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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]

Viral infections pose significant threats to human health, leading to a diverse spectrum of infectious diseases. The innate immune system serves as the primary barrier against viruses and bacteria in the early stages of infection. A rapid and forceful antiviral innate immune response is triggered by distinguishing between self-nucleic acids and viral nucleic acids. RNA-binding proteins (RBPs) are a diverse group of proteins which contain specific structural motifs or domains for binding RNA molecules. In the last decade, numerous of studies have outlined that RBPs influence viral replication via diverse mechanisms, directly recognizing viral nucleic acids and modulating the activity of pattern recognition receptors (PRRs). In this review, we summarize the functions of RBPs in regulation of host-virus interplay by controlling the activation of PRRs, such as RIG-I, MDA5, cGAS and TLR3. RBPs are instrumental in facilitating the identification of viral RNA or DNA, as well as viral structural proteins within the cellular cytoplasm and nucleus, functioning as co-receptor elements. On the other hand, RBPs are capable of orchestrating the activation of PRRs and facilitating the transmission of antiviral signals to downstream adaptor proteins by post-translational modifications or aggregation. Gaining a deeper comprehension of the interaction between the host and viruses is crucial for the development of novel therapeutics targeting viral infections. [ABSTRACT FROM AUTHOR]

Porcine reproductive and respiratory syndrome virus (PRRSV) induces a poor innate immune response following infection. This study evaluates the effects of transforming growth factor beta 1 (TGFβ1) up-regulated by PRRSV on gene expressions of co-stimulatory molecules, type I interferon (IFN), type I IFN-regulated genes (IRGs), pattern recognition receptors, and pro-inflammatory cytokines in PRRSV-inoculated monocyte-derived macrophages (MDMs). Phosphorothioate-modified antisense oligodeoxynucleotides (AS ODNs) specific to various regions of porcine TGFβ1 mRNA were synthesized, and those specific to the AUG region efficiently knockdown TGFβ1 mRNA expression and protein translation. Transfection of TGFβAS ODNs in MDMs inoculated with either classical PRRSV-2 (cPRRSV-2) or highly pathogenic PRRSV-2 (HP-PRRSV-2) significantly reduced TGFβ1 mRNA expression and significantly increased mRNA expressions of CD80, CD86, IFNβ, IRGs (i.e. IFN regulatory factor 3 (IRF3), IRF7, myxovirus resistance 1, osteopontin, and stimulator of IFN genes), Toll-like receptor 3, and tumor necrosis factor-alpha. Transfection of TGFβAS ODNs in MDMs inoculated with HP-PRRSV-2 also significantly increased mRNA expressions of IFNα, IFNγ, and 2'-5'-oligoadenylate synthetase 1. The quantity of PRRSV-2 RNA copy numbers was significantly reduced in MDMs transfected with TGFβAS ODNs as compared to untransfected MDMs. Recombinant porcine TGFβ1 (rTGFβ1) and recombinant porcine IFNα (rIFNα) sustained and reduced the yields of PRRSV-2 RNA copy numbers in PRRSV-2 inoculated MDMs, respectively. These findings demonstrate a strategy of PRRSV for innate immune suppression via an induction of TGFβ expression. These findings also suggest TGFβ as a potential parameter that future PRRSV vaccine and vaccine adjuvant candidates should take into consideration. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are key pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) and elicit broadly acting innate immune responses. This study accomplished the identification, cloning, and sequencing of Labeo rohita TLR18 (LrTLR18). Structurally, LrTLR18 possesses a signal peptide, six leucine-rich repeats (LRRs), an LRR-C-terminal (LRR-CT) domain, a transmembrane (TM) region, and a Toll/IL-1 receptor (TIR) domain. Phylogenetically, LrTLR18 is evolutionarily closely related to the Schizothorax prenanti and Cyprinus carpio TLR18. The quantitative real-time PCR analysis revealed that LrTLR18 gene was expressed in all tested tissues, and among the tissues, the highest expression was observed in the eye followed by spleen, intestine, and gill in the descending order. During the ontogenic developments, the highest expression of LrTLR18 gene has been detected in the late blastula and gastrula stages. In response to the Aeromonas hydrophila and Edwardsiella tarda infections, LrTLR18 gene was differentially expressed in the blood, kidney, liver, and gills. Labeo rohita gills (LRG) cells in vitro infected with A. hydrophila and E. tarda, and red blood cells (RBCs) and peripheral blood leucocytes (PBLs) isolated from the rohu fingerlings infected with these pathogens revealed significantly (p < 0.05) enhanced expression of LrTLR18 gene. Following in vivo and in vitro stimulations with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I: C), LrTLR18 gene expression was also significantly (p < 0.05) enhanced in various tissues, RBCs, PBLs, and macrophages. Together, these results highlight the important roles of the TLR18 against pathogenic invasions in fish. [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]

