Rab蛋白参与结核分枝杆菌胞内吞噬的研究进展

结核分枝杆菌(Mtb)是结核病的病原体,可通过调控细胞吞噬作用来促进胞内细菌的存活,并干扰宿主细胞的生理功能。Rab蛋白是胞内膜转运过程的重要组分,参与和调节了Mtb的吞噬过程。本文主要介绍Mtb及其菌体成分对胞内吞噬的影响,并就Rab蛋白在其中的作用进行论述,从而探讨Rab蛋白与Mtb胞内吞噬的关系,为进一步研究Mtb胞内免疫机制提供理论基础。     

巨噬细胞的自噬及其在抗结核分枝杆菌感染中的作用

自噬是广泛存在于真核细胞内的一种溶酶体依赖性的自降解途径,可通过降解长寿蛋白和受损细胞器维持细胞内的平衡.近年来的研究发现,巨噬细胞的自噬还是固有免疫和适应性免疫的重要组成部分,可参与胞内感染病原体的清除.目前已发现有多种途径参与自噬的诱导和调节.在感染的巨噬细胞内,诱导自噬的发生能促进吞噬体和溶酶体的融合,抑制胞内结核分枝杆菌(Mtb)的存活.但同时Mtb也可通过某些机制抑制巨噬细胞自噬的发生以逃避巨噬细胞的杀伤,进而长期持留于巨噬细胞内.深入了解巨噬细胞自噬与胞内Mtb相互作用的机制,有助于人类更好的预防和控制结核病.     

巨噬细胞的自噬及其在抗结核分枝杆菌感染中的作用

白噬是广泛存在于真核细胞内的一种溶酶体依赖性的自降解途径,可通过降解长寿蛋白和受损细胞器维持细胞内的平衡。近年来的研究发现,巨噬细胞的自噬还是固有免疫和适应性免疫的重要组成部分,可参与胞内感染病原体的清除。目前已发现有多种途径参与自噬的诱导和调节。在感染的巨噬细胞内,诱导自噬的发生能促进吞噬体和溶酶体的融合,抑制胞内结核分枝杆菌（Mtb）的存活。但同时Mtb也可通过某些机制抑制巨噬细胞自噬的发生以逃避巨噬细胞的杀伤,进而长期持留于巨噬细胞内。深入了解巨噬细胞自噬与胞内Mtb相互作用的机制,有助于人类更好的预防和控制结核病。     

microRNA调控结核分枝杆菌感染巨噬细胞凋亡的研究进展

细胞凋亡对于机体抑制或清除胞内结核分枝杆菌( Mycobacterium tuberculosis, Mtb)尤为重要, Mtb感染巨噬细胞后,往往会诱导机体启动一系列机制调控巨噬细胞凋亡。在 Mtb感染的巨噬细胞内存在差异表达的microRNAs (miRNAs),miRNA可直接结合凋...     

TRIM21的抗病毒作用研究进展

TRIM(tripartite motif)家族因具有相似的N端结构又被称为RBCC家族,其成员在诸多与固有免疫相关的生物学过程中发挥重要作用.近年来的研究发现,TRIM家族参与宿主的胞内抗病毒作用,其中一些TRIM家族蛋白被认为是病毒的限制因子.最近,TRIM21作为E3泛素连接酶的抗病毒作用相继被报道,其可通过抗体依赖的细胞内抗病毒作用(antibody dependent intracellular neutralization,ADIN)及参与固有免疫通路发挥抗病毒作用,现就TRIM21的结构、表达分布、抗病毒作用及其机制的研究进展进行总结和综述.     

