Phagosome as the organelle linking innate and adaptive immunity

The means by which phagocytosis and antimicrobial defense mechanisms are linked have expanded greatly in recent years. It is now clear that the process of phagocytosis does more than just degrade internalized microbes, but also helps coordinate the actions of the innate and adaptive immune system. This review will discuss the means by which Toll-like receptor signaling pathways are coordinated around the processes of phagocytosis, phagosome trafficking and autophagy and how these signaling pathways influence T-cell-mediated immunity. In this regard, we propose that at the subcellular level, phagosomes represent the smallest definable unit that links innate and adaptive immunity.     

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.     

Structural and functional characterization of a highly specific serpin in the insect innate immunity

The Toll signaling pathway, an essential innate immune response in invertebrates, is mediated via the serine protease cascade. Once activated, the serine proteases are irreversibly inactivated by serine protease inhibitors (serpins). Recently, we identified three serpin-serine protease pairs that are directly involved in the regulation of Toll signaling cascade in a large beetle, Tenebrio molitor. Of these, the serpin SPN48 was cleaved by its target serine protease, Spätzle-processing enzyme, at a noncanonical P1 residue of the serpin''s reactive center loop. To address this unique cleavage, we report the crystal structure of SPN48, revealing that SPN48 exhibits a native conformation of human antithrombin, where the reactive center loop is partially inserted into the center of the largest β-sheet of SPN48. The crystal structure also shows that SPN48 has a putative heparin-binding site that is distinct from those of the mammalian serpins. Ensuing biochemical studies demonstrate that heparin accelerates the inhibition of Spätzle-processing enzyme by a proximity effect in targeting the SPN48. Our finding provides the molecular mechanism of how serpins tightly regulate innate immune responses in invertebrates.     

Toll-like receptors and innate immunity

Toll-like receptors (TLRs) are evolutionarily conserved innate receptors expressed in various immune and non-immune cells of the mammalian host. TLRs play a crucial role in defending against pathogenic microbial infection through the induction of inflammatory cytokines and type I interferons. Furthermore, TLRs also play roles in shaping pathogen-specific humoral and cellular adaptive immune responses. In this review, we describe the recent advances in pathogen recognition by TLRs and TLR signaling.     

The fifth dimension of innate immunity

Innate immunity has evolved as a first line defense against invading pathogens. Cellular and humoral elements of the innate immune system detect infectious parasites, initiate inflammatory resistance reactions and finally contribute to the elimination of the invaders. Repeated attacks by pathogenic agents induce adaptive responses of the innate immune system. Typically, reapplication of pathogens provokes tolerance of the affected organism. However, also stimulatory effects of primary infections on subsequent innate immune responses have been observed. The present overview touches an undervalued aspect in the innate immune response: Its pronounced dependency on pathogen load. In addition to localization and timing of innate immune responses the pathogen dose dependency might be considered as a “fifth dimension of innate immunity”. Experimental results and literature data are presented proposing a hormetic reaction pattern of innate immune cells depending on the dose of pathogens.     

Regulation of immunity and pathogenesis in infectious diseases by CD1d-restricted NKT cells

CD1d-restricted NKT cells are emerging as an unusual lymphoid lineage with important immunoregulatory properties. To date, much of our understanding of the biology of the CD1/NKT system comes from studies that utilise non-natural glycolipid ligands. Recent evidence suggests that NKT cells play an important role in the response to pathogens, manifesting a range of functions including cytotoxicity, help for antibody formation and regulation of Th1/Th2 differentiation. Infectious disease models provide appropriate physiological and pathophysiological systems to explore the biological roles of this lineage in immunity and disease. Novel insights are emerging from infection models, particularly with respect to the nature of ligands recognised by the T cell receptor of NKT cells, and to the role of diverse non-T cell receptor NK activation and inhibitory receptors in regulation of the lineage. Such insights have the potential to add considerably to our understanding of the CD1/NKT cell system and to the immunology and pathogenesis of infectious diseases.     

