Peptidoglycan recognition proteins of the innate immune system

Peptidoglycan (PGN) is the major component of bacterial cell walls and one of the main microbial products recognized by the innate immune system. PGN recognition is mediated by several families of pattern recognition molecules, including Toll-like receptors, nucleotide-binding oligomerization domain-containing proteins, and peptidoglycan recognition proteins (PGRPs). However, only the interaction of PGN with PGRPs, which are highly conserved from insects to mammals, has so far been characterized at the molecular level. Here, we describe recent structural studies of PGRPs that reveal the basis for PGN recognition and provide insights into the signal transduction and antibacterial activities of these innate immune proteins.     

Evolutionary origin of peptidoglycan recognition proteins in vertebrate innate immune system

Background  

Innate immunity is the ancient defense system of multicellular organisms against microbial infection. The basis of this first line of defense resides in the recognition of unique motifs conserved in microorganisms, and absent in the host. Peptidoglycans, structural components of bacterial cell walls, are recognized by Peptidoglycan Recognition Proteins (PGRPs). PGRPs are present in both vertebrates and invertebrates. Although some evidence for similarities and differences in function and structure between them has been found, their evolutionary history and phylogenetic relationship have remained unclear. Such studies have been severely hampered by the great extent of sequence divergence among vertebrate and invertebrate PGRPs. Here we investigate the birth and death processes of PGRPs to elucidate their origin and diversity.     

Evolutionary perspective on innate immune recognition

Analysis of human and Drosophila genomes demonstrates an ancient origin of innate immunity and the diversity of the mechanisms of innate immune recognition.     

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.     

Molecular basis for immune complex recognition: a comparison of Fc-receptor structures

Once antigen is opsonised by IgG it is removed from the circulation by Fcgamma-receptor expressing cells. Fcgamma-receptors are type I transmembrane molecules that carry extracellular parts consisting of two or three immunoglobulin domains. Previously solved structures of Fc-receptors reveal that the N-terminal two Ig-like domains are arranged in a steep angle forming a heart-shaped structure. The crystal structure of the FcgammaRIII/hIgG1-Fc-fragment demonstrated that the Fc-fragment is recognised through loops of the C-terminal receptor domain of the FcgammaRIII. As the overall structure of the FcRs and their Ig ligands are very similar we modelled the Ig complexes with FcgammaRI, FcgammaRII and FcepsilonRIalpha based on the FcgammaRIII/hIgG1-Fc-fragment structure. The obtained models are consistent with the observed biochemical data and may explain the observed specificity and affinities.     

An integrated model of the recognition of Candida albicans by the innate immune system

The innate immune response was once considered to be a limited set of responses that aimed to contain an infection by primitive 'ingest and kill' mechanisms, giving the host time to mount a specific humoral and cellular immune response. In the mid-1990s, however, the discovery of Toll-like receptors heralded a revolution in our understanding of how microorganisms are recognized by the innate immune system, and how this system is activated. Several major classes of pathogen-recognition receptors have now been described, each with specific abilities to recognize conserved bacterial structures. The challenge ahead is to understand the level of complexity that underlies the response that is triggered by pathogen recognition. In this Review, we use the fungal pathogen Candida albicans as a model for the complex interaction that exists between the host pattern-recognition systems and invading microbial pathogens.     

Collectins and ficolins: sugar pattern recognition molecules of the mammalian innate immune system

Collectins and ficolins represent two important groups of pattern recognition molecules, which bind to oligosaccharide structures on the surface of microorganisms, leading to the killing of bound microbes through complement activation and phagocytosis. Collectins and ficolins bear no significant sequence homology except for the presence of collagen-like sequences over the N-terminal halves of the polypeptides that enable the assembly of these molecules into oligomeric structures. Collectins and ficolins both contain lectin activities within the C-terminal halves of their polypeptides, the C-type carbohydrate recognition domain (CRDs) and fibrinogen beta/gamma (homology) (FBG) domain, respectively. These domains form trimeric clusters at the ends of the collagen triple helices emanating from a central hub, where the N-terminal ends of the polypeptides merge. The collectins and ficolins seem to have evolved to recognize the surface sugar codes of microbes and their binding, to these arrays of cell surface carbohydrate molecules, targets the microbe for subsequent clearance by phagocytic cells.     

Solution NMR studies provide structural basis for endotoxin pattern recognition by the innate immune receptor CD14

CD14 functions as a key pattern recognition receptor for a diverse array of Gram-negative and Gram-positive cell-wall components in the host innate immune response by binding to pathogen-associated molecular patterns (PAMPs) at partially overlapping binding site(s). To determine the potential contribution of CD14 residues in this pattern recognition, we have examined using solution NMR spectroscopy, the binding of three different endotoxin ligands, lipopolysaccharide, lipoteichoic acid, and a PGN-derived compound, muramyl dipeptide to a ¹⁵N isotopically labeled 152-residue N-terminal fragment of sCD14 expressed in Pichia pastoris. Mapping of NMR spectral changes upon addition of ligands revealed that the pattern of residues affected by binding of each ligand is partially similar and partially different. This first direct structural observation of the ability of specific residue combinations of CD14 to differentially affect endotoxin binding may help explain the broad specificity of CD14 in ligand recognition and provide a structural basis for pattern recognition. Another interesting finding from the observed spectral changes is that the mode of binding may be dynamically modulated and could provide a mechanism for binding endotoxins with structural diversity through a common binding site.     

