Interaction investigations of crustacean β‐GBP recognition toward pathogenic microbial cell membrane and stimulate upon prophenoloxidase activation

In invertebrates, crustaceans' immune system consists of pattern recognition receptors (PRRs) instead of immunoglobulin's, which involves in the microbial recognition and initiates the protein–ligand interaction between hosts and pathogens. In the present study, PRRs namely β‐1,3 glucan binding protein (β‐GBP) from mangrove crab Episesarma tetragonum and its interactions with the pathogens such as bacterial and fungal outer membrane proteins (OMP) were investigated through microbial aggregation and computational interaction studies. Molecular recognition and microbial aggregation results of Episesarma tetragonum β‐GBP showed the specific binding affinity toward the fungal β‐1,3 glucan molecule when compared to other bacterial ligands. Because of this microbial recognition, prophenoloxidase activity was enhanced and triggers the innate immunity inside the host animal. Our findings disclose the role of β‐GBP in molecular recognition, host–pathogen interaction through microbial aggregation, and docking analysis. In vitro results were concurred with the in silico docking, and molecular dynamics simulation analysis. This study would be helpful to understand the molecular mechanism of β‐GBP and update the current knowledge on the PRRs of crustaceans. Copyright © 2014 John Wiley & Sons, Ltd.     

Innate immunity: structure and function of TLRs

The innate immune system provides the first line of defence against infection. Through a limited number of germline-encoded receptors called pattern recognition receptors (PRRs), innate cells recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). PRRs are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins characterized by an intracellular Toll/IL 1 receptor homology domain that are expressed by innate immune cells (dendritic cells, macrophages, NK cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts). In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The crucial role played by TLR in immune cell activation has been detailed in dendritic cells. A TLR-dependent activation of dendritic cells is required to induce their maturation and migration to regional lymph nodes and to activate na?ve T cells. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Recent studies suggest that the nature of the endocytic and signaling receptors engaged by PAMPs may determine the nature of the immune response generated against the microbial molecules, highlighting the role of TLRs as molecular interfaces between innate and adaptive immunity. In this review are summarized the main biological properties of the TLR molecules.     

Plant pattern recognition receptor complexes at the plasma membrane

A key feature of innate immunity is the ability to recognize and respond to potential pathogens in a highly sensitive and specific manner. In plants, the activation of pattern recognition receptors (PRRs) by pathogen-associated molecular patterns (PAMPs) elicits a defense programme known as PAMP-triggered immunity (PTI). Although only a handful of PAMP-PRR pairs have been defined, all known PRRs are modular transmembrane proteins containing ligand-binding ectodomains. It is becoming clear that PRRs do not act alone but rather function as part of multi-protein complexes at the plasma membrane. Recent studies describing the molecular interactions and protein modifications that occur between PRRs and their regulatory proteins have provided important mechanistic insight into how plants avoid infection and achieve immunity.     

Innate recognition of microbial-derived signals in immunity and inflammation

Microbes generate a vast array of different types of conserved structural components called pathogen-associated molecular patterns(PAMPs),which canbe recognized by cells of the innate immune system.This recognition of "nonself" signatures occurs through host pattern recognition receptors(PRRs),suggesting that microbial-derived signals are good targets for innate immunity to discriminate between self- and nonself.Such PAMP-PRR interactions trigger multiple but distinct downstream signaling cascades,subsequently leading to production of proinflammatory cytokines and interferons that tailor immune responses to particular microbes.Aberrant PRR signals have been associated with various inflammatory diseases and fine regulation of PRR signaling is essential for avoiding excessive inflammatory immune responses and maintaining immune homeostasis.In this review we summarize the ligands and signal transduction pathways of PRRs and highlight recent progress of the mechanisms involved in microbe-specific innate immune recognition during immune responses and inflammation,which may provide new targets for therapeutic intervention to the inflammatory disorders.     

Structural bioinformatics insights into the CARD-CARD interaction mediated by the mitochondrial antiviral-signaling protein of black carp

The innate immune system offers the first line of defense against invading microbial pathogens through the recognition of conserved pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). The host innate immune system through PRRs, the sensors for PAMPs, induces the production of cytokines. Among different families of PRRs, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and its mitochondrial adaptor ie, the mitochondrial antiviral-signaling (MAVS) protein, are crucial for RLR-triggered interferon (IFN) antiviral immunity. Recent studies have shown that the N-terminal caspase recruitment domain (CARD) and transmembrane domain play a pivotal role in oligomerization of black carp MAVS (BcMAVS), crucial for the host innate immune response against viral invasion. In this study, we have used molecular modeling, docking, and molecular dynamics (MD) simulation approaches to shed molecular insights into the oligomerization mechanism of BcMAVS^CARD. MD simulation and interaction analysis portrayed that the type-I surface patches of BcMAVS ^CARD make the major contribution to the interaction. Moreover, the evidence from surface patches and critical residues involved in the said interaction is found to be similar to that of the human counterpart and requires further investigation for legitimacy. Altogether, our study provided crucial information on oligomerization of BcMAVS CARDs and might be helpful for clarifying the innate immune response against pathogens and downstream signaling in fishes.     