Effects of a reputed immunostimulant on the innate immune system of goat kids

Forty newborn Majorera goats were randomly assigned to one of two groups. On the first day of life, the kids were fed atomized colostrum. The kids were subsequently fed a milk replacer (16% w/v) twice a day. The experimental group received two intramuscular doses of a reputed immunostimulant composed of a Propionibacterium acnes extract, Ochrobactrum intermedium lipopolysaccharides, and Proclin^® at 10 and 40 days of age, whereas, the control group received two doses of saline solution. Blood samples were collected weekly from kids age 10 to 66 days postpartum to measure the total and differential white blood cell counts, the plasma IgG, IgA, and IgM levels, and the activities of the total and the alternative complement systems. The white blood cell and the differential cell counts were the same for both groups. No statistical differences were found for the plasma IgG, IgA, and IgM concentrations. Complement system activity was undetectable in both groups. Summarizing, the reputed immunostimulant did not affect the immune system of goats. Thus, veterinarians should carefully consider whether it is prudent to recommended this kind of product, because while it increases farmers’ expenses it apparently does not improve the state of the innate immune system of the neonatal goat.     

The molecular genetic approach to malarial pathogenesis and immunity

It is poorly understood why some malarial infections are fatal while others resolve without complications. Host genetic factors are partly responsible. More than ten specific susceptibility determinants have already been defined, including both structural and regulatory polymorphisms of erythyrocytes and of the immune system, and it is likely that many more have yet to be discovered. A vast number of DNA polymorphisms, scattered throughout the human genome, cause individual variation in probably all immunological and biochemical processes. Advances in DNA technology offer the prospect of screening thousands of candidate genes for association with susceptibility to severe malaria in large multicentre case-control and family-based studies. Saturation mapping of candidate gene regions, combined with cellular and molecular analysis of disease-associated polymorphisms, is essential for understanding the functional basis of the genetic associations that such an exercise will generate. This information will pinpoint critical molecular pathways in immunity and pathogenesis and may lead to fundamentally new strategies for treatment and prevention of severe malaria.     

Human myeloperoxidase in innate and acquired immunity

Polymorphonuclear leukocytes (PMNs) are important players in innate and acquired immunity. These cells accumulate at inflammatory sites and contribute to host defence, regulation of the inflammatory process, and also to tissue injury. One of the key components of PMNs is the heme-containing enzyme myeloperoxidase (MPO) that is stored in large amount in azurophilic granules of resting cells. Here we review the (patho)physiological role of MPO from the viewpoint of participation of PMNs in immune reactions. Myeloperoxidase is able to catalyse a wide range of one- and two-electron substrate oxidations. With special products, MPO contributes to apoptosis induction in PMNs and other cells, and, thus, to termination of inflammatory response. On the other hand, MPO released from necrotic cells promotes an inflammation by further recruitment of PMNs, and chemical modification of proteins and other tissue constituents. Myeloperoxidase is a fascinating, multifunctional, and challenging enzyme that hasn’t yet revealed all its secrets.     

Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity

RNase L and RNA-dependent protein kinase (PKR) are effectors of the interferon antiviral response that share homology in their pseudokinase and protein kinase domains, respectively. Sunitinib is an orally available, ATP-competitive inhibitor of VEGF and PDGF receptors used clinically to suppress angiogenesis and tumor growth. Sunitinib also impacts IRE1, an endoplasmic reticulum protein involved in the unfolded protein response that is closely related to RNase L. Here, we report that sunitinib is a potent inhibitor of both RNase L and PKR with IC(50) values of 1.4 and 0.3 μM, respectively. In addition, flavonol activators of IRE1 inhibited RNase L. Sunitinib treatment of wild type (WT) mouse embryonic fibroblasts resulted in about a 12-fold increase in encephalomyocarditis virus titers. However, sunitinib had no effect on encephalomyocarditis virus growth in cells lacking both PKR and RNase L. Furthermore, oral delivery of sunitinib in WT mice resulted in 10-fold higher viral titers in heart tissues while suppressing by about 2-fold the IFN-β levels. In contrast, sunitinib had no effect on viral titers in mice deficient in both RNase L and PKR. Also, sunitinib reduced mean survival times from 12 to 6 days in virus-infected WT mice while having no effect on survival of mice lacking both RNase L and PKR. Results indicate that sunitinib treatments prevent antiviral innate immune responses mediated by RNase L and PKR.     

