模式识别受体介导的病原免疫逃逸

天然免疫通过细胞模式识别受体识别病原相关分子模式来清除感染。但是,在长期的进化过程中,许多病原体已经形成了自身的保护机制,从而逃逸天然免疫的杀伤。综述了模式识别受体介导的病原体的主要逃逸机制,以期为疾病的控制和预防提供新认识。     

Domain architecture evolution of pattern-recognition receptors

In animals, the innate immune system is the first line of defense against invading microorganisms, and the pattern-recognition receptors (PRRs) are the key components of this system, detecting microbial invasion and initiating innate immune defenses. Two families of PRRs, the intracellular NOD-like receptors (NLRs) and the transmembrane Toll-like receptors (TLRs), are of particular interest because of their roles in a number of diseases. Understanding the evolutionary history of these families and their pattern of evolutionary changes may lead to new insights into the functioning of this critical system. We found that the evolution of both NLR and TLR families included massive species-specific expansions and domain shuffling in various lineages, which resulted in the same domain architectures evolving independently within different lineages in a process that fits the definition of parallel evolution. This observation illustrates both the dynamics of the innate immune system and the effects of “combinatorially constrained” evolution, where existence of the limited numbers of functionally relevant domains constrains the choices of domain architectures for new members in the family, resulting in the emergence of independently evolved proteins with identical domain architectures, often mistaken for orthologs.     

Plant pattern-recognition receptors controlling innate immunity

Plants are exposed to numerous potential pathogenic microbes. To counter the threat, plants have evolved diverse patternrecognition receptors(PRRs), which are receptor kinases(RKs) and receptor proteins(RPs) specialized to detect conserved pathogen/microbe-associated molecular patterns(PAMPs/MAMPs). Although only a handful of RKs and RPs are known PRRs,they belong to the receptor-like kinase(RLK) and receptor-like protein(RLP) superfamilies that undergo lineage-specific expansion, suggesting that many of these RLKs and RLPs are potential PRRs. Analyses of existing PRRs have uncovered ligand-induced RLK-RK or RLK-RP oligomerization as a common mechanism for immune activation. PRRs can recruit additional components to form dynamic receptor complexes, which mediate specific cellular responses. Detailed analyses of these components are shedding light on molecular mechanisms underlying the regulation of PRR activity and downstream signaling.     

Immunophysiology of epithelial cells and pattern-recognition receptors

Many types of pattern-recognition receptors, including the group of signaling Toll-like receptors, have been found in epithelial cells. They serve for recognizing microorganisms, which induces the activation of epithelial cells followed by production of chemokines and antimicrobial substances. On the one hand, this attracts macrophages, neutrophils, and other cells of innate immunity eliminating microorganisms to the epithelial locus. The same pattern-recognition receptors are involved in cell activation resulting in the production of cytokines that trigger the controlled activation of adaptive-immunity cells. This leads to the formation of anti-bodies or cytotoxic T lymphocytes. On the other hand, activated epithelial cells produce an array of antimicrobial substances suppressing enteropathogenic microflora inhabiting external epithelial spaces. Conversely, local tolerance is developed with respect to predominant microflora of epithelial tracts. This tolerance encompasses both innate and adaptive immunities of subepithelial spaces. Although much remains to be understood regarding the mechanisms of its formation and maintenance, it is obvious that epithelial cells play an important role in these processes. Thus, epithelial cells “conduct” immune responses to both pathogenic microorganisms penetrating the host body and microorganisms inhabiting epithelial cellular spaces. The maintenance of the optimal composition of the microbial biocenosis of the human body is a function of its immune system.     