PRRs in pathogen recognition

The innate immune system provides the first line of host defense against invading microorganisms before the development of adaptive immune responses. Innate immune responses are initiated by germline-encoded pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Toll-like receptors (TLRs) are pattern-recognition receptors that sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLRs exist either on the cell surface or in the lysosome/endosome compartment and induce innate immune responses. Recently, cytoplasmic PRRs have been identified which detect pathogens that have invaded the cytosol. This review focuses on the pathogen recognition of PRRs in innate immunity.     

植物与病原菌互作的分子机制研究进展

植物的先天免疫主要包括模式识别受体对保守的微生物病原相关分子模式的识别和抗病蛋白对效应蛋白的识别。植物与病原体互作过程中存在广泛的信号交流,信号分子在植物与病原体的互作攻防中发挥了重要的调控作用,决定了二者的竞争关系。当前,大量植物与病原体互作中的信号分子被定位和克隆,其作用方式被揭示。本文总结了这些信号分子及其在植物免疫过程中的作用机制,主要包括植物细胞表面的模式识别受体分子对病原相关分子模式的识别与应答,植物抗病蛋白对病原体效应蛋白的识别与应答,以及免疫反应下游相关信号分子及其在植物抗病中的作用。此外,本文对未来相关研究提出了展望。     

Characterisation of innate fungal recognition in the lung

The innate recognition of fungi by leukocytes is mediated by pattern recognition receptors (PRR), such as Dectin-1, and is thought to occur at the cell surface triggering intracellular signalling cascades which lead to the induction of protective host responses. In the lung, this recognition is aided by surfactant which also serves to maintain the balance between inflammation and pulmonary function, although the underlying mechanisms are unknown. Here we have explored pulmonary innate recognition of a variety of fungal particles, including zymosan, Candida albicans and Aspergillus fumigatus, and demonstrate that opsonisation with surfactant components can limit inflammation by reducing host-cell fungal interactions. However, we found that this opsonisation does not contribute directly to innate fungal recognition and that this process is mediated through non-opsonic PRRs, including Dectin-1. Moreover, we found that pulmonary inflammatory responses to resting Aspergillus conidia were initiated by these PRRs in acidified phagolysosomes, following the uptake of fungal particles by leukocytes. Our data therefore provides crucial new insights into the mechanisms by which surfactant can maintain pulmonary function in the face of microbial challenge, and defines the phagolysosome as a novel intracellular compartment involved in the innate sensing of extracellular pathogens in the lung.     

Dendritic cells and C-type lectin receptors: coupling innate to adaptive immune responses

Dendritic cells (DCs) have an important function in the initiation and differentiation of immune responses, linking innate information to tailored adaptive responses. Depending on the pathogen invading the body, specific immune responses are built up that are crucial for eliminating the pathogen from the host. Host recognition of invading microorganisms relies on evolutionarily ancient, germline-encoded pattern recognition receptors (PRRs) that are highly expressed on the cell surface of DCs, of which the Toll-like receptors (TLRs) are well characterized and recognize bacterial or viral components. Moreover, they bind a variety of self-proteins released from damaged tissues including several heat-shock proteins. The membrane-associated C-type lectin receptors (CLRs) recognize glycan structures expressed by host cells of the immune system or on specific tissues, which upon recognition allow cellular interactions between DCs and other immune or tissue cells. In addition, CLRs can function as PRRs. In contrast to TLRs, CLRs recognize carbohydrate structures present on the pathogens. Modification of glycan structures on pathogens to mimic host glycans can thereby alter CLR interactions that subsequently modifies DC-induced polarization. In this review, we will discuss in detail how specific glycosylation of antigens can dictate both the innate and adaptive interactions that are mediated by CLRs on DCs and how this balances immune activation and inhibition of DC function.     