Toll-like receptors (TLRs) are a key family of pattern recognition receptors (PRRs) in the innate immune system. The activation of TLRs will not only prevent pathogen infection but also respond to damage-induced danger signaling. Increasing evidence suggests that TLRs play a critical role in breast cancer development and treatment. However, the activation of TLRs is a doubleedged sword that can induce either pro-tumor activity or anti-tumor effect. The underlying mechanisms of these opposite effects of TLR signaling in cancer are not fully understood. Targeting TLRs is a promising strategy for improving breast cancer treatment, either as monotherapies or by improving other current therapies. Here we provide an update on the role of TLRs in breast cancer immunity and immunotherapy. [ABSTRACT FROM AUTHOR]

Repression of human cytomegalovirus (HCMV) immediate-early (IE) gene expression is a key regulatory step in the establishment and maintenance of latent reservoirs. Viral IE transcription and protein accumulation can be elevated during latency by treatment with histone deacetylase inhibitors such as valproic acid (VPA), rendering infected cells visible to adaptive immune responses. However, the latency-associated viral protein UL138 inhibits the ability of VPA to enhance IE gene expression during infection of incompletely differentiated myeloid cells that support latency. UL138 also limits the accumulation of IFNβ transcripts by inhibiting the cGAS-STING-TBK1 DNA-sensing pathway. Here, we show that, in the absence of UL138, the cGAS-STING-TBK1 pathway promotes both IFNβ accumulation and VPA-responsive IE gene expression in incompletely differentiated myeloid cells. Inactivation of this pathway by either genetic or pharmacological inhibition phenocopied UL138 expression and reduced VPA-responsive IE transcript and protein accumulation. This work reveals a link between cytoplasmic pathogen sensing and epigenetic control of viral lytic phase transcription and suggests that manipulation of pattern recognition receptor signaling pathways could aid in the refinement of MIEP regulatory strategies to target latent viral reservoirs. [ABSTRACT FROM AUTHOR]

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

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

An increasing number of studies have highlighted the existence of a sex-specific immune response, wherein men experience a worse prognosis in cases of acute inflammatory diseases. Initially, this sex-dependent inflammatory response was attributed to the influence of sex hormones. However, a growing body of evidence has shifted the focus toward the influence of chromosomes rather than sex hormones in shaping these inflammatory sex disparities. Notably, certain pattern recognition receptors, such as Toll-like receptors (TLRs), and their associated immune pathways have been implicated in driving the sex-specific immune response. These receptors are encoded by genes located on the X chromosome. TLRs are pivotal components of the innate immune system, playing crucial roles in responding to infectious diseases, including bacterial and viral pathogens, as well as trauma-related conditions. Importantly, the TLRmediated inflammatory responses, as indicated by the production of specific proteins and cytokines, exhibit discernible sex-dependent patterns. In this review, we delve into the subject of sex bias in TLR activation and explore its clinical implications relatively to both the X chromosome and the hormonal environment. The overarching objective is to enhance our understanding of the fundamental mechanisms underlying these sex differences. [ABSTRACT FROM AUTHOR]