宿主蛋白质乙酰化修饰在结核病发生发展中的作用

病原微生物诱导宿主蛋白质翻译后修饰与疾病的预防、发生和治疗密切相关。结核分枝杆菌作为胞内病原菌, 其诱导宿主蛋白质翻译后修饰是结核病发生发展和转归的重要因素之一。近年来, 研究发现结核分枝杆菌感染诱导宿主蛋白质乙酰化修饰在调控宿主抗结核免疫功能中发挥重要作用, 显著影响结核病的发生发展。本文通过对结合分枝杆菌调控宿主蛋白质乙酰化修饰的作用及机制研究进展进行综述, 为进一步探究靶向宿主蛋白质乙酰化修饰的结核病免疫治疗靶点和策略提供理论参考。     

泛素系统在免疫信号转导过程中的作用研究进展

泛素(Ubiquitin)系统是目前已知最重要且有高度选择性的蛋白质降解体系。近来许多研究发现该系统在免疫信号转导过程中发挥重要的调控功能。泛素系统可以通过识别某些酪氨酸磷酸化标记的免疫细胞膜受体使其降解,从而终止免疫信号转导。另外,在免疫系统重要转录因子NF-κB活化的不同阶段也有泛素系统参与。通过作用于免疫信号转导过程的上述环节,泛素系统调控免疫应答及炎症反应,本文拟就有关内容作一综述。     

病毒免疫逃逸机制研究进展

在宿主和病毒的长期共同进化过程中,病毒发展了各种免疫逃逸机制以逃避宿主的免疫应答.这些免疫逃逸机制可大致分为三类(1)逃避体液免疫系统的识别;(2)抑制细胞免疫应答;(3)干扰免疫效应功能.而且,一些病毒还可通过与免疫系统隔离而逃避免疫应答.     

基质金属蛋白酶对结核肉芽肿形成及免疫调控作用的研究进展

<正>结核病(tuberculosis,TB)是由结核分枝杆菌(Mycobacterium tuberculosis,Mtb)感染引起的具有高致病性及死亡率的人畜共患传染病^[1]。作为一种胞内致病菌,Mtb通过气溶胶等途径感染肺部,随后被驻留在肺泡中的巨噬细胞识别、吞噬并发生复杂的相互作用^[2]。一方面,当Mtb感染巨噬细胞时,     

结核性肉芽肿的代谢免疫调控机制研究进展

结核病仍然严重威胁人类健康。结核性肉芽肿是结核病的典型病理特征,也是结核分枝杆菌Mtb逃避宿主免疫杀伤实现长期存活及潜伏感染的“避难所”。结核分枝杆菌还利用肉芽肿促进其在体内扩散和传播,导致疾病迁延不愈,难以根除。肉芽肿环境中的代谢级联反应和免疫细胞产生的相关代谢物在疾病进展和诱导抗结核保护性免疫中发挥关键作用。 而 Mtb可以通过自身毒力因子,靶向宿主关键代谢通路抵抗免疫防御,实现长期存活并伺机增殖促进肉芽肿进展。本文对结核性肉芽肿中 Mtb与宿主相互作用的关键代谢免疫通路及其调控机制展开论述,为后续靶向肉芽肿发病进程开发新的结核病防治策略提供参考。     

Macrophages in tuberculosis: friend or foe

Tuberculosis (TB) remains one of the greatest threats to human health. The causative bacterium, Mycobacterium tuberculosis (Mtb), is acquired by the respiratory route. It is exquisitely human adapted and a prototypic intracellular pathogen of macrophages, with alveolar macrophages (AMs) being the primary conduit of infection and disease. The outcome of primary infection is most often a latently infected healthy human host, in whom the bacteria are held in check by the host immune response. Such individuals can develop active TB later in life with impairment in the immune system. In contrast, in a minority of infected individuals, the host immune response fails to control the growth of bacilli, and progressive granulomatous disease develops, facilitating spread of the bacilli via infectious aerosols coughed out into the environment and inhaled by new hosts. The molecular details of the Mtb–macrophage interaction continue to be elucidated. However, it is clear that a number of complex processes are involved at the different stages of infection that may benefit either the bacterium or the host. Macrophages demonstrate tremendous phenotypic heterogeneity and functional plasticity which, depending on the site and stage of infection, facilitate the diverse outcomes. Moreover, host responses vary depending on the specific characteristics of the infecting Mtb strain. In this chapter, we describe a contemporary view of the behavior of AMs and their interaction with various Mtb strains in generating unique immunologic lung-specific responses.     