The innate immune system in the intestine

The innate immune system provides the first line of host defense against invading pathogens. Innate immune responses are initiated by germline-encoded PRR, which recognize specific structures expressed by microorganisms. TLR are a family of PRR which sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLR are also expressed in the intestine and are critical for intestinal homeostasis. Recently, cytoplasmic PRR, such as NLR and RLR, have been shown to detect pathogens that have invaded the cytosol. One of the NLR, NOD2, is thought to be involved in the pathogenesis of Crohn's disease. This review focuses on the innate immune responses triggered by PRR in the intestine.     

Immunological memory within the innate immune system

Immune memory has traditionally been the domain of the adaptive immune system, present only in antigen‐specific T and B cells. The purpose of this review is to summarize the evidence for immunological memory in lower organisms (which are not thought to possess adaptive immunity) and within specific cell subsets of the innate immune system. A special focus will be given to recent findings in both mouse and humans for specificity and memory in natural killer (NK) cells, which have resided under the umbrella of innate immunity for decades. The surprising longevity and enhanced responses of previously primed NK cells will be discussed in the context of several immunization settings.     

乙型脑炎病毒感染神经元细胞的固有免疫识别及其调控分子的研究进展

流行性乙型脑炎(epidemic encephalitis type B,简称乙脑)是由乙型脑炎病毒(encephalitis B virus,简称乙脑病毒)感染引起的中枢神经系统疾病。乙脑病毒感染具有明显的嗜神经性,它在神经元细胞中大量增殖并造成其损伤,以干扰素(interferons, IFNs)为核心的固有免疫应答在机体抵御乙脑病毒感染的过程中发挥重要作用。多项研究表明,乙脑病毒感染神经元细胞后,宿主细胞模式识别受体可识别病毒的结构成分,并经接头分子和转录因子等信号传递,介导IFN的产生。IFN随后激活下游干扰素信号通路,转录多种干扰素诱导基因(interferon stimulated genes, ISGs),启动宿主对病毒的固有免疫应答反应。现就乙脑病毒感染神经元细胞的固有免疫相关分子,如模式识别分子、关键接头分子、转录因子及IFN信号转导过程中相关的调控分子作一概述。     

泛素-蛋白酶体系统在昆虫先天免疫中的调控作用

完善的先天免疫系统使得昆虫成为分布最广、适应性最强、物种多样性最丰富的动物类群。在长期的进化过程中,昆虫建立了一套安全有效的先天免疫系统,一方面在面对外界微生物攻击的时候及时有效的发生免疫应答反应;另一方面通过免疫抑制来调控适度免疫应答,避免对自身发动攻击和控制环境共生菌刺激引起的免疫应答信号通路的持续激活。泛素-蛋白酶体系统在昆虫先天免疫中具有重要的调控作用,在Toll和IMD信号通路中,通过对免疫应答通路中信号分子的泛素化修饰加工,促进或抑制抗菌肽的表达,从而使免疫反应达到一个平衡。本文通过对泛素-蛋白酶体系统在Toll和IMD信号通路中的免疫应答和免疫抑制方面的研究进行综述,阐明了该系统在昆虫先天免疫中的调控作用,将有助于开展农业害虫与其天敌之间相互关系的深入研究,揭示其免疫调控机理,为开发生物农药,进行生物防控提供理论依据。     

Molecular battle between host and bacterium: recognition in innate immunity

During infection, our innate immune system is the first line of defense and has evolved to clear invading bacteria immediately. To do so, recognition is the key element. However, how does the innate immune system distinguish self from nonself, and how does it recognize all bacteria (estimated to be far over a million species)? The answer lies in the recognition of evolutionary conserved structures. In this review, we approach this phenomenon from the bacterial perspective. What are the evolutionary conserved structures in bacteria, and what strategies are there in the human innate immune system to sense these structures? We illustrate most examples both at the functional as well as at the molecular level. Furthermore, we highlight how pathogenic bacteria can evade this recognition to survive better in the human host which in turn can result in life‐threatening diseases. Copyright © 2011 John Wiley & Sons, Ltd.     

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.     

The innate immune system in allograft rejection and tolerance

As T cells alone are both necessary and sufficient for the rejection of virtually all allogeneic tissues, much of transplantation immunology has focused on cells of the adaptive immune system. During the past decade, advances in our understanding of innate responses to pathogen-associated molecules have spurred a "rediscovery" of innate immunity. Fueled by this, an increasing body of literature has emerged in which the role of the innate immune system in allograft rejection and tolerance has been examined more closely. This review will give an overview of recent studies and emerging concepts of how the cellular components of the innate immune system participate in the immune response to solid organ transplantation. These important studies highlight the complex interplay between diverse cells of the immune response and provide the basis for optimal strategies of tolerance induction.