This article explores the challenges and potential impacts of micro and nanoplastic particles (MNPs) on the innate immune system. MNPs, small plastic particles, are released into the environment and can interact with various species, including humans. The innate immune system, responsible for recognizing and eliminating foreign materials, plays a crucial role in responding to MNPs. The article suggests that studying the effects of MNPs on the innate immune system across different species can provide valuable insights into the mechanisms and potential impacts of MNP exposure. It emphasizes the importance of adopting an evolutionary immunology framework and proposes using in vitro and in vivo models, as well as genome-wide association studies and multiomics analyses, to understand these interactions. This research aligns with the One Health initiative and can contribute to a better understanding of the environmental and human health risks associated with MNP pollution. [Extracted from the article]

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

Introduction: Sepsis remains a major cause of death in Intensive Care Units. Sepsis is a life-threatening multi-organ dysfunction caused by a dysregulated systemic inflammatory response. Pattern recognition receptors, such as TLRs and NLRs contribute to innate immune responses. Upon activation, some NLRs form multimeric protein complexes in the cytoplasm termed "inflammasomes" which induce gasdermin d-mediated pyroptotic cell death and the release of mature forms of IL-1b and IL-18. The NLRP6 inflammasome is documented to be both a positive and a negative regulator of host defense in distinct infectious diseases. However, the role of NLRP6 in polymicrobial sepsis remains elusive. Methods: We have used NLRP6 KO mice and human septic spleen samples to examine the role of NLRP6 in host defense in sepsis. Results: NLRP6 KO mice display enhanced survival, reduced bacterial burden in the organs, and reduced cytokine/chemokine production. Co-housed WT and KO mice following sepsis show decreased bacterial burden in the KO mice as observed in singly housed groups. NLRP6 is upregulated in CD3, CD4, and CD8 cells of septic patients and septic mice. The KO mice showed a higher number of CD3, CD4, and CD8 positive T cell subsets and reduced T cell death in the spleen following sepsis. Furthermore, administration of recombinant IL-18, but not IL-1b, elicited excessive inflammation and reversed the survival advantages observed in NLRP6 KO mice. Conclusion: These results unveil NLRP6 as a negative regulator of host defense during sepsis and offer novel insights for the development of new treatment strategies for sepsis. [ABSTRACT FROM AUTHOR]

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

Toll‐like receptors (TLRs) are inflammatory triggers and belong to a family of pattern recognition receptors (PRRs) that are central to the regulation of host protective adaptive immune responses. Activation of TLRs in innate immune myeloid cells directs lymphocytes to produce the most appropriate effector responses to eliminate infection and maintain homeostasis of the body's internal environment. Inappropriate TLR stimulation can lead to the development of general autoimmune diseases as well as chronic and acute inflammation, and even cancer. Therefore, TLRs are expected to be targets for therapeutic treatment of inflammation‐related diseases, autoimmune diseases, microbial infections, and human cancers. This review summarizes the recent discoveries in the molecular and structural biology of TLRs. The role of different TLR signaling pathways in inflammatory diseases, autoimmune diseases such as diabetes, cardiovascular diseases, respiratory diseases, digestive diseases, and even cancers (oral, gastric, breast, colorectal) is highlighted and summarizes new drugs and related clinical treatments in clinical trials, providing an overview of the potential and prospects of TLRs for the treatment of TLR‐related diseases. [ABSTRACT FROM AUTHOR]

