Inactivation of inflammasomes by pathogens regulates inflammation

Inflammatory response is initiated and sustained by the action of quintessential pro-inflammatory cytokines of immune system namely IL-1β and IL-18. The maturation process of those cytokines is ensured by caspase-1 enzymatic activity, that is in turn is tightly controlled by multiprotein complexes called inflammasomes. Inflammasomes are activated in cells of innate immune system in response to recognition of conservative parts of microbes (pathogen-associated molecular patterns) or by sensing molecular signs of tissue damage (damage-associated molecular patterns). Inflammasome activation apart of cytokines secretion leads to pro-inflammatory cell death, so-called pyroptosis. That culminates in release of cytoplasmatic content of cells including cytokines and alarmins that boost immune response against pathogens, as well as pyroptosis destroys replicative niches of intracellular pathogens. During co-evolution with the host, bacterial and viral pathogens developed a range of molecular inhibitors targeting each step of inflammasome activation. In current review, we will discuss the latest knowledge of inflammasomes’ signaling pathways and tricks that pathogens use to avoid immune recognition and clearance. Our better understanding of inflammasome inhibition by pathogens can lead to better therapeutic approaches for the treatment of infectious diseases.     

Recognition of bacterial pathogens and mucosal immunity

Rapid detection and elimination of pathogens invasive to intestinal tissue is essential to avoid prolonged gut inflammation, or systemic sepsis. The discovery of transmembrane or intracytoplasmic pattern recognition receptors that detect the presence of conserved microbial macromolecular structures has significantly advanced the understanding of how metazoans respond to and eliminate bacteria that have entered the intestinal mucosa. In this review, we highlight recent advances in the field of host recognition of bacterial pathogens and subsequent mucosal innate immune response. Additionally, some bacteria are pathogenic because they have evolved sophisticated mechanisms to evade the host mucosal innate immune response. We discuss advances in identifying the mechanisms by which pathogens evade detection by dampening the immune response.     

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.     

New insights into TRP channels: Interaction with pattern recognition receptors

An increasing number of studies have implicated that the activation of innate immune system and inflammatory mechanisms are of importance in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms in response to pathogens or tissue injury, which is performed via germ-line encoded pattern-recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) or dangers-associated molecular patterns (DAMPs). Intracellular pathways linking immune and inflammatory response to ion channel expression and function have been recently identified. Among ion channels, transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes. In this review, we summarize current knowledge about classifications, functions, and interactions of TRP channels and PRRs, which may provide new insights into their roles in the pathogenesis of inflammatory diseases.     

昆虫天然免疫反应分子机制研究进展

昆虫体内缺乏高等脊椎动物所具有的获得性免疫系统, 只能依赖发达的天然免疫系统抵抗细菌、 真菌、 病毒等外源病原物的侵染。本文概括了昆虫天然免疫反应发生和作用的分子机制相关进展, 重点阐述了重要免疫相关因子在昆虫天然免疫反应中的功能和作用机制。昆虫天然免疫反应分为体液免疫和细胞免疫两种, 二者共同作用完成对病原物的吞噬 (phagocytosis)、 集结 (nodulation)、 包囊 (encapsulation)、 凝结 (coagulation)和黑化（melanization）等。当昆虫受到外界病原物的侵染时, 首先通过体内的模式识别蛋白（pattern recognition proteins/receptor, PRPs）识别并结合病原物表面特有的模式分子（pathogen-associated molecular pattern, PAMPs）, 继而一系列包括丝氨酸蛋白酶和丝氨酸蛋白酶抑制剂在内的级联激活反应被激活和调控, 产生抗菌肽、 黑色素等免疫效应分子, 清除或杀灭外源物。抗菌肽是一类小分子量的阳离子肽, 具有广谱抗菌活性, 针对不同类型的病原物, 抗菌肽的产生机制也不尽相同。昆虫体内存在着两种信号转导途径调节抗菌肽的产生： 一是由真菌和大部分革兰氏阳性菌激活的Toll途径; 二是由革兰氏阴性菌激活的Imd途径（immune deficiency pathway）。这两个途径通过激活不同转录因子调控不同抗菌肽基因的表达参与昆虫体内的天然免疫反应。     

Manipulation of autophagy by bacteria for their own benefit

Autophagy is the host innate immune system's first line of defense against microbial intruders. When the innate defense system recognizes invading bacterial pathogens and their infection processes, autophagic proteins act as cytosolic sensors that allow the autophagic pathway to be rapidly activated. However, many intracellular bacterial pathogens deploy highly evolved mechanisms to evade autophagic recognition, manipulate the autophagic pathway, and remodel the autophagosomal compartment for their own benefit. Here current topics regarding the recognition of invasive bacteria by the cytosolic innate immune system are highlighted, including autophagy and the mechanisms that enable bacteria to evade autophagy. Also highlighted are some selective examples of bacterial activities that manipulate the autophagic pathways for their own benefit.     