Role of Nods in bacterial infection

Research into intracellular sensing of microbial products is an up and coming field in innate immunity. Nod1 and Nod2 are members of the rapidly expanding family of NACHT domain-containing proteins involved in intracellular recognition of bacterial products. Nods proteins are involved in the cytosolic detection of peptidoglycan motifs of bacteria, recognized through the LRR domain. The role of the NACHT-LRR system of detection in innate immune responses is highlighted at the mucosal barrier, where most of the membranous Toll like receptors (TLRs) are not expressed, or with pathogens that have devised ways to escape TLR sensing. For a given pathogen, the sum of the pathways induced by the recognition of the different "pathogen associated molecular patterns" (PAMPs) by the different pattern recognition receptors (PRRs) trigger and shape the subsequent innate and adaptive immune responses. Knowledge gathered during the last decade on PRR and their agonists, and recent studies on bacterial infections provide new insights into the immune response and the pathogenesis of human infectious diseases.     

From virus to inflammation: mechanisms of RIG-I-induced IL-1β production

Early detection of viruses by the innate immune system is critical for host defense. Antiviral immunity is initiated by germline encoded pattern recognition receptors (PRRs) that recognize viral pathogen-associated molecular patterns (PAMPs) such as nucleic acids. Intracellular PRRs then drive the production of interferons and cytokines to orchestrate immune responses. One key host factor that is critical for antiviral immunity and for systemic inflammatory reactions including fever is interleukin-1beta (IL-1β). Here we discuss current insights into the molecular mechanisms how the cytosolic RNA helicase RIG-I triggers NF-κB signaling and inflammasome activation specifically for RNA virus-induced IL-1β production.     

Review of innate and specific immunity in plants and animals

Innate immunity represents a trait common to plants and animals, based on the recognition of pathogen associated molecular patterns (PAMPs) by the host pattern recognition receptors (PRRs). It is generally assumed that a pathogen strain, or race, may have elaborated mechanisms to suppress, or evade, the PAMP-triggered immunity. Once this plan was successful, the colonization would have been counteracted by an adaptive strategy that a plant cultivar must have evolved as a second line of defence. In this co-evolutionary context, adaptive immunity and host resistance (cultivar-pathogen race/strain-specific) has been differently selected, in animals and plants respectively, to face specialized pathogens. Notwithstanding, plant host resistance, based on matching between resistance (R) and avirulence (avr) genes, represents a form of innate immunity, being R proteins similar to PRRs, although able to recognize specific virulence factors (avr proteins) rather than PAMPs. Besides, despite the lack of adaptive immunity preserved plants from autoimmune disorders, inappropriate plant immune responses may occur, producing some side-effects, in terms of fitness costs of induced resistance and autotoxicity. A set of similar defence responses shared from plants and animals, such as defensins, reactive oxygen species (ROS), oxylipins and programmed cell death (PCD) are briefly described.     

Molecular regulation of inflammation and cell death

Cell death and innate immunity are ancient evolutionary conserved processes that utilize a dazzling number of related molecular effectors and parallel signal transduction mechanisms. The investigation of the molecular mechanisms linking the sensing of a danger signal (pathogens or tissue damage) to the induction of an inflammatory response has witnessed a renaissance in the last few years. This was initiated by the identification of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and more recently cytosolic Nod-like receptors (NLRs), that brought innate immunity to center stage and opened the field to the study of signal transduction pathways, adaptors and central effectors linked to PRRs. This led to the characterization of the inflammasome, a macromolecular complex, scaffolded by NLRs, that recruits and activates inflammatory caspases, which are essential effectors in inflammation and cell death responses. In this review, we describe the molecular pathways of cell death and innate immunity with a focus on recent advancements in both fields and an emphasis on the striking analogies between NLR innate immunity and mitochondrial apoptosis pathways.     

A major role for intestinal epithelial nucleotide oligomerization domain 1 (NOD1) in eliciting host bactericidal immune responses to Campylobacter jejuni

Campylobacter jejuni is the foremost cause of bacterial-induced diarrhoeal disease worldwide. Although it is well established that C. jejuni infection of intestinal epithelia triggers host innate immune responses, the mechanism(s) involved remain poorly defined. Innate immunity can be initiated by families of structurally related pattern-recognition receptors (PRRs) that recognize specific microbial signature motifs. Here, we demonstrated maximal induction of epithelial innate responses during infection with live C. jejuni cells. In contrast when intestinal epithelial cells (IECs) were exposed to paraformaldehyde-fixed bacteria, host responses were minimal and a marked reduction in the number of intracellular bacteria was noted in parallel. These findings suggested a role for intracellular host-C. jejuni interactions in eliciting early innate immunity. We therefore investigated the potential involvement of a family of intracellular, cytoplasmic PRRs, the nucleotide-binding oligomerization domain (NOD) proteins in C. jejuni recognition. We identified NOD1, but not NOD2, as a major PRR for C. jejuni in IEC. We also found that targeting intestinal epithelial NOD1 with small interfering RNA resulted in an increase in number of intracellular C. jejuni, thus highlighting a critical role for NOD1-mediated antimicrobial defence mechanism(s) in combating this infection at the gastrointestinal mucosal surface.     