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

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

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

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

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

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

The Epstein-Barr virus (EBV) is a ubiquitous human pathogen linked to various diseases, including infectious mononucleosis and multiple types of cancer. To control and eliminate EBV, the host's immune system deploys its most potent defenses, including pattern recognition receptors, Natural Killer cells, CD8+ and CD4+ T cells, among others. The interaction between EBV and the human immune system is complex and multifaceted. EBV employs a variety of strategies to evade detection and elimination by both the innate and adaptive immune systems. This demonstrates EBV's mastery of navigating the complexities of the immunological landscape. Further investigation into these complex mechanisms is imperative to advance the development of enhanced therapeutic approaches with heightened efficacy. This review provides a comprehensive overview of various mechanisms known to date, employed by the EBV to elude the immune response, while establishing enduring latent infections or instigate its lytic replication. [ABSTRACT FROM AUTHOR]

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

Following virus recognition of host cell receptors and viral particle/genome internalization, viruses replicate in the host via hijacking essential host cell machinery components to evade the provoked antiviral innate immunity against the invading pathogen. Respiratory viral infections are usually acute with the ability to activate pattern recognition receptors (PRRs) in/on host cells, resulting in the production and release of interferons (IFNs), proinflammatory cytokines, chemokines, and IFN-stimulated genes (ISGs) to reduce virus fitness and mitigate infection. Nevertheless, the game between viruses and the host is a complicated and dynamic process, in which they restrict each other via specific factors to maintain their own advantages and win this game. The primary role of the non-structural protein 1 (NS1 and Nsp1) of influenza A viruses (IAV) and the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively, is to control antiviral host-induced innate immune responses. This review provides a comprehensive overview of the genesis, spatial structure, viral and cellular interactors, and the mechanisms underlying the unique biological functions of IAV NS1 and SARS-CoV-2 Nsp1 in infected host cells. We also highlight the role of both non-structural proteins in modulating viral replication and pathogenicity. Eventually, and because of their important role during viral infection, we also describe their promising potential as targets for antiviral therapy and the development of live attenuated vaccines (LAV). Conclusively, both IAV NS1 and SARS-CoV-2 Nsp1 play an important role in virus–host interactions, viral replication, and pathogenesis, and pave the way to develop novel prophylactic and/or therapeutic interventions for the treatment of these important human respiratory viral pathogens. [ABSTRACT FROM AUTHOR]

Nucleic acids are among the most essential PAMPs (pathogen-associated molecular patterns). Animals have evolved numerous sensors to recognize nucleic acids and trigger immune signaling against pathogen replication, cellular stress and cancer. Many sensor proteins (e.g., cGAS, AIM2, and TLR9) recognize the molecular signature of infection or stress and are responsible for the innate immune response to DNA. Remarkably, recent evidence demonstrates that cGAS-like receptors acquire the ability to sense RNA in some forms of life. Compared with the nucleic-acid sensing by cGAS, innate immune responses to RNA are based on various RNA sensors, including RIG-I, MDA5, ADAR1, TLR3/7/8, OAS1, PKR, NLRP1/6, and ZBP1, via a broad-spectrum signaling axis. Importantly, new advances have brought to light the potential clinical application of targeting these signaling pathways. Here, we highlight the latest discoveries in the field. We also summarize the activation and regulatory mechanisms of RNA-sensing signaling. In addition, we discuss how RNA sensing is tightly controlled in cells and why the disruption of immune homeostasis is linked to disease. [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]