Protease-dependent mechanisms of complement evasion by bacterial pathogens

Abstract The human immune system has evolved a variety of mechanisms for the primary task of neutralizing and eliminating microbial intruders. As the first line of defense, the complement system is responsible for rapid recognition and opsonization of bacteria, presentation to phagocytes and bacterial cell killing by direct lysis. All successful human pathogens have mechanisms of circumventing the antibacterial activity of the complement system and escaping this stage of the immune response. One of the ways in which pathogens achieve this is the deployment of proteases. Based on the increasing number of recent publications in this area, it appears that proteolytic inactivation of the antibacterial activities of the complement system is a common strategy of avoiding targeting by this arm of host innate immune defense. In this review, we focus on those bacteria that deploy proteases capable of degrading complement system components into non-functional fragments, thus impairing complement-dependent antibacterial activity and facilitating pathogen survival inside the host.     

昆虫天然免疫相关基因研究进展

在长期进化过程中,昆虫形成了强大的天然免疫防御系统,即体液免疫和细胞免疫。体液免疫主要包括Toll、IMD和JAK/STAT 3条信号通路,通过信号转导及免疫途径调控免疫相关基因的表达,诱导产生抗菌肽和其他效应分子。细胞免疫由血细胞介导,主要完成对病原物的包裹、吞噬和集结等。近年来,昆虫基因组学快速发展,通过生物信息学等方法从昆虫基因组数据中已鉴定到大量免疫相关基因,对这些基因的研究加深了人们对昆虫天然免疫分子机制的认识和理解。根据基因功能,免疫相关基因分为识别、信号转导、调制器、效应分子、黑化反应、RNA干扰和其他基因等7类,这些基因通过互作来调控体液免疫和细胞免疫。本文对昆虫免疫相关基因的分类、功能及家族进化等方面的研究成果进行总结,并对今后昆虫免疫的研究重点进行了展望,以期为昆虫免疫分子机制的研究及开发新的害虫防治策略提供依据。     

Anti-immunology: evasion of the host immune system by bacterial and viral pathogens

Multicellular organisms possess very sophisticated defense mechanisms that are designed to effectively counter the continual microbial insult of the environment within the vertebrate host. However, successful microbial pathogens have in turn evolved complex and efficient methods to overcome innate and adaptive immune mechanisms, which can result in disease or chronic infections. Although the various virulence strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms that are used to subvert and exploit immune systems that are shared between these diverse microbial pathogens. The success of each pathogen is directly dependant on its ability to mount an effective anti-immune response within the infected host, which can ultimately result in acute disease, chronic infection, or pathogen clearance. In this review, we highlight and compare some of the many molecular mechanisms that bacterial and viral pathogens use to evade host immune defenses.     

秀丽隐杆线虫固有免疫功能神经调控机制研究进展

固有免疫系统是动植物个体应对外来微生物侵入感染时非常重要的抵御防线。秀丽隐杆线虫(Caenorhabditis elegans,简称线虫)作为研究宿主与病原菌之间相互作用的经典模式动物,近年来在神经和免疫之间相互作用的分子与遗传机制等方面的研究取得了长足进展。研究表明,线虫神经元通过释放神经递质与神经多肽(如多巴胺、NLP-20)等,激活相关信号通路途经,参与线虫对病原菌的识别、逃避、调节物理屏障防御能力和激活固有免疫反应,并表达分泌抗菌肽以清除病原菌等的调控进程。本文综述了线虫神经系统调控固有免疫功能机制的最新研究进展,为人们深入了解神经与免疫系统间相互作用的功能分子及其调控机制和揭示人类神经与免疫系统相关疾病的病理机理提供了重要信息。     

MITA/STING: A central and multifaceted mediator in innate immune response

The recognition of nucleic acids is a general strategy used by the host to detect invading pathogens. Many studies have established that MITA/STING is a central component in the innate immune response to cytosolic DNA and RNA derived from pathogens. MITA can act both as a direct sensor of cyclic dinucleotides (CDNs) and as an adaptor for the recruitment of downstream signaling components. In both roles, MITA is part of signaling cascades that orchestrate innate immune defenses against various pathogens, including viruses, bacteria and parasites. Here, we highlight recent studies that have uncovered the molecular mechanisms of MITA-mediated signal transduction and regulation, and discuss some notable issues that remain elusive.     

肠道病毒调控固有免疫的分子机制研究进展

肠道病毒属于小核糖核酸病毒科,包括脊髓灰质炎病毒等多种重要人类病原体,已成为全球公共卫生安全的重大威胁之一。固有免疫是机体早期抵御病毒感染的重要防线。不同肠道病毒在进化中已经具备了多种途径躲避免疫识别或诱导固有免疫系统失活。本文重点对肠道病毒调控宿主固有免疫的相关分子机制进行综述,系统整理了肠道病毒逃避干扰素依赖与干扰素非依赖的抗病毒固有免疫防御的分子特征与作用规律,为肠道病毒致病机制的探究和抗病毒药物的研发提供参考。     

