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.     

Viral modulation of NK cell immunity

Natural killer (NK) cells have been implicated in innate immune responses against viruses such as herpesviruses, which cause persistent infections in the host. In response to the selective pressure that is exerted by NK cells, many viruses have evolved strategies either to evade detection by NK cells or to modulate the activity of NK cells. Here, we review the unique relationship that exists between NK cells and viruses, with a focus on herpesviruses.     

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。     

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.     

病毒感染对宿主TLRs模式识别与免疫应答信号的影响

TLRs是一类古老的天然模式识别分子,通过识别病毒的PAMPs,活化依赖和非依赖于MyD88的信号通路,诱导IFNs、促炎性细胞因子和趋化因子等分子的释放和表达,清除病毒的感染;同时,病毒为了感染宿主,采用多种免疫逃避策略干扰机体TLRs的信号,尤其调节MyD88、NF-κB、TRIF和IRFs等重要信号分子,以逃避机体天然PRRs的监视、识别和清除。因此,本文重点以VACV、HCV和HIV为例,介绍病毒感染对宿主TLRs模式识别与免疫应答信号的调节,以进一步理解病毒与宿主相互作用的复杂性,为病毒病的有效防治提供理论依据。     

Scaling of immune responses against intracellular bacterial infection

Macrophages detect bacterial infection through pattern recognition receptors (PRRs) localized at the cell surface, in intracellular vesicles or in the cytosol. Discrimination of viable and virulent bacteria from non-virulent bacteria (dead or viable) is necessary to appropriately scale the anti-bacterial immune response. Such scaling of anti-bacterial immunity is necessary to control the infection, but also to avoid immunopathology or bacterial persistence. PRR-mediated detection of bacterial constituents in the cytosol rather than at the cell surface along with cytosolic recognition of secreted bacterial nucleic acids indicates viability and virulence of infecting bacteria. The effector responses triggered by activation of cytosolic PRRs, in particular the RIG-I-induced simultaneous rapid type I IFN induction and inflammasome activation, are crucial for timely control of bacterial infection by innate and adaptive immunity. The knowledge on the PRRs and the effector responses relevant for control of infection with intracellular bacteria will help to develop strategies to overcome chronic infection.     

Antiviral signaling through pattern recognition receptors

Viral infection is detected by the host innate immune system. Innate immune cells such as dendritic cells and macrophages detect nucleic acids derived from viruses through pattern recognition receptors (PRRs). Viral recognition by PRRs initiates the activation of signaling pathways that lead to production of type I interferon and inflammatory cytokines, which are important for the elimination of viruses. Two types of PRRs that recognize viral nucleic acids, Toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH), have been identified. Of the TLRs, TLR3 recognizes viral double-stranded (ds) RNA, TLR7 and human TLR8 identify viral single-stranded (ss) RNA and TLR9 detects viral DNA. TLRs are located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA. Here we review the role of TLRs and RLHs in the antiviral innate immune response.     

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.     

Lipoglycans contribute to innate immune detection of mycobacteria

Innate immune recognition is based on the detection, by pattern recognition receptors (PRRs), of molecular structures that are unique to microorganisms. Lipoglycans are macromolecules specific to the cell envelope of mycobacteria and related genera. They have been described to be ligands, as purified molecules, of several PRRs, including the C-type lectins Mannose Receptor and DC-SIGN, as well as TLR2. However, whether they are really sensed by these receptors in the context of a bacterium infection remains unclear. To address this question, we used the model organism Mycobacterium smegmatis to generate mutants altered for the production of lipoglycans. Since their biosynthesis cannot be fully abrogated, we manipulated the biosynthesis pathway of GDP-Mannose to obtain some strains with either augmented (～1.7 fold) or reduced (～2 fold) production of lipoglycans. Interestingly, infection experiments demonstrated a direct correlation between the amount of lipoglycans in the bacterial cell envelope on one hand and the magnitude of innate immune signaling in TLR2 reporter cells, monocyte/macrophage THP-1 cell line and human dendritic cells, as revealed by NF-κB activation and IL-8 production, on the other hand. These data establish that lipoglycans are bona fide Microbe-Associated Molecular Patterns contributing to innate immune detection of mycobacteria, via TLR2 among other PRRs.     

Early immune events in the induction of allergic contact dermatitis

The skin is a barrier site that is exposed to a wide variety of potential pathogens. As in other organs, pathogens that invade the skin are recognized by pattern-recognition receptors (PRRs). Recently, it has been recognized that PRRs are also engaged by chemical contact allergens and, in susceptible individuals, this elicits an inappropriate immune response that results in allergic contact dermatitis. In this Review, we focus on how contact allergens promote inflammation by activating the innate immune system. We also examine how innate immune cells in the skin, including mast cells and dendritic cells, cooperate with each other and with T cells and keratinocytes to initiate and drive early responses to contact allergens.     

DNA sensor cGAS-mediated immune recognition

The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.     