Toll-like receptors: a family of pattern-recognition receptors in mammals

The innate immune system uses a variety of germline-encoded pattern-recognition receptors that recognize conserved microbial structures or pathogen-associated molecular patterns, such as those that occur in the bacterial cell-wall components peptidoglycan and lipopolysaccharide. Recent studies have highlighted the importance of Toll-like receptors (TLRs) as a family of pattern-recognition receptors in mammals that can discriminate between chemically diverse classes of microbial products. First identified on the basis of sequence similarity with the Drosophila protein Toll, TLRs are members of an ancient superfamily of proteins, which includes related proteins in invertebrates and plants. TLRs activate innate immune defense reactions, such as the release of inflammatory cytokines, but increasing evidence supports an additional critical role for TLRs in orchestrating the development of adaptive immune responses. The sequence similarity between the intracellular domains of the TLRs and the mammalian interleukin-1 and interleukin-18 cytokine receptors reflects the use of a common intracellular signal-transduction cascade triggered by these receptor classes. But more recent findings have demonstrated that there are in fact TLR-specific signaling pathways and cellular responses. Thus, TLRs function as sentinels of the mammalian immune system that can discriminate between diverse pathogen-associated molecular patterns and then elicit pathogen-specific cellular immune responses.     

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。     

Physiology of adaptive immunity regulation via signaling pattern-recognition receptors

In the past fifty years, adaptive immune response has been studied from the standpoint of Burnet’s clonal selection theory. Much progress in understanding the mechanisms of specific cellular (T-cell) and antibody (B-cell) immune response has been made. However, it remained unclear why different pathogen types induce principally different types of immune response. Effective immune response in different cases may develop either by cellular or humoral type, and antibodies are produced on the basis of immunoglobulins of different classes. These facts could only be explained by specific regulation of differentiation of immunocompetent cells during the development of adaptive immune response to different pathogens. The discovery of the system of signaling pattern-recognition receptors (PRRs) in immunocompetent cells made it possible to understand these specific physiological mechanisms of regulation of T- and B-cell response to various pathogens. Upon interaction with pathogens, signaling PRRs activate the synthesis of various cytokines in the cells, which then regulate further activation of cells in different directions. Dendritic cells not only provide naive T cells with a processed antigen but also supply them with various cytokines inducing formation of type 1 or 2 T-helpers; as a result, adaptive immune response develops by the cellular or humoral type, respectively. Antigens of pathogens activate PRRs in B lymphocytes, which initiate the synthesis of various cytokines in cells. These are cytokines that determine predominant production by plasma cells of class A, M, G, or E antibodies depending on the pathogen type.     

天然免疫模式识别受体与树突状细胞的发现和意义——2011年诺贝尔生理学或医学奖成果和相关研究简介

2011年的诺贝尔生理学或医学奖授予了Bruce A．Beutler,Jules A．Hoffmann以及Ralph M．Steinman教授,以奖励他们在天然免疫模式识别受体和树突状细胞研究领域所做出的开创性贡献。宿主的天然免疫系统依赖模式识别受体识别入侵的病原微生物,并通过树突状细胞对其加工处理将抗原提呈给T细胞,从而激活适应性免疫。回顾模式识别受体和树突状细胞发现的过程,介绍该领域最近的研究进展,并对它们在疾病预防和治疗中的应用进行了讨论。     

Roles of ubiquitination in pattern-recognition receptors and type I interferon receptor signaling

Post-translational protein modifications are involved in all functions of living cells. This includes the ability of cells to recognize pathogens and regulate genes involved in their clearance, a concept known as innate immunity. While phosphorylation mechanisms play essential roles in regulating different aspects of the innate immune response, ubiquitination is now recognized as another post-translational modification that works in parallel with phosphorylation to orchestrate the final proper innate immune response against invading pathogens. More precisely, this review will discuss the most recent advances that address the role of ubiquitination in pattern-recognition receptors and type I interferon receptor signaling.     