病原菌操控宿主固有免疫细胞以求生存的机制研究进展

在急性感染和传统感染模式中,宿主利用固有免疫机制应对一系列病原体的入侵。然而,一些病原菌可以成功逃避、抑制或颠覆免疫检测、信号转导或有效杀伤。该文就病原菌如何操纵宿主细胞的防御功能,调节胞内杀伤、信号转导,破坏固有免疫系统受体间分子信号的交联作用,并最终使微生物在宿主体内适应性生长、持续感染等方面作一综述。     

Therapeutic implications of the TLR and VDR partnership

The innate immune system provides the host with an immediate and rapid defense against invading microbes. Detection of foreign invaders is mediated by a class of receptors that are known as the pattern recognition receptors, such as the family of Toll-like receptors (TLRs). In humans, ten functional TLRs have been identified and they respond to conserved pathogen-associated molecular patterns derived from bacteria, mycoplasma, fungi and viruses. TLR activation leads to direct antimicrobial activity against both intracellular and extracellular bacteria, and induces an antiviral gene program. Recently, it was reported that TLR2 activation leads to the use of vitamin D3 as a mechanism to combat Mycobacterium tuberculosis. Here, we focus on recent findings concerning the TLR-induced antimicrobial mechanisms in humans and the therapeutic implications of these findings. Owing to their capability to combat a wide array of pathogens, TLRs are attractive therapeutic targets. However, additional knowledge about their antimicrobial mechanisms is needed.     

Monocyte and macrophage heterogeneity and Toll-like receptors in the lung

Mononuclear phagocytes are crucial components of the innate host defense system. Cells such as macrophages and monocytes phagocytose and process pathogens, produce inflammatory mediators, and link the innate and the adaptive immune systems. The role of innate immune receptors such as Toll-like receptors (TLRs) in the recognition of pathogens is critical for mounting a precise and targeted immune response. This review focuses attention on the development of monocytes and macrophages, various populations of macrophages, and the expression and function of TLRs on macrophages.     

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.     

Innate host responses to enteric bacterial pathogens: a balancing act between resistance and tolerance

Infection by enteric bacterial pathogens activates pathogen recognition receptors, leading to innate responses that promote host defence. While responses that promote host 'resistance' to infection, through the release of antimicrobial mediators, or the recruitment of inflammatory cells aimed at clearing the infection are best known, recent studies have begun to identify additional innate driven responses that instead promote intestinal tissue repair and host survival. Described as infection 'tolerance' responses, we and others have primarily studied these responses in the Citrobacter rodentium infection model. In this review we discuss the impact of innate resistance mechanisms on host defence, and describe how 'tolerance' responses act primarily on the intestinal epithelium, triggering epithelial cell proliferation, repair or promoting barrier function. Resistance and tolerance responses appear to work together, with tolerance repairing the tissue injury caused by resistance driven inflammation. Tolerance responses fit a pattern where innate immunity and inflammation are tightly regulated in the gastrointestinal tract. Moreover, tolerance may have developed due to the successful subversion and avoidance of host resistance by enteric bacterial pathogens. Further studies are needed to clarify the contribution of different pathogen recognition receptors to tolerance and resistance responses against bacterial pathogens, in the gut or in other host tissues.     

Innate immune response in insects: recognition of bacterial peptidoglycan and amplification of its recognition signal

The major cell wall components of bacteria are lipopolysaccharide, peptidoglycan, and teichoic acid. These molecules are known to trigger strong innate immune responses in the host. The molecular mechanisms by which the host recognizes the peptidoglycan of Gram-positive bacteria and amplifies this peptidoglycan recognition signals to mount an immune response remain largely unclear. Recent, elegant genetic and biochemical studies are revealing details of the molecular recognition mechanism and the signalling pathways triggered by bacterial peptidoglycan. Here we review recent progress in elucidating the molecular details of peptidoglycan recognition and its signalling pathways in insects. We also attempt to evaluate the importance of this issue for understanding innate immunity.     

The lipopolysaccharide-activated toll-like receptor (TLR)-4 induces synthesis of the closely related receptor TLR-2 in adipocytes

The central regulatory role of the adipocyte in whole body energy homeostasis is well established. However, recent findings suggest that preadipocytes and adipocytes may play an important physiological role in the regulation of both the innate and adaptive immune response. To systematically characterize the molecular machinery of the adipocyte that mediates the recognition of pathogens, we have focused our analysis on the recently identified Toll-like receptors (TLRs). These receptors have been implicated as mediators of the cellular response to bacterial lipopolysacharides (LPSs). Here, we report the cloning and functional characterization of mouse TLR-2 from 3T3-L1 adipocytes. TLR-2 synthesis is strongly induced in the adipocyte by LPS, TNFalpha, and the yeast cell wall extract zymosan. TLR-2 undergoes a lengthy intracellular maturation process with a half-life of exit from the ER of approximately 3 h. Furthermore, LPS treatment of adipocytes results in dramatic changes at the level of gene expression, including the synthesis of a distinct set of secretory proteins such as interleukin-6. Our studies demonstrate the presence of a fully intact pathway of innate immunity in the adipocyte that can be activated by LPS binding to the cell surface and results in the secretion of immunomodulatory molecules.     

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.