结核分枝杆菌免疫逃避机制研究进展

结核病(Tuberculosis TB)主要由结核分枝杆菌(Mycobacterium tuberculosis,Mtb)感染引起,结核分枝杆菌在机体中长期存在与其逃避机体免疫杀伤机制密切相关。已发现的结核分枝杆菌免疫逃避机制包括阻止巨噬细胞吞噬溶酶体的成熟及酸化,抑制氧化应激反应,抑制细胞凋亡及自噬等。结核分枝杆菌逃避宿主免疫杀伤的机制错综复杂,目前尚未完全明了,本文就结核分枝杆菌免疫逃避机制做一综述,为其深入研究提供参考。     

结核分枝杆菌逃逸免疫杀伤机制的研究进展

结核分枝杆菌(Mycobacterium tuberculosis, MTB)是典型的胞内致病菌,感染机体后主要寄居于宿主巨噬细胞内。巨噬细胞作为机体防御系统的第一道防线,可通过介导和调控自身及其他细胞凋亡而实现其免疫调节、免疫杀伤及清除病原菌的作用。MTB感染机体后可通过多种途径使巨噬细胞不能正常凋亡,借以逃避巨噬细胞的免疫监视及清除,继而在体内衍生繁殖。进一步探讨结核分枝杆菌逃逸宿主细胞的免疫杀伤机制,对宿主细胞抗结核免疫及人们更好地防治结核病具有深远影响。     

巨噬细胞与结核分枝杆菌的免疫反应的研究进展

巨噬细胞是结核分枝杆菌在机体内的主要宿主细胞.细胞介导的免疫反应是机体抗结核分枝杆菌的主要免疫保护机制,巨噬细胞可通过吞噬、溶酶体融合,提呈结核分枝杆菌抗原,产生多种细胞因子、反应氧中间产物和反应氮中间产物,以及细胞凋亡等多种途径来杀灭结核分枝杆菌;同时,结核分枝杆菌也可采取各种方式来逃逸巨噬细胞的免疫作用.本文就巨噬细胞与结核分枝杆菌的免疫反应的研究进展作一综述.     

巨噬细胞与结核分枝杆菌的免疫反应的研究进展

巨噬细胞是结核分枝杆菌在机体内的主要宿主细胞.细胞介导的免疫反应是机体抗结核分枝杆菌的主要免疫保护机制,巨噬细胞可通过吞噬、溶酶体融合,提呈结核分枝杆菌抗原,产生多种细胞因子、反应氧中间产物和反应氮中间产物,以及细胞凋亡等多种途径来杀灭结核分枝杆菌;同时,结核分枝杆菌也可采取各种方式来逃逸巨噬细胞的免疫作用.本文就巨噬细胞与结核分枝杆菌的免疫反应的研究进展作一综述.     

巨噬细胞与结核分枝杆菌的免疫反应的研究进展

巨噬细胞是结核分枝杆菌在机体内的主要宿主细胞.细胞介导的免疫反应是机体抗结核分枝杆菌的主要免疫保护机制,巨噬细胞可通过吞噬、溶酶体融合,提呈结核分枝杆菌抗原,产生多种细胞因子、反应氧中间产物和反应氮中间产物,以及细胞凋亡等多种途径来杀灭结核分枝杆菌;同时,结核分枝杆菌也可采取各种方式来逃逸巨噬细胞的免疫作用.本文就巨噬细胞与结核分枝杆菌的免疫反应的研究进展作一综述.     

巨噬细胞在抗结核感染中的作用

巨噬细胞在结核病发病过程及机体抗结核免疫过程中扮演重要的角色。巨噬细胞是机体天然免疫的重要组成细胞,同时又是一类主要的抗原提呈细胞。在天然免疫和获得性免疫中都起着关键的作用。结核病是由结核分枝杆菌引起的严重危害人类健康的主要传染病,结核分枝杆菌可以通过多种途径来干扰机体巨噬细胞的免疫应答。本篇综述的目的在于讨论宿主被结核分枝杆菌入侵后,巨噬细胞在各种抗结核感染的免疫应答中的作用机制。     

