can help resist IBV invasion. Retinoic acid-induced gene I-like receptor (RLRs) recognize virus RNA in virus infection, and LGP2 is a member of RLRs. According to the current studies, LGP2 exhibited certain inhibition in the virus, and there is a lack of investigation for chicken's LGP2. It is important to figure out the role of chLGP2 in host immune recognition of IBV. Our results showed that chLGP2 inhibited the proliferation of IBV Beaudette in cells. Also, chLGP2 can identify and combine with IBV RNA. The domains of chLGP2 were separately expressed and inspired by related literature, and the chLGP2 K30A mutant was constructed. Our results suggested its structural integrity and the adenosine triphosphatase (ATPase) activity are critical for IBV inhibiting activity. chTRBP was selected after CO-IP and Mass spectrometry test. We found chTRBP and chLGP2 are the interacting partners and promote mutual expression. Our study showed that chTRBP could also suppress IBV infections via chLGP2, which provided a basis for future innate immunity research for IBV. [ABSTRACT FROM AUTHOR]

Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis. [ABSTRACT FROM AUTHOR]

RIG‐I is our first line of defense against RNA viruses, serving as a pattern recognition receptor that identifies molecular features common among dsRNA and ssRNA viral pathogens. RIG‐I is maintained in an inactive conformation as it samples the cellular space for pathogenic RNAs. Upon encounter with the triphosphorylated terminus of blunt‐ended viral RNA duplexes, the receptor changes conformation and releases a pair of signaling domains (CARDs) that are selectively modified and interact with an adapter protein (MAVS), thereby triggering a signaling cascade that stimulates transcription of interferons. Here, we describe the structural determinants for specific RIG‐I activation by viral RNA, and we describe the strategies by which RIG‐I remains inactivated in the presence of host RNAs. From the initial RNA triggering event to the final stages of interferon expression, we describe the experimental evidence underpinning our working knowledge of RIG‐I signaling. We draw parallels with behavior of related proteins MDA5 and LGP2, describing evolutionary implications of their collective surveillance of the cell. We conclude by describing the cell biology and immunological investigations that will be needed to accurately describe the role of RIG‐I in innate immunity and to provide the necessary foundation for pharmacological manipulation of this important receptor. [ABSTRACT FROM AUTHOR]

In their never‐ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype). [ABSTRACT FROM AUTHOR]

Adjuvants are used to maximize the potency of vaccines by enhancing immune reactions. Components of adjuvants include pathogen-associated molecular patterns (PAMPs) and damage-associate molecular patterns (DAMPs) that are agonists for innate immune receptors. Innate immune responses are usually activated when pathogen recognition receptors (PRRs) recognize PAMPs derived from invading pathogens or DAMPs released by host cells upon tissue damage. Activation of innate immunity by PRR agonists in adjuvants activates acquired immune responses, which is crucial to enhance immune reactions against the targeted pathogen. For example, agonists for Toll-like receptors have yielded promising results as adjuvants, which target PRR as adjuvant candidates. However, a comprehensive understanding of the type of immunological reaction against agonists for PRRs is essential to ensure the safety and reliability of vaccine adjuvants. This review provides an overview of the current progress in development of PRR agonists as vaccine adjuvants, the molecular mechanisms that underlie activation of immune responses, and the enhancement of vaccine efficacy by these potential adjuvant candidates. [ABSTRACT FROM AUTHOR]