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

Pseudomonas aeruginosa is a major human pathogen, particularly effective at colonizing the airways of patients with cystic fibrosis. Bacteriophages are highly abundant at infection sites, but their impact on mammalian immunity remains unclear. We previously showed that Pf4, a temperate filamentous bacteriophage produced by P. aeruginosa, modifies the innate immune response to P. aeruginosa infections via TLR3 signaling, but the underlying mechanisms remained unclear. Notably, Pf4 is a single-stranded DNA and lysogenic phage, and its production does not typically result in lysis of its bacterial host. We identified previously that internalization of Pf4 by human or murine immune cells triggers maladaptive viral pattern recognition receptors and resulted in bacterial persistence based on the presence of phage RNA. We report now that Pf4 phage dampens inflammatory responses to bacterial endotoxin and that this is mediated in part via bacterial vesicles attached to phage particles. Outer membrane vesicles (OMVs) are produced by Gram-negative bacteria and play a key role in host pathogen interaction. Recently, evidence has emerged that OMVs differentially package small RNAs. In this study, we show that Pf4 are decorated with OMVs that remain affixed to Pf4 despite of purification steps. These phages are endocytosed by human cells and delivered to endosomal vesicles. We demonstrate that short RNAs within the OMVs form hairpin structures that trigger TLR3-dependent type I interferon production and antagonize production of antibacterial cytokines and chemokines. In particular, Pf4 phages inhibit CXCL5, preventing efficient neutrophil chemotaxis in response to endotoxin. Moreover, blocking IFNAR orTLR3 signaling abrogates the effect of Pf4 bound to OMVs on macrophage activation. In a murine acute pneumonia model, mice treated with Pf4 associated with OMVs show significantly less neutrophil infiltration in BAL fluid than mice treated with purified Pf4. These changes in macrophage phenotype are functionally relevant: conditioned media from cells exposed to Pf4 decorated with OMVs are significantly less effective at inducing neutrophil migration in vitro and in vivo. These results suggest that Pf4 phages alter innate immunity to bacterial endotoxin and OMVs, potentially dampening inflammation at sites of bacterial colonization or infection. [ABSTRACT FROM AUTHOR]

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

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

C-reactive protein (CRP) is an acute phase, predominantly hepatically synthesized protein, secreted in response to cytokine signaling at sites of tissue injury or infection with the physiological function of acute pro- inflammatory response. Historically, CRP has been classified as a mediator of the innate immune system, acting as a pattern recognition receptor for phosphocholine-containing ligands. For decades, CRP was envisioned as a single, non-glycosylated, multi-subunit protein arranged non-covalently in cyclic symmetry around a central void. Over the past few years, however, CRP has been shown to exist in at least three distinct isoforms: 1.) a pentamer of five identical globular subunits (pCRP), 2.) a modified monomer (mCRP) resulting from a conformational change when subunits are dissociated from the pentamer, and 3.) a transitional isoform where the pentamer remains intact but is partially changed to express mCRP structural characteristics (referred to as pCRP* ormCRPm). The conversion of pCRP intomCRP can occur spontaneously and is observed under commonly used experimental conditions. In careful consideration of experimental design used in published reports of in vitro pro- and anti-inflammatory CRP bioactivities, we herein provide an interpretation of how distinctive CRP isoforms may have affected reported results. We argue that pro-inflammatory amplification mechanisms are consistent with the biofunction of mCRP, while weak anti-inflammatory mechanisms are consistent with pCRP. The interplay of each CRP isoform with specific immune cells (platelets, neutrophils, monocytes, endothelial cells, natural killer cells) and mechanisms of the innate immune system (complement), as well as differences in mCRP and pCRP ligand recognition and effector functions are discussed. This review will serve as a revised understanding of the structure-function relationship between CRP isoforms as related to inflammation and innate immunity mechanisms. [ABSTRACT FROM AUTHOR]