抗病毒感染固有免疫应答的信号转导

入侵病毒的探知和适应性免疫应答启动均依靠固有免疫系统。三种模式识别受体(PRRs)在宿主防御系统第一线占据极其重要地位:Toll样受体、维甲酸诱导基因I样受体、核苷酸结合寡聚化结构域样受体。PRRs识别病原相关分子模式(PAMP)或危险信号分子模式(DAMPs)启动和调节固有免疫和适应性免疫应答。每种PRR都有单独的识别配体和细胞定位。激活的PRRs将信号分子传递给其配体分子(MyD88,TRIF,IRAK,IPS-1),配体活化后作为信使激活信号途径下游激酶(IKK复合物,MAPKs,TBK1,RIP-1)和转录因子(NF-κB,AP-1,IRF3),最终产生细胞因子、趋化因子、促炎细胞因子和I型干扰素。本文重点讨论PRRs信号通路及该领域取得的成果,以期为人类健康和免疫疾病防治提供策略。     

Cytokine synergy: An underappreciated contributor to innate anti-viral immunity

Inflammatory cytokines, such as tumor necrosis factor and the members of the interferon family, are potent mediators of the innate anti-viral immune response. The intracellular anti-viral states resulting from treatment of cultured cells with each of these molecules independently has been well studied; but, within complex tissues, the early inflammatory response is likely mediated by simultaneously expressed mixtures of these, and other, protective anti-viral cytokines. Such cytokine mixtures have been shown to induce potently synergistic anti-viral responses in vitro which are more complex than the simple summation of the individual cytokine response profiles. The physiological role of this ‘cytokine synergy’, however, remains largely unappreciated in vivo. This brief commentary will attempt to summarize the potential effects and mechanisms of anti-viral cytokine synergy as well as present several ‘real-world’ applications where this phenomenon might play an important role.     

Structure function analysis of an ADP-ribosyltransferase type III effector and its RNA-binding target in plant immunity

The Pseudomonas syringae type III effector HopU1 is a mono-ADP-ribosyltransferase that is injected into plant cells by the type III protein secretion system. Inside the plant cell it suppresses immunity by modifying RNA-binding proteins including the glycine-rich RNA-binding protein GRP7. The crystal structure of HopU1 at 2.7-Å resolution reveals two unique protruding loops, L1 and L4, not found in other mono-ADP-ribosyltransferases. Site-directed mutagenesis demonstrates that these loops are essential for substrate recognition and enzymatic activity. HopU1 ADP-ribosylates the conserved arginine 49 of GRP7, and this reduces the ability of GRP7 to bind RNA in vitro. In vivo, expression of GRP7 with Arg-49 replaced with lysine does not complement the reduced immune responses of the Arabidopsis thaliana grp7-1 mutant demonstrating the importance of this residue for GRP7 function. These data provide mechanistic details how HopU1 recognizes this novel type of substrate and highlights the role of GRP7 in plant immunity.     

Scavenger receptors: role in innate immunity and microbial pathogenesis

Accumulating evidence shows that many scavenger receptors (SR), including SR-A, MARCO and CD36, represent an important part of the innate immune defence by acting as pattern-recognition receptors, in particular against bacterial pathogens. Several SR are expressed on macrophages and dendritic cells, where they act as phagocytic receptors mediating non-opsonic phagocytosis of pathogenic microbes. Another important function of some SR is to act as co-receptors to Toll-like receptors (TLR), modulating the inflammatory response to TLR agonists. On bacteria, the SR ligands have commonly been reported to be lipopolysaccharide and lipoteichoic acid, but recent advances in the field indicate that bacterial surface proteins play a more important role as target molecules for SR than previously thought. Interestingly, recent data show that major pathogens, including Streptococcus pyogenes and the group B streptococcus, have evolved mechanisms to evade SR-mediated recognition. Moreover, intracellular pathogens, such as hepatitis C virus and Plasmodium falciparum, utilize the SR to gain entry into host cells, focusing interest on the importance of SR also in the molecular pathogenesis of infectious diseases. This review highlights the complex interactions between SR and pathogenic microbes, and discusses the role of these interactions in host defence and microbial pathogenesis.     

RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity

Viral infection is detected by cellular sensors as foreign nucleic acid and initiates innate antiviral responses, including the activation of type I interferon (IFN) and proinflammatory cytokines. Recent advances in cytoplasmic virus sensors highlight their essential role in the induction of innate immunity. Moreover, it is intriguing to understand how they can discriminate innate RNA from viral foreign RNA. In this mini-review, we focus on these cytoplasmic virus sensors, termed retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), and discuss their function in the innate immune system.     