Failure of current therapies to cure chronic hepatitis B has led to renewed interest in therapies that stimulate the host immune system. APOBEC3 (A3) family enzymes have been shown to induce mutations in hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) leading to inhibition of HBV transcription and replication. Pattern recognition receptor (PRR) agonists have been reported to suppress HBV, but it is unclear whether these agonists induce A3 gene expression in hepatocytes. We, therefore, evaluated whether PRR signaling activates the expression of A3 genes and other innate immunity genes and restricts HBV infection. HepG2-sodium taurocholate cotransporting polypeptide (NTCP) cells were infected with HBV and treated with various PRR agonists. The level of HBV infection was subsequently assessed by measurement of HBV biomarkers, including HBV DNA, cccDNA, HBs, and HBe antigens in infected hepatocytes. Among all tested PRR ligands, only Poly(I:C)-HMW/LyoVec and Poly(I:C)-HMW significantly inhibited hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), HBV DNA, and cccDNA, whereas R848 and lipopolysaccharide (LPS) only showed significant inhibition on HBsAg and HBeAg, but not virus DNA. CpG and Pam3CSK4, on the other hand, had no significant inhibitory effect on any of the HBV infection parameters. Moreover, Poly(I:C)-HMW/LyoVec and Poly(I:C)-HMW were the only ligands that significantly increased IL-8 secretion. Interestingly, HBV infection reduced IL-8 secretion induced by Poly(I:C)-HMW and to a lesser extent Poly(I:C)-HMW/LyoVec. Poly(I:C)-HMW/LyoVec had a significant effect on increasing the expression level of A3F, A3G, A3H, TLR3, RIG-1, and MDA5 genes. Our data suggest that PRR agonists may control HBV infection through different mechanisms. The RIG-1 and MDA5 agonist, Poly(I:C)-HMW/LyoVec, seems to downregulate HBV infection through induction of A3 genes. [ABSTRACT FROM AUTHOR]

Study Question: Is the innate immunity system active in early human embryo development?Summary Answer: The pattern recognition receptors and innate immunity Toll-like receptor (TLR) genes are widely expressed in preimplantation human embryos and the pathway appears to be active in response to TLR ligands.What Is Known Already: Early human embryos are highly sensitive to their local environment, however relatively little is known about how embryos detect and respond to specific environmental cues. While the maternal immune response is known to be key to the establishment of pregnancy at implantation, the ability of human embryos to detect and signal the presence of pathogens is unknown.Study Design, Size, Duration: Expression of TLR family and related genes in human embryos was assessed by analysis of published transcriptome data (n = 40). Day 5 (D-5) human embryos (n = 25) were cultured in the presence of known TLR ligands and gene expression and cytokine production measured compared to controls.Participants/materials, Setting, Methods: Human embryos surplus to treatment requirements were donated with informed consent from several ART centres. Embryos were cultured to Day 6 (D-6) in the presence of the TLR3 and TLR5 ligands Poly (I: C) and flagellin, with gene expression measured by quantitative PCR and cytokine release into medium measured using cytometric bead arrays.Main Results and the Role Of Chance: TLR and related genes, including downstream signalling molecules, were expressed variably at all human embryo developmental stages. Results showed the strongest expression in the blastocyst for TLRs 9 and 5, and throughout development for TLRs 9, 5, 2, 6 and 7. Stimulation of Day 5 blastocysts with TLR3 and TLR5 ligands Poly (I: C) and flagellin produced changes in mRNA expression levels of TLR genes, including the hyaluronan-mediated motility receptor (HMMR), TLR5, TLR7, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and monocyte chemoattractant Protein-1 (MCP-1) (P < 0.05, P < 0.001 compared to unstimulated controls), and release into culture medium of cytokines and chemokines, notably IL8 (P = 0.00005 and 0.01277 for flagellin and Poly (I: C), respectively).Limitations, Reasons For Caution: This was a descriptive and experimental study which suggests that the TLR system is active in human embryos and capable of function, but does not confirm any particular role. Although we identified embryonic transcripts for a range of TLR genes, the expression patterns were not always consistent across published studies and expression levels of some genes were low, leaving open the possibility that these were expressed from the maternal rather than embryonic genome.Wider Implications Of the Findings: This is the first report of the expression and activity of a number of components of the innate immunity TLR system in human embryos. Understanding the role of TLRs during preimplantation human development may be important to reveal immunological mechanisms and potential clinical markers of embryo quality and pregnancy initiation during natural conception and in ART.Study Funding/competing Interest(s): This work was funded by the Ministry of Higher Education, The State of Libya, the UK Medical Research Council, and the NIHR Local Comprehensive Research Network and NIHR Manchester Clinical Research Facility and the European Union's Horizon 2020 Research and Innovation Programmes under the Marie Skłodowska-Curie Grant Agreement No. 812660 (DohART-NET). In accordance with H2020 rules, no new human embryos were sacrificed for research activities performed from the EU funding, which concerned only in silico analyses of recorded time-lapse and transcriptomics datasets. None of the authors has any conflict of interest to declare.Trial Registration Number: n/a. [ABSTRACT FROM AUTHOR]