Critical role of AIM2 in Mycobacterium tuberculosis infection

Abstract Absent in melanoma 2 (AIM2) is a sensor of cytosolic DNA that is responsible for activation of the inflammasome and host immune responses to DNA viruses and intracellular bacteria. However, the role of AIM2 in host defenses against Mycobacterium tuberculosis is unknown. Here, we show that AIM2-deficient mice were highly susceptible to intratracheal infection with M. tuberculosis and that this was associated with defective IL-1± and IL-18 production together with impaired T (h) 1 responses. Macrophages from AIM2-deficient mice infected with M. tuberculosis showed severely impaired secretion of IL-1± and IL-18 as well as activation of the inflammasome, determined by caspase-1 cleavage. Genomic DNA extracted from M. tuberculosis (Mtb DNA) induced caspase-1 activation and IL-1±/IL-18 secretion in an AIM2-dependent manner. Mtb DNA, which was present in the cytosol, co-localized with AIM2. Taken together, these findings demonstrate that AIM2 plays an important role in M. tuberculosis infection through the recognition of Mtb DNA.     

Inoculum size and traits of the infecting clinical strain define the protection level against Mycobacterium tuberculosis infection in a rabbit model

Host protective immunity against pathogenic Mycobacterium tuberculosis (Mtb) infection is variable and poorly understood. Both prior Mtb infection and BCG vaccination have been reported to confer some protection against subsequent infection and/or disease. However, the immune correlates of host protection with or without BCG vaccination remain poorly understood. Similarly, the host response to concomitant infection with mixed Mtb strains is unclear. In this study, we used the rabbit model to examine the host response to various infectious doses of virulent Mtb HN878 with and without prior BCG vaccination, as well as simultaneous infection with a mixture of two Mtb clinical isolates HN878 and CDC1551. We demonstrate that both the ability of host immunity to control pulmonary Mtb infection and the protective efficacy of BCG vaccination against the progression of Mtb infection to disease is dependent on the infectious inoculum. The host response to infection with mixed Mtb strains mirrors the differential responses seen during infection with each of the strains alone. The protective response mounted against a hyperimmunogenic Mtb strain has a limited impact on the control of disease caused by a hypervirulent strain. This preclinical study will aid in predicting the success of any vaccination strategy and in optimizing TB vaccines.     

The role of IL-10 in immune regulation during M. tuberculosis infection

During gaseous exchange the lungs are exposed to a vast variety of pathogens, allergens, and innocuous particles. A feature of the lung immune response to lung-tropic aerosol-transmitted bacteria such as Mycobacterium tuberculosis (Mtb) is a balanced immune response that serves to restrict pathogen growth while not leading to host-mediated collateral damage of the delicate lung tissues. One immune-limiting mechanism is the inhibitory and anti-inflammatory cytokine interleukin (IL)-10. IL-10 is made by many hematopoietic cells and a major role is to suppress macrophage and dendritic cell (DC) functions, which are required for the capture, control, and initiation of immune responses to pathogens such as Mtb. Here, we review the role of IL-10 on bacterial control during the course of Mtb infection, from early innate to adaptive immune responses. We propose that IL-10 is linked with the ability of Mtb to evade immune responses and mediate long-term infections in the lung.     

MR1-restricted mucosal associated invariant T (MAIT) cells in the immune response to Mycobacterium tuberculosis

The intracellular pathogen Mycobacterium tuberculosis (Mtb) and its human host have long co-evolved. Although the host cellular immune response is critical to the control of the bacterium information on the specific contribution of different immune cell subsets in humans is incomplete. Mucosal associated invariant T (MAIT) cells are a prevalent and unique T-cell population in humans with the capacity to detect intracellular infection with bacteria including Mtb. MAIT cells detect bacterially derived metabolites presented by the evolutionarily conserved major histocompatibility complex-like molecule MR1. Here, we review recent advances in our understanding of this T-cell subset and address the potential roles for MR1-restricted T cells in the control, diagnosis, and therapy of tuberculosis.     

Host/pathogen interactions at mucosal surfaces: immune consequences

The mucosal immune system has evolved to protect the host against the establishment of infections at or through the mucosal surfaces of the body. Protective immunity must be activated to specific pathogenic agents or their products but inappropriate immune responses to food/environmental antigens must be avoided. Thus, the mucosal immune system is under tight regulation. Pathogenic bacteria and their products can be exploited as specific probes of mucosal immune responses. Bacterial enterotoxins such as cholera toxin are potent mucosal immunogens and adjuvants that activate both mucosal and systemic immune responses. Infection models involving microorganisms such as Citrobacter rodentium can also be used to investigate the consequences of mucosal colonisation that lead to immune disfunction.     