Pattern recognition receptors acting in innate immune system of shrimp against pathogen infections

Invertebrates, including shrimp, have developed very complicated innate immune system against pathogens. Much work has been performed on the innate immunity of shrimp, including immune recognition, signal transduction, effector molecules and antiviral responses due to its great economic value. Pattern recognition is the first step of innate immunity. Pattern recognition receptors (PRRs) sense the presence of infection and activate immune responses. The studies on shrimp PRRs revealed the recognition mechanism of shrimp at a certain degree. To date, 11 types of pattern recognition receptors (PRRs) have been identified in shrimp, namely, β-1,3-glucanase-related proteins, β-1,3-glucan-binding proteins, C-type lectins, scavenger receptors, galectins, fibrinogen-related proteins, thioester-containing protein, Down syndrome cell adhesion molecule, serine protease homologs, trans-activation response RNA-binding protein and Toll like receptors. A number of PRRs have been functionally studied and have been found to have different binding specificities and immune functions. The present review aims to summarize the current knowledge on the PRRs of shrimp.     

Recognition of herpesviruses by the innate immune system

Advances in innate immunity over the past decade have revealed distinct classes of pattern recognition receptors (PRRs) that detect pathogens at the cell surface and in intracellular compartments. This has shed light on how herpesviruses, which are large disease-causing DNA viruses that replicate in the nucleus, are initially recognized during cellular infection. Surprisingly, this involves multiple PRRs both on the cell surface and within endosomes and the cytosol. In this article we describe recent advances in our understanding of innate detection of herpesviruses, how this innate detection translates into anti-herpesvirus host defence, and how the viruses seek to evade this innate detection to establish persistent infections.     

鱼类模式识别受体的研究进展

天然免疫（innate immunity）是基于对病原微生物成分的非克隆性识别而启动的快速防御反应。天然免疫系统可通过胚系编码的模式识别受体（pattern-recognition receptors,PRR）识别恒定不变的病原基元,即病原相关分子模式（pathogen-associated molecular patterns,PAMPs）,启动信号级联转导,最终PRRs信号激活宿主免疫和前炎性基因的表达,引发针对所识别病原的免疫反应。目前PRRs主要分为5类,即C-型Lectins、Toll样受体（Toll-like receptors,TLRs）、视黄酸诱导基因I样受体（retinoic acid inducible gene I-like receptors,RLRs）、包含核苷酸结合区和亮氨酸富集区蛋白（the nucleotide-binding domain,leucine-rich repeatcontaining proteins,NLRs,也称NOD样受体）和最近发现的AIM样受体（absent in melanoma（AIM）-like receptors,ALRs）。近年来,随着5种鱼类基因组序列草图的完成,大量鱼类PRRs基因被发现,一些PRRs的配体特异性及其相关信号途径正在逐渐明晰。为此,将对鱼类Toll样受体（TLRs）、视黄酸诱导基因I样受体（RLRs）和NOD样受体（NLRs）的研究进展进行综述。     

Elicitation and suppression of microbe-associated molecular pattern-triggered immunity in plant-microbe interactions

Recent studies have uncovered fascinating molecular mechanisms underlying plant-microbe interactions that coevolved dynamically. As in animals, the primary plant innate immunity is immediately triggered by the detection of common pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs). Different MAMPs are often perceived by distinct cell-surface pattern-recognition receptors (PRRs) and activate convergent intracellular signalling pathways in plant cells for broad-spectrum immunity. Successful pathogens, however, have evolved multiple virulence factors to suppress MAMP-triggered immunity. Specifically, diverse pathogenic bacteria have employed the type III secretion system to deliver a repertoire of virulence effector proteins to interfere with host immunity and promote pathogenesis. Plants challenged by pathogens have evolved the secondary plant innate immunity. In particular, some plants possess the specific intracellular disease resistance (R) proteins to effectively counteract virulence effectors of pathogens for effector-triggered immunity. This potent but cultivar-specific effector-triggered immunity occurs rapidly with localized programmed cell death/hypersensitive response to limit pathogen proliferation and disease development. Remarkably, bacteria have further acquired virulence effectors to block effector-triggered immunity. This review covers the latest findings in the dynamics of MAMP-triggered immunity and its interception by virulence factors of pathogenic bacteria.