The innate immune system represents the first line of defense against influenza viruses, which cause severe inflammation of the respiratory tract and are responsible for more than 650,000 deaths annually worldwide. mRNA vaccines are promising alternatives to traditional vaccine approaches due to their safe dosing, low-cost manufacturing, rapid development capability, and high efficacy. In this review, we provide our current understanding of the innate immune response that uses pattern recognition receptors to detect and respond to mRNA vaccination. We also provide an overview of mRNA vaccines, and discuss the future directions and challenges in advancing this promising therapeutic approach. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) are evolutionarily ancient and crucial components of innate immunity, recognizing danger-associated molecular patterns (DAMPs) and activating host defenses. Basal non-bilaterian animals such as cnidarians must rely solely on innate immunity to defend themselves from pathogens. By investigating cnidarian PRR repertoires we can gain insight into the evolution of innate immunity in these basal animals. Here we utilize the increasing amount of available genomic resources within Cnidaria to survey the PRR repertoires and downstream immune pathway completeness within 15 cnidarian species spanning two major cnidarian clades, Anthozoa and Medusozoa. Overall, we find that anthozoans possess prototypical PRRs, while medusozoans appear to lack these immune proteins. Additionally, anthozoans consistently had higher numbers of PRRs across all four classes relative to medusozoans, a trend largely driven by expansions in NOD-like receptors and C-type lectins. Symbiotic, sessile, and colonial cnidarians also have expanded PRR repertoires relative to their non-symbiotic, mobile, and solitary counterparts. Interestingly, cnidarians seem to lack key components of mammalian innate immune pathways, though similar to PRR numbers, anthozoans possess more complete immune pathways than medusozoans. Together, our data indicate that anthozoans have greater immune specificity than medusozoans, which we hypothesize to be due to life history traits common within Anthozoa. Overall, this investigation reveals important insights into the evolution of innate immune proteins within these basal animals. [ABSTRACT FROM AUTHOR]

The animal immune system mediates host-microbe interactions from the host perspective. Pattern recognition receptors (PRRs) and the downstream signaling cascades they induce are a central part of animal innate immunity. These molecular immune mechanisms are still not fully understood, particularly in terms of baseline immunity vs induced specific responses regulated upon microbial signals. Early-divergent phyla like sponges (Porifera) can help to identify the evolutionarily conserved mechanisms of immune signaling. We characterized both the expressed immune gene repertoire and the induced response to lipopolysaccharides (LPS) in Halichondria panicea , a promising model for sponge symbioses. We exposed sponges under controlled experimental conditions to bacterial LPS and performed RNA-seq on samples taken 1h and 6h after exposure. H. panicea possesses a diverse array of putative PRRs. While part of those PRRs was constitutively expressed in all analyzed sponges, the majority was expressed individual-specific and regardless of LPS treatment or timepoint. The induced immune response by LPS involved differential regulation of genes related to signaling and recognition, more specifically GTPases and post-translational regulation mechanisms like ubiquitination and phosphorylation. We have discovered individuality in both the immune receptor repertoire and the response to LPS, which may translate into holobiont fitness and susceptibility to stress. The three different layers of immune gene control observed in this study, - namely constitutive expression, individual-specific expression, and induced genes -, draw a complex picture of the innate immune gene regulation in H. panicea. Most likely this reflects synergistic interactions among the different components of immunity in their role to control and respond to a stable microbiome, seawater bacteria, and potential pathogens. [ABSTRACT FROM AUTHOR]

The innate immune system relies on a germ-line-encoded repertoire of pattern recognition receptors (PRRs), activated by deeply conserved pathogen signatures, such as bacterial cell wall components or foreign nucleic acids. To enable effective defence against invading pathogens and prevent from deleterious inflammation, PRR-driven immune responses are tightly controlled by a dense network of nuclear and cytoplasmic regulators. Long non-coding RNAs (lncRNAs) are increasingly recognized as important components of these regulatory circuitries, providing positive and negative control of PRR-induced innate immune responses. The present review provides an overview of the presently known roles of lncRNAs in human and murine innate antiviral and antibacterial immunity. The emerging roles in host defence and inflammation suggest that further mechanistic insights into the cellular functions of lncRNAs will decisively advance our molecular understanding of immune-associated diseases and open new avenues for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Innate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity. [ABSTRACT FROM AUTHOR]