结核分枝杆菌靶向宿主细胞蛋白逃逸免疫杀伤的研究进展

结核分枝杆菌是引发结核病的一种人兽共患病原菌,严重危害人类健康以及公共安全,作为一种兼性胞内感染菌,其引发结核病的关键是破坏宿主免疫防御机制以提高其在胞内生存能力。结核分枝杆菌感染宿主细胞的过程中,分枝杆菌效应蛋白通过与宿主靶蛋白的相互作用来影响细胞凋亡、炎性因子表达、抗原提呈等多种免疫效应,从而逃逸宿主细胞的杀伤,并在机体免疫状态低下时复发从而引起结核病。深入了解结核分枝杆菌效应蛋白和宿主靶蛋白的相互作用及分子机制,将为结核病的防治提供新的线索。     

结核分枝杆菌及结核疫苗新作用方式的研究

结核病主要是由结核分枝杆菌引起的传染性疾病，是严重威胁人类健康的重大公共卫生问题。目前，卡介苗仍是唯一被批准应用于人体的预防性疫苗，其对婴幼儿具有较好的保护效果，但对成年人的保护作用存在巨大争议。巨噬细胞和树突状细胞吞噬结核分枝杆菌之后，启动适应性免疫应答，活化的效应性CD4⁺和CD8⁺T细胞通过释放细胞因子和细胞毒作用发挥免疫效应。然而，结核分枝杆菌可通过抑制吞噬溶酶体形成、改变代谢途径、抑制抗原提呈等作用发生免疫逃逸，使其在宿主体内长期存在。近年来，随着多组学的发展，针对结核分枝杆菌感染免疫机制的研究有了一定的进展，但通过接种疫苗对结核病进行防控的结果依然不尽人意。本文重点探讨了结核分枝杆菌和宿主之间的免疫反应以及逃逸机制，并概述了结核疫苗的研发情况，有助于我们利用结核菌感染的免疫学知识对结核病疫苗进行快速高效的研发。     

结核分枝杆菌感染致巨噬细胞脂代谢改变的研究进展

结核分枝杆菌引起的结核病是全球致死性传染病之一,结核感染期间结核分枝杆菌利用巨噬细胞脂质作为主要碳源。结核分枝杆菌与巨噬细胞间的相互作用、巨噬细胞内的免疫应答及脂质平衡密切相关。结核病患者肺内脂质含量明显增加,而外周血内胆固醇含量却明显降低。本文从巨噬细胞中结核分枝杆菌的能量代谢、结核分枝杆菌感染致肺部及血中巨噬细胞脂代谢改变等方面对结核分枝杆菌感染致巨噬细胞脂代谢改变的研究进展作一综述,以期发现结核病治疗的新靶点和新方法。     

巨噬细胞在抗结核免疫中的作用及其研究进展

据估计世界上有1/3人口感染了结核分枝杆菌。在大多数情况下,结核分枝杆菌感染者是无症状和没有传染性的,即潜伏性结核感染。为何机体免疫反应可使绝大多数人免患活动性结核病,而又不能完全清除这种感染呢？研究表明,巨噬细胞在控制结核分枝杆菌感染中起着重要作用,而结核分枝杆菌本身也已产生了逃避巨噬细胞杀灭的机制。本文就以上方面的研究进展综述如下。     

Protective immunity against Mycobacterium tuberculosis

Mycobacterium tuberculosis (MTB) is a facultative intracellular pathogen with which over a billion people have been infected and 3 million people die annually. The bacterium induces vigorous immune responses, yet evades host immunity, persisting within phagosomes of the infected macrophages. Thus, it is necessary to delineate that the virulence-related intracellular survival mechanism and the host immune responses to eradicate M. tuberculosis on the molecular basis. In this regard, recent findings clearly indicated that Toll-like receptors (TLRs) play an essential role in the recognition of MTB components by macrophages and dendritic cells, resulting in not only activation of innate immunity but also development of antigen-specific adaptive immunity. It has been also reported that induction of early death of the infected cells may be one of the strategy of host defense against MTB because macrophages go into apoptosis upon infection with MTB, resulting in suppression of the intracellular replication. Furthermore, recent report has shown that autophagy is induced by IFN-gamma and suppress intracellular survival of mycobacteria, suggesting that activation of autophagy pathway is required to overcome phagosome maturation arrest induced by MTB. In addition, it is known that IFN-gamma plays an important role in protection. The cytokine that is produced from NK cells and dendritic cells at the early period of infection strongly induces not only macrophage activation but also development of antigen-specific IFN-gamma-producing CD4+T cells. Since antigen-specific CD8+ T cells and CD1-restricted T cells are also reported to contribute to the protective immunity, cooperation of these T cells is essential for the host resistance. In this paper, I am going to summarize the recent progress of the understanding of protective immunity against MTB.     

Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages

Macrophages are central to host defense against microbes, but intracellular pathogens have evolved to evade their antimicrobial functions. Mycobacterium tuberculosis (MTB) has successfully exploited macrophages as its primary niche in vivo, but the bacterial genome-wide requirements that promote its intracellular survival remain undefined. Here we comprehensively identify the MTB genes required for survival by screening for transposon mutants that fail to grow within primary macrophages. We identify mutants showing decreased growth in macrophage environments that model stages of the host immune response. By systematically analyzing several biologically relevant data sets, we have been able to identify putative pathways that could not be predicted by genome organization alone. In one example, phosphate transport, requiring physically unlinked genes, was found to be critical for MTB growth in macrophages and important for establishing persistent infection in lungs. Remarkably, the majority of MTB genes found by this analysis to be required for survival are constitutively expressed rather than regulated by macrophages, revealing the host-adapted lifestyle of an evolutionarily selected intracellular pathogen.     

Immunität gegen Mycobacterium tuberculosis

Infections with Mycobacterium tuberculosis (MTB) induce complex immune responses involving an orchestrated interplay of innate and adaptive immune mechanisms. Why the immune system fails to eradicate the pathogen and at best achieves control of infection in the latent stage, still remains an unsolved mystery even more than 100 years after the discovery of MTB by Robert Koch. This article provides an overview of the current state of the art in the constantly evolving field of tuberculosis (TB) immunology. This review focuses on a change of paradigm proposing that in the latent stage MTB is anything but dormant and that latent TB is not merely a state of bacterial stasis but a state of dynamic bacterial and immunological equilibrium. The understanding of these dynamics is crucial for the development of new drugs against MTB as well as vaccines that aim to provide effective protection against the disease.     

结核分枝杆菌PE/PPE蛋白家族生物学研究进展

结核分枝杆菌(Mycobacterium tuberculosis,MTB)是引起结核病的病原体,也是单一感染微生物导致死亡的最重要原因。在MTB基因组上有一类特殊的蛋白家族——PE/PPE蛋白家族,该蛋白家族对细菌毒力、抗原变异、宿主细胞命运等至关重要,且在特异性诊断试剂和疫苗研制中具有广阔的应用前景。本文将从PE/PPE蛋白家族的结构特征、生物学功能、及其对宿主免疫反应调控等方面的近年来研究进展作一综述。     

Expression of CCR5 is increased in human monocyte-derived macrophages and alveolar macrophages in the course of in vivo and in vitro Mycobacterium tuberculosis infection.

Human immunodeficiency virus (HIV) replicates more efficiently in Mycobacterium tuberculosis (MTB)-infected macrophages than in uninfected controls. We investigated whether this may be partly explained by changes in expression of CCR5 in the course of mycobacterial infection, as this molecule has been shown to be a coreceptor for HIV entry. Since the lung is the preferential organ of HIV replication in the course of tuberculosis, we preliminarily analyzed beta-chemokine receptor expression in alveolar macrophages from patients with active tuberculosis, using flow cytometry based on an MIP-1alpha ligand-biotin/avidin-FITC detection system. Increased MIP-1alpha receptor (MIP-1alphaR) expression in alveolar macrophages from infected patients was observed whereas no detectable expression could be revealed in uninfected controls. Since MIP-la can also bind CCR1 and CCR4, the presence of CCR5 mRNA was investigated in bronchoalveolar lavage (BAL) cells and detected in alveolar macrophages from tuberculosis patients only. The study was then extended to in vitro MTB-infected macrophages. Monocyte-derived macrophages (MDMs) were left to differentiate for 7 days before MTB H37Rv infection, and CCR5 expression was monitored, by using a specific monoclonal antibody, on days 1, 6, and 11 after infection. Increased CCR5 expression in MTB-infected macrophages was observed, with a peak on day 6 (64% in MTB-infected versus 33% in control cultures) and a decrease by day 11 (25% in MTB infected versus 13% in control cultures). These results show that CCR5 expression is enhanced in the course of in vitro MTB infection and during active pulmonary tuberculosis.     