Commensal gut bacteria: mechanisms of immune modulation

Mucosal immune responses to pathogenic gut bacteria and the mechanisms that govern disease progression and outcome have been researched intensely for decades. More recently, the influence of the resident non-pathogenic or 'commensal' microflora on mucosal immune function and gut health has emerged as an area of scientific and clinical importance. Major differences occur in the mucosal immune response to pathogens and commensals. In part, this functional dichotomy is explained by the presence of virulence factors in pathogenic species, which are generally absent in commensals. Additionally, immunological 'unresponsiveness' towards the resident commensal microflora is thought to permit their successful colonisation and co-existence within the host gut. However, evidence of an active dialogue between members of the commensal microflora and the host mucosal immune system is rapidly unfolding. This crosstalk is likely to affect immunological tolerance and homeostasis within the gut and to explain some of the differential host responses to commensal and pathogenic bacteria.     

结核分枝杆菌与巨噬细胞的相互作用

结核分枝杆菌(Mtb)是人类一种较难克服的致病菌.巨噬细胞(Mφ)作为机体固有免疫的重要组成部分在抵抗外来病原微生物中发挥着至关重要的作用.它们之间的相互作用一直被研究者所重视,近年来随着多重耐药菌株的出现以及结核病的死灰复燃使得对其更加受到研究者的重视.因而,深入了解Mφ抵抗Mtb的侵害及Mtb躲避Mφ杀伤的各种机制可以寻找防治结核病的新的治疗靶点.     

Rv2468c, a novel Mycobacterium tuberculosis protein that costimulates human CD4+ T cells through VLA-5

Mtb regulates many aspects of the host immune response, including CD4+ T lymphocyte responses that are essential for protective immunity to Mtb, and Mtb effects on the immune system are paradoxical, having the capacity to inhibit (immune evasion) and to activate (adjuvant effect) immune cells. Mtb regulates CD4+ T cells indirectly (e.g., by manipulation of APC function) and directly, via integrins and TLRs expressed on T cells. We now report that previously uncharacterized Mtb protein Rv2468c/MT2543 can directly regulate human CD4+ T cell activation by delivering costimulatory signals. When combined with TCR stimulation (e.g., anti-CD3), Rv2468c functioned as a direct costimulator for CD4+ T cells, inducing IFN-γ secretion and T cell proliferation. Studies with blocking antibodies and soluble RGD motifs demonstrated that Rv2468c engaged integrin VLA-5 (α5β1) on CD4+ T cells through its FN-like RGD motif. Costimulation by Rv2468c induced phosphorylation of FAKs and Pyk2. These results reveal that by expressing molecules that mimic host protein motifs, Mtb can directly engage receptors on CD4+ T cells and regulate their function. Rv2468c-induced costimulation of CD4+ T cells could have implications for TB immune pathogenesis and Mtb adjuvant effect.     

Immunoevasion and immunosuppression of the macrophage by Mycobacterium tuberculosis

By virtue of their position at the crossroads between the innate and adaptive immune response, macrophages play an essential role in the control of bacterial infections. Paradoxically, macrophages serve as the natural habitat to Mycobacterium tuberculosis (Mtb). Mtb subverts the macrophage's mechanisms of intracellular killing and antigen presentation, leading ultimately to the development of tuberculosis (TB) disease. Here, we describe mechanisms of Mtb uptake by the macrophage and address key macrophage functions that are targeted by Mtb-specific effector molecules enabling this pathogen to circumvent host immune response. The macrophage functions described in this review include fusion between phagosomes and lysosomes, production of reactive oxygen and nitrogen species, antigen presentation and major histocompatibility complex class II expression and trafficking, as well as autophagy and apoptosis. All these are Mtb-targeted key cellular pathways, normally working in concert in the macrophage to recognize, respond, and activate ‘proper’ immune responses. We further analyze and discuss major molecular interactions between Mtb virulence factors and key macrophage proteins and provide implications for vaccine and drug development.