免疫的代价

免疫系统发育的代价主要是为B淋巴细胞和T淋巴细胞发育抗原识别多样性时的低效率过程提供能量 ,为开始形成白血球提供基质 (如氨基酸和脂肪 ) ,并为胚胎和雏鸟提供白细胞。维持免疫系统的代价与持续产生白细胞、免疫球蛋白以及其它血浆蛋白时的营养分配有关 ,这些血浆蛋白用于取代在正常的细胞代谢中丢失的蛋白质以及细胞间的蛋白质。利用免疫系统阻碍可能的病源体入侵的代价有两种主要形式。第一 ,由于白细胞参与效应子机制时发生的损害、组织整合性以及寄主细胞的存活力的损伤 ,组织功能有一些损失。第二 ,在活化相应类型的细胞并产生其效应子作用时存在着营养耗费。病源体挑战所带来的主要代价是系统的急性期反应(特别是肝脏的复原 )通过产生保护性的蛋白质来帮助免疫系统     

蝙蝠抗病毒天然免疫的研究进展

近年来,健康的蝙蝠体内检测到了很多与人类传染病相关的病毒,包括狂犬病病毒(Rabies virus)、埃博拉病毒(Ebola virus)、严重急性呼吸综合征病毒(SARS-CoV)以及最近新出现的新型冠状病毒(SARS-CoV-2)等。与其他哺乳动物不同,蝙蝠在感染了这些病毒后不会表现出明显的临床症状。因此,人类可以通过研究蝙蝠的免疫系统获得抗病毒免疫的新知识。本文综述了蝙蝠抗病毒天然免疫研究的最新进展,指出了蝙蝠在天然免疫方面的特殊性:蝙蝠独有的飞行能力可能导致其演化出一套独特的抗病毒免疫响应机制,同时具有一套独特的机制限制炎症反应。蝙蝠物种的多样性丰富(超过1 400种),超过了哺乳动物的五分之一。因此对蝙蝠免疫基因的多样性研究,将促进对蝙蝠特殊免疫机制的理解,对人类传染病防治和畜牧业发展具有重要意义。     

肠道病毒71型与天然免疫系统相互作用的研究进展

肠道病毒71型(enterovirus 71,EV71)为小RNA病毒科肠道病毒属成员,是引起手足口病的主要病原体之一。EV71流行广泛,其感染可引发中枢神经系统疾病,并造成重症手足口病,给公共卫生安全带来极大挑战。EV71的致病机制与病毒和宿主天然免疫系统的相互作用关系密切,涉及病毒逃逸干扰素反应、病毒抑制核因子κB(nuclear factorκB,NF-κB)信号通路及病毒与天然免疫细胞相互作用等多个环节。本文就近年来EV71与宿主天然免疫系统相互作用的研究进展进行综述。     

The implication of SUMO in intrinsic and innate immunity

Since its discovery, SUMOylation has emerged as a key post-translational modification involved in the regulation of host-virus interactions. SUMOylation has been associated with the replication of a large number of viruses, either through the direct modification of viral proteins or through the modulation of cellular proteins implicated in antiviral defense. SUMO can affect protein function via covalent or non-covalent binding. There is growing evidence that SUMO regulates several host proteins involved in intrinsic and innate immunity, thereby contributing to the process governing interferon production during viral infection; as well as the interferon-activated Jak/STAT pathway. Unlike the interferon-mediated innate immune response, intrinsic antiviral resistance is mediated by constitutively expressed antiviral proteins (defined as restriction factors), which confer direct viral resistance through a variety of mechanisms. The aim of this review is to evaluate the role of SUMO in intrinsic and innate immunity; highlighting the involvement of the TRIM family proteins, with a specific focus on the mechanism through which SUMO affects i- interferon production upon viral infection, ii-interferon Jak/STAT signaling and biological responses, iii-the relationship between restriction factors and RNA viruses.     

c-di-AMP在细菌感染与免疫中的作用

环二腺苷酸(Cyclic diadenosine monophosphate,c-di-AMP)是细菌中广泛存在的第二信号分子。c-di-AMP在细菌中的代谢受二腺苷酸环化酶(Diadenylatecyclase, DAC)和磷酸二酯酶(Phosphodiesterase,PDE)的精密调控。c-di-AMP不仅调节细菌生长、细胞壁稳态、离子转运等多种生理过程,而且能够被真核宿主胞内多种感应子/受体蛋白识别,从而调控抗感染免疫。细菌c-di-AMP参与调控宿主I型干扰素应答、NF-κB信号通路活性、自噬以及炎症小体应答等固有免疫应答。此外,c-di-AMP作为黏膜佐剂可诱导宿主适应性免疫。c-di-AMP被认为是一种新发现的病原体相关的分子模式(Pathogen associated molecular pattern,PAMP),已成为细菌疫苗和药物研究中的新靶点。