Activation of solubilized G-proteins by muscarinic acetylcholine receptors

Binding of GTP and its analogue, guanosine 5′-O-[γ-thio]triphosphate (GTP[S]) to G-proteins, and release of GTP[S] from G-proteins are stimulated by muscarinic acetylcholine (mACh) receptors in intact cardiac membranes. Upon solubilization of receptors and G-proteins by membrane extraction with the detergent, 3-[(cholamidopropyl)dimethylammonio]-1-propanesulphonate, followed by sucrose density gradient centrifugation, agonist-liganded mACh receptors stimulated binding of GTP[S] and hydrolysis of GTP by G-proteins with similar requirements as in intact membranes. One soluble agonist-activated mACh receptor induced binding of GTP[S] to several (about seven) soluble G-proteins. In contrast to intact membranes, however, agonist activation of mACh receptors did not induce release of GTP[S] from solubilized G-proteins. The data presented indicate that mACh receptors can interact with and efficiently activate G-proteins even in solution, whereas the possible interaction of receptors with GTP[S]-liganded G-proteins observed in intact membranes is lost upon solubilization of these components.     

Activation of B2 bradykinin receptors by neurotensin

Many previous reports suggested that relatively high concentrations of neurotensin were required to exert its effects on neurotransmitter secretion. The neurotensin binding sites, which recognize high concentrations of neurotensin, were characterized in rat pheochromocytoma (PC12) cells. When PC12 cells were treated with neurotensin, [3H]norepinephrine secretion and elevation of cytosolic calcium were evoked at EC(50) values of 59+/-4 and 37+/-7 microM, respectively. Both calcium release and inositol 1,4,5-trisphosphate (IP(3)) production induced by neurotensin suggested involvement of phospholipase C. Experiments with simultaneous or sequential treatment with neurotensin and bradykinin suggested that neurotensin and bradykinin act on the same binding sites. Furthermore, both inhibition of bradykinin- and neurotensin-induced calcium rises by bradykinin receptor antagonists with similar IC(50) values and receptor binding analysis using [3H]bradykinin confirmed that neurotensin directly binds to B2 bradykinin receptors. The data suggest that neurotensin binds and activates the B2 bradykinin receptors.     

Activation of a plant invertase by inorganic phosphate

Activation by orthophosphate of a plant invertase from root nodules of Lupinus luteus L. has been demonstrated. The activation affects an increase in maximum velocity (V(max)) of the reaction. Activation was also achieved with a number of similar anions and it has been possible to infer a broad classification of anions capable of serving as activators. The possibility of orthophosphate activation in vivo has been considered, and there is some evidence to suggest that this could regulate invertase activity under physiological conditions.     

Endophytic colonization of plant roots by nitrogen-fixing bacteria

Plant and Soil - Nitrogen-fixing bacteria are able to enter into roots from the rhizosphere, particularly at the base of emerging lateral roots, between epidermal cells and through root hairs. In...     

Activation of human bitter taste receptors by polymethoxylated flavonoids

Tangeretin and nobiletin are polymethoxylated flavonoids in citrus peel. Both tangeretin and nobiletin are bitter; however, their bitterness has not been evaluated using human bitter taste receptors (hTAS2Rs). We screened 25 kinds of hTAS2Rs and found that hTAS2R14 and hTAS2R46 received both compounds.     

Activation of two environmental mixtures by plant S9

Nitrated and ozonized pyrene mixtures were assayed for their mutagenic activity in the presence or absence of pea S9 using Salmonella typhimurium TA98 as the indicator organism. The plant enzymes increased the mutagenic response of these mixtures above that obtained in the absence of S9. The optimum S9 protein concentration for the activation of the nitrated pyrene mixture at 0.1 microgram was 3.9 mg/plate whereas that for the ozonized pyrene mixture at 33.3 micrograms was 3.2 mg protein/plate. BSA could not replace S9, and NADPH was a required co-factor in the activation of both mixtures by pea S9. Although the nitrated pyrene mixture was determined to consist of approximately 90% 1-nitropyrene, the mutagenic response due to this compound ranged from 30 to 50% of that of the mixture.