Plant Surface Receptors Recognizing Microbe-Associated Molecular Patterns

As sessile, plants are inevitably exposed to environmental threats including pathogens. Due to the lack of mobile immune cells, plants solely depend on the innate immune system to defend against pathogens. The first layer of pathogen detection in plant immunity is to recognize microbe-associated molecular patterns (MAMPs) that compose structural or functional units in microbial pathogens. For this, plants utilize pattern-recognition receptors (PRRs). Continuous attack by pathogens resulting from immotility likely contributes to the extension of PRR numbers in plants, although genomeencoded. Recent findings revealed that plant PRRs as a complex dynamically switch between inactive and active forms at the plasma membrane depending on a cognate MAMP. In addition, by regulating the activity and stability of a downstream signal-relaying receptor-like cytoplasmic kinase (RLCK), plants can control the immune homeostasis. Therefore, we in this review discuss on how plants detect a pathogen and how they control immune responses at the level of PRRs in a correct and delicate way. We additionally provide a possible balancing mechanism between growth and responses to biotic and abiotic stresses in plants, which is required for survival in nature.     

Expansion of effector memory TCR Vbeta4+ CD8+ T cells is associated with latent infection-mediated resistance to transplantation tolerance

Therapies that control largely T cell-dependent allograft rejection in humans also possess the undesirable effect of impairing T cell function, leaving transplant recipients susceptible to opportunistic viruses. Prime among these opportunists are the ubiquitous herpesviruses. To date, studies are lacking that address the effect of viruses that establish a true latent state on allograft tolerance or the effect of tolerance protocols on the immune control of latent viruses. By using a mixed chimerism-based tolerance-induction protocol, we found that mice undergoing latent infection with gammaHV68, a murine gamma-herpesvirus closely related to human gamma-herpesviruses such as EBV and Kaposi's sarcoma-associated herpesvirus, significantly resist tolerance to allografts. Limiting the degree of virus reactivation or innate immune response did not reconstitute chimerism in latently infected mice. However, gammaHV68-infected mice showed increased frequency of CD8+ T cell alloreactivity and, interestingly, expansion of virus-induced, alloreactive, "effector/effector memory" TCR Vbeta4+CD8+ T cells driven by the gammaHV68-M1 gene was associated with resistance to tolerance induction in studies using gammaHV68-M1 mutant virus. These results define the viral gene and immune cell types involved in latent infection-mediated resistance to allograft tolerance and underscore the influence of latent herpesviruses on allograft survival.     

A Novel 2-dimensional Multiplex qPCR Assay for Single-Tube Detection of Nine Human Herpesviruses

Human herpesviruses are double-stranded DNA viruses that are classified into nine species. More than 90% of adults are ever infected with one or more herpesviruses. The symptoms of infection with different herpesviruses are diverse ranging from mild or asymptomatic infections to deadly diseases such as aggressive lymphomas and sarcomas. Timely and accurate detection of herpesvirus infection is critical for clinical management and treatment. In this study, we established a single-tube nonuple qPCR assay for detection of all nine herpesviruses using a 2-D multiplex qPCR method with a house-keeping gene as the internal control. The novel assay can detect and distinguish different herpesviruses with 30 to 300 copies per 25 μL single-tube reaction, and does not cross-react with 20 other human viruses, including DNA and RNA viruses. The robustness of the novel assay was evaluated using 170 clinical samples. The novel assay showed a high consistency (100%) with the single qPCR assay for HHVs detection. The features of simple, rapid, high sensitivity, specificity, and low cost make this assay a high potential to be widely used in clinical diagnosis and patient treatment.     

固有免疫细胞及其模式识别受体与表观遗传学调控研究进展

固有免疫细胞是机体抵御病原微生物的首道防线,亦是机体有效启动和维持免疫反应的重要参与者,而模式识别受体是固有免疫细胞发挥免疫功能的重要免疫分子,因此,机体对固有免疫细胞及其模式识别受体的精细调控尤为重要。表观遗传学是近年研究热点,其在固有免疫调节中的作用逐渐受到重视。就近年表观遗传学中的DNA甲基化、组蛋白共价修饰及非编码RNA等在调节固有免疫细胞分化发育及其模式识别受体的相关研究作一简述,以期为感染、炎症、自身免疫病等研究与防治提供新的思路和策略。     

Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response

The antiviral innate immune response follows the detection of viral components by host pattern recognition receptors (PRRs). Two families of PRRs have emerged as key sensors of viral infection: Toll-like receptors (TLRs) and retinoic acid inducible gene-I like RNA helicases (RLHs). TLRs patrol the extracellular and endosomal compartments; signalling results in a type-1 interferon response and/or the production of pro-inflammatory cytokines. In contrast, RLHs survey the cytoplasm for the presence of viral double-stranded RNA. In the face of such host defence, viruses have developed strategies to evade TLR/RLH signalling. Such host-virus interactions provide the opportunity for manipulation of PRR signalling as a novel therapeutic approach.     

Identification and function of MicroRNAs encoded by herpesviruses

MicroRNAs (miRNAs) play important roles in eukaryotes,plants and some viruses.It is increasingly clear that miRNAs-encoded by viruses can affect the viral life cycle and host physiology.Viral miRNAs could repress the innate and adaptive host immunity,modulate cellular signaling pathways,and regulate the expression of cellular and viral genes.These functions facilitate viral acute and persistent infections,and have profound effects on the host cell survival and disease progression.Here,we discuss the miRNAs encoded by herpesviruses,and their regulatory roles involved in virus-host interactions.