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

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

Maintaining homeostasis is central to organismal health. Deviation is detected by a variety of sensors that react to alarm signals arising from injury, infection, and other inflammatory triggers. One important element of this alarm system is the innate immune system, which recognizes pathogen‐/microbe‐ or damage‐associated molecular patterns via pattern recognition receptors localized in the cytosol or in membranes of innate immune cells such as macrophages, dendritic cells, and mast cells but also of T cells, B cells, and epithelial cells. Activation of the innate immune system results in inflammation and is a pre‐requisite for activation of the adaptive immune system. Another important element is represented by the unfolded protein response (UPR), a stress response of the endoplasmic reticulum. The UPR regulates proteostasis and also contributes to the course of inflammatory diseases such as cancer, diabetes, obesity, and neurodegenerative diseases. In addition, the UPR is instrumental in allergic contact dermatitis. This inflammatory skin disease, affecting 5–10% of the population, is caused by T cells recognizing low‐molecular weight organic chemicals and metal ions. In this mini‐review, we discuss the orchestration of inflammatory responses by the interplay of the innate immune system with cellular stress responses in allergic contact dermatitis, with a focus on the UPR. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a deadly malignancy with limited treatment options. NLRX1 is a unique, understudied member of the Nod-like Receptor (NLR) family of pattern recognition receptors that regulates a variety of biological processes that are highly relevant to pancreatic cancer. The role of NLRX1 in cancer remains highly enigmatic, with some studies defining its roles as a tumor promoter, while others characterize its contributions to tumor suppression. These seemingly contradicting roles appear to be due, at least in part, to cell type and temporal mechanisms. Here, we define roles for NLRX1 in regulating critical hallmarks of pancreatic cancer using both gain-of-function and loss-of-function studies in murine Pan02 cells. Our data reveals that NLRX1 increases susceptibility to cell death, while also suppressing proliferation, migration, and reactive oxygen species production. We also show that NLRX1 protects against upregulated mitochondrial activity and limits energy production in the Pan02 cells. Transcriptomics analysis revealed that the protective phenotypes associated with NLRX1 are correlated with attenuation of NF-kB, MAPK, AKT, and inflammasome signaling. Together, these data demonstrate that NLRX1 diminishes cancer-associated biological functions in pancreatic cancer cells and establishes a role for this unique NLR in tumor suppression. [ABSTRACT FROM AUTHOR]

Innate immune receptors that form complexes with secondary receptors, activating multiple signalling pathways, modulate cellular activation and play essential roles in regulating homeostasis and immunity. We have previously identified a variety of bovine C-type lectin-like receptors that possess similar functionality than their human orthologues. Mincle (CLEC4E), a heavily glycosylated monomer, is involved in the recognition of the mycobacterial component Cord factor (trehalose 6,6′-dimycolate). Here we characterise the bovine homologue of Mincle (boMincle), and demonstrate that the receptor is structurally and functionally similar to the human orthologue (huMincle), although there are some notable differences. In the absence of cross-reacting antibodies, boMincle-specific antibodies were created and used to demonstrate that, like the human receptor, boMincle is predominantly expressed by myeloid cells. BoMincle surface expression increases during the maturation of monocytes to macrophages. However, boMincle mRNA transcripts were also detected in granulocytes, B cells, and T cells. Finally, we show that boMincle binds to isolated bovine CD4+ T cells in a specific manner, indicating the potential to recognise endogenous ligands. This suggests that the receptor might also play a role in homeostasis in cattle. [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]

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

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

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]

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

Interferon (IFN), the most effective antiviral cytokine, is involved in innate and adaptive immune responses and is essential to the host defense against virus invasion. Once the host was infected by pathogens, the pathogen-associated molecular patterns (PAMPs) were recognized by the host pattern recognition receptors (PRRs), which activates interferon regulatory transcription factors (IRFs) and nuclear factor-kappa B (NF-κB) signal transduction pathway to induce IFN expression. Pathogens have acquired many strategies to escape the IFN-mediated antiviral immune response. Pestiviruses cause massive economic losses in the livestock industry worldwide every year. The immune escape strategies acquired by pestiviruses during evolution are among the major difficulties in its control. Previous experiments indicated that Erns, as an envelope glycoprotein unique to pestiviruses with RNase activity, could cleave viral ss- and dsRNAs, therefore inhibiting the host IFN production induced by viral ss- and dsRNAs. In contrast, Npro, the other envelope glycoprotein unique to pestiviruses, mainly stimulates the degradation of transcription factor IRF-3 to confront the IFN response. This review mainly summarized the current progress on mechanisms mediated by Npro of pestiviruses to antagonize IFN production. [ABSTRACT FROM AUTHOR]

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

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

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

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]