Post-translational modifications (PTMs) play a pivotal role in expanding functional protein diversity. During viral infection, pathogen-associated molecular patterns derived from viruses are recognized by pattern recognition receptors present in the membrane surface and the cytoplasm of infected cells, which subsequently induces the antiviral innate immunity to protect the host from the invading viruses. Fatty acylation modification is identified as a post-translation lipid modification process. Mounting evidence is presented that lipid modification functions as a novel regulatory mechanism of antiviral innate immunity. In mammalian cells, DHHC (Asp-His-His-Cys) domain is indispensable for most of the palmitoylation modification, which belongs to fatty acylation. ZDHHC family proteins are composed of 23 members in human cells. In this review, we will summarize the recent findings of the regulatory mechanism of the palmitoylation in the process of host antiviral innate immunity against viruses. [ABSTRACT FROM AUTHOR]

An innate immune response is essential to mobilize protective immunity upon the infection of respiratory epithelial cells with influenza A virus (IAV). The response is classified as early (nonspecific effectors), local systematic (effector cells recruitment) and late (antigen to lymphoid organ transport, naive B and T cells recognition, effector cells clonal expansion and differentiation). Virus particles are detected by the host cells as non-self by various sensors that are present on the cell surface, endosomes and cytosol. These sensors are collectively termed as pattern recognition receptors (PRRs). The PRRs distinguish unique molecular signatures known as pathogen-associated molecular pattern, which are present either on the cell surface or within intracellular compartments. PRRs have been classified into five major groups: C-Type Lectin Receptor (CLR), Toll-like receptor (TLR), Nod-like receptor (NLR), Retinoic acid-inducible gene-I-like receptor (RLR), which play a role in innate immunity to IAV infection, and the pyrin and hematopoietic interferon-inducible nuclear (PYHIN) domain protein. Here, we discuss the role of PRRs in cellular infectivity of IAV and highlight the recent progress. [ABSTRACT FROM AUTHOR]

Innate immunity driven by pattern recognition receptor (PRR) protects the host from invading pathogens. Aquatic animals like fish where the adaptive immunity is poorly developed majorly rely on their innate immunity modulated by PRRs like toll-like receptors (TLR) and NOD-like receptors (NLR). However, current development to improve the fish immunity via TLR/NLR signaling is affected by a poor understanding of its mechanistic and structural features. This review discusses the structure of fish TLRs/NLRs and its interaction with pathogen associated molecular patterns (PAMPs) and downstream signaling molecules. Over the past one decade, significant progress has been done in studying the structure of TLRs/NLRs in higher eukaryotes; however, structural studies on fish innate immune receptors are undermined. Several novel TLR genes are identified in fish that are absent in higher eukaryotes, but the function is still poorly understood. Unlike the fundamental progress achieved in developing antagonist/agonist to modulate human innate immunity, analogous studies in fish are nearly lacking due to structural inadequacy. This underlies the importance of exploring the structural and mechanistic details of fish TLRs/NLRs at an atomic and molecular level. This review outlined the mechanistic and structural basis of fish TLR and NLR activation. [ABSTRACT FROM AUTHOR]

The tripartite motif (TRIM) proteins have been intensively studied as essential modulators in various biological processes, especially in regulating a wide range of signaling pathways involved in immune responses. Most TRIM proteins have E3 ubiquitin ligase activity, mediating polyubiquitination of target proteins. Emerging evidence demonstrates that TRIM proteins play important roles in innate immunity by regulating pattern recognition receptors, vital adaptor proteins, kinases, and transcription factors in innate immune signaling pathways. Additionally, the critical roles of TRIM proteins in adaptive immunity, especially in T cell development and activation, are increasingly appreciated. In this review, we aim to summarize the studies on TRIMs in both innate and adaptive immunity, focusing on their E3 ubiquitin ligase functions in pattern recognition receptor signaling pathways and T cell functions, shedding light on the developing new strategies for modulating innate and adaptive immune responses against invading pathogens and avoiding autoimmunity. [ABSTRACT FROM AUTHOR]