结核分枝杆菌与宿主作用相关蛋白研究进展

结核分枝杆菌(MTB)是第二大致死性感染性疾病的病原体,以呼吸道感染为主要途径,一旦侵入宿主体内即很难被清除。本文主要阐述了结核分枝杆菌侵入人体后有些蛋白可以调节宿主免疫机制、抵御宿主的清除作用,从而与宿主长期共存;其蛋白作用机制包括阻止吞噬溶酶体的形成和酸化、抑制自噬体的形成、抗氧化应激、抑制细胞凋亡等。如何打破两者的“共存”现象还需要继续研究。     

Host genetic factors in resistance and susceptibility to tuberculosis infection and disease

The worldwide public health threat of tuberculosis and the search for novel strategies for preventing and treating disease have focused attention on the interaction between host and pathogen. Despite widespread presence of Mycobacterium tuberculosis, only a relatively small percentage of people exposed to the organism progress to clinical disease. Increasing evidence indicates that host genetic factors influence the outcome of exposure to M. tuberculosis. This evidence is presented here, along with strategies used to identify host genes responsible for resistance/susceptibility in MTB infection. Studies on host genes involved in response to infection by MTB and the relationships between infection and polymorphisms in immune response genes are reviewed. Research on how host genes can influence vaccine responses and the efficacy of drugs or other interventions as well as studies into the relationship of host genes to tuberculosis outcomes may lead to new strategies for prevention and control.     

Recent advances in tuberculosis immunity

Primary tuberculosis infection is acquired by the inhalation of droplets containing Mycobacterium tuberculosis (MTB) bacilli. Only 5-10% of those individuals infected by MTB develop clinical diseases, and disease presentation itself is heterogeneous, suggesting that host factors play a large role in disease susceptibility. Protective immunity in the lung against MTB consist of the innate immunity in which alveolar macrophages play an central role, and the acquired immunity including various type of effector T cells. Recent studies show that the important roles of the receptors which recognize MTB for the development of protective immunity, the difference in the anti-MTB activity of macrophages between human and mice, the macrophage-heterogeneity that affects the anti-MTB activity, the role of IL-10 in the activation of anti-MTB activity of human macrophages, and the role of Th17/IL-17, Th22/ IL-22 and TNF in the protective immunity against human tuberculosis. In this review, these recent advances in tuberculosis immunity will be described.     

Human splenic macrophages as a model for in vitro infection with Mycobacterium tuberculosis

Macrophages play an important role during Mycobacterium tuberculosis (MTB) infection. In humans most of the studies on MTB-macrophage interactions have been performed using circulating monocytes and monocyte-derived macrophages. However, little research has been performed on this interaction using tissue macrophages. Herein, we used human splenic macrophages to characterize particular responses to MTB infection. Based on morphological, biochemical, and immunological markers, splenic adherent cells exhibit characteristics of tissue macrophages. They were able to efficiently phagocytose both live and heat-killed (h-k) MTB H37Rv. Upon infection with live, but not h-k MTB, an increase in secreted TNF-alpha was elicited. Splenic macrophages produced high basal levels of IL-10; however, infection with live or h-k MTB resulted in decrease IL-10 secretion. Both IL-12p40 and IL-12p70 basal levels were also decreased upon infection with live or h-k MTB; however, while the reduction for IL-12p40 levels was observed at earlier time points (4h) for both live and h-k MTB, infection with live MTB, but not h-k MTB, resulted in a time-dependent secretion of IL-12p40 at 24 and 48h after infection. IL-12p70 levels were completely reduced upon infection by either live or h-k MTB. These results support that human splenic macrophages may represent a potential useful model to study MTB-macrophage interactions in vitro.