C-type lectins (CTLs) play important roles in innate immune system of crustaceans as pattern recognition receptors (PRRs). In this study, a novel CTL gene was obtained from the red swamp crayfish, Procambarus clarkii , designated as PcLec. PcLec encodes a peptide with 175 amino acids, with a signal peptide and a single carbohydrate recognition domain (CRD). The PcLec transcripts were specifically expressed in crayfish stomach and were induced by bacterial challenge. In vitro assays with recombinant PcLec protein revealed that it had bacterial binding activity, polysaccharide binding activity, bacterial agglutination activity, and antimicrobial activity. Most importantly, PcLec knockdown significantly impaired the survivability of crayfish upon oral infection with its pathogen A. hydrophila. According to these results, we infer that the PcLec plays a crucial role in antibacterial defense of crayfish. • PcLec is stomach specific and responds to bacterial challenge. • PcLec has direct antimicrobial activity against both Gram+ and Gram-bacteria. • PcLec knockdown impaired the survivability of crayfish upon oral infection with bacteria. [ABSTRACT FROM AUTHOR]

The disease caused by duck Tembusu virus (DTMUV) is characterized by severe egg-drop in laying ducks. Currently, the disease has spread to most duck-raising areas in China, leading to great economic losses in the duck industry. In the recent years, DTMUV has raised some concerns, because of its expanding host range and increasing pathogenicity, as well as the potential threat to public health. Innate immunity is crucial for defending against invading pathogens in the early stages of infection. Recently, studies on the interaction between DTMUV and host innate immune response have made great progress. In the review, we provide an overview of DTMUV and summarize current advances in our understanding of the interaction between DTMUV and innate immunity, including the host innate immune responses to DTMUV infection through pattern recognition receptors (PRRs), signaling transducer molecules, interferon-stimulated genes (ISGs), and the immune evasion strategies employed by DTMUV. The aim of the review is to gain an in-depth understanding of DTMUV pathogenesis to facilitate future studies. [ABSTRACT FROM AUTHOR]

Renal ischemia reperfusion injury (IRI), a common event after renal transplantation, causes acute kidney injury (AKI), increases the risk of delayed graft function (DGF), primes the donor kidney for rejection, and contributes to the long-term risk of graft loss. In the last decade, epidemiological studies have linked even mild episodes of AKI to chronic kidney disease (CKD) progression, and innate immunity seems to play a crucial role. The ischemic insult triggers an acute inflammatory reaction that is elicited by Pattern Recognition Receptors (PRRs), expressed on both infiltrating immune cells as well as tubular epithelial cells (TECs). Among the PRRs, Toll-like receptors (TLRs), their synergistic receptors, Nod-like receptors (NLRs), and the inflammasomes, play a pivotal role in shaping inflammation and TEC repair, in response to renal IRI. These receptors represent promising targets to modulate the extent of inflammation, but also function as gatekeepers of tissue repair, protecting against AKI-to-CKD progression. Despite the important considerations on timely use of therapeutics, in the context of IRI, treatment options are limited by a lack of understanding of the intra- and intercellular mechanisms associated with the activation of innate immune receptors and their impact on adaptive tubular repair. Accumulating evidence suggests that TEC-associated innate immunity shapes the tubular response to stress through the regulation of immunometabolism. Engagement of innate immune receptors provides TECs with the metabolic flexibility necessary for their plasticity during injury and repair. This could significantly affect pathogenic processes within TECs, such as cell death, mitochondrial damage, senescence, and pro-fibrotic cytokine secretion, well-known to exacerbate inflammation and fibrosis. This article provides an overview of the past 5 years of research on the role of innate immunity in experimental and human IRI, with a focus on the cascade of events activated by hypoxic damage in TECs: from programmed cell death (PCD) and mitochondrial dysfunction-mediated metabolic rewiring of TECs to maladaptive repair and progression to fibrosis. Finally, we will discuss the important crosstalk between metabolism and innate immunity observed in TECs and their therapeutic potential in both experimental and clinical research. [ABSTRACT FROM AUTHOR]