自噬与微生物感染

自噬作为一种维持胞内代谢稳态的机制,与机体微生物感染有着紧密的关系。一方面,自噬能够协助宿主清除病原体;而另一方面也有细菌通过进化,利用自噬体为其增殖提供必要条件,甚至在其中潜伏增殖。同时,病原体也可诱导过度自噬,促进细胞死亡。总之,自噬与微生物感染的关系,可能远比我们知道的复杂。本篇综述即是从自噬分子机制出发,寻找多种病原体与宿主细胞自噬之间的最新进展,深入探讨了自噬之于微生物感染的作用和意义。     

细胞自噬在病毒感染与免疫调节中的作用机制

细胞自噬(autophagy)是一种主要由溶酶体介导的降解通路,作为细胞维持内环境稳态的一种保护性机制,不仅通过将长寿命蛋白和衰老细胞器降解为小肽或氨基酸为细胞提供再生资源,而且也可作为防御机制抵抗病原微生物感染和寄生. 自噬缺失与许多疾病如癌症、心血管疾病等的发生关系密切,在机体生理、病理过程中发挥重要作用. 本文拟就细胞自噬与病毒感染、机体免疫的关系加以综述,以期为研究细胞自噬的发生、参与机体免疫、发挥抗病毒感染作用及其分子机制提供参考,也为进一步研究抗病毒治疗的靶标提供新思路.     

鱼类细胞自噬与炎症反应

细胞自噬和炎症反应是先天性免疫的重要组成部分。细胞自噬是通过溶酶体降解自身组分以维持细胞稳态的一种高度保守的代谢过程，在降解受损的细胞器、抵抗病原感染、调节炎症反应等方面具有举足轻重的地位。在过去的几十年里，对酵母和哺乳动物自噬的研究显著增加了人们对自噬及其与人类疾病关系的理解：调节自噬水平可用于预防或治疗神经退行性疾病、炎症性疾病、肿瘤以及各种病原微生物感染。炎症反应是一个高度复杂的生物过程，是机体在受到紫外线、病原体感染、氧化应激以及机械性损伤等刺激下的一种自然防御反应。鱼类作为低等的脊椎动物，其获得性免疫功能较为低下，先天性免疫是其抵御病原体感染的主要防线。相较于高等动物，鱼类细胞自噬研究虽起步较晚，但近些年围绕病原感染引起的自噬现象及机制、自噬相关基因的表达调控等方面已取得较多进展。作为先天免疫的重要组成部分，自噬参与多种鱼类病原感染，而鱼类疾病通常伴随炎症反应的发生。基于此，本文对于鱼类病原感染引起的细胞自噬、炎症反应以及二者之间相关性研究进行系统阐述，以期深入理解鱼类细胞自噬的发生机制及其与炎症反应的相关关系，为全面解析鱼类的免疫机制提供指导，为制定鱼类疾病防控策略提供依据...     

自噬在抵御微生物免疫反应中的功能

在发现初期,自噬被认为是细胞降解自身成分、适应饥饿应急的代谢机制。进一步研究发现自噬对许多生命过程行使重要的调节作用,其中可以调节机体的免疫防御系统。自噬可以直接捕获并清除感染的微生物病原体,也能够与模式识别受体信号通路相互作用,调节天然免疫反应,抵御微生物感染。而且,自噬可通过调节抗原递呈和T细胞的激活,促进抗原特异的获得性免疫。本文旨在讨论自噬调节机体免疫防御的机制,集中于三方面的功能:直接清除微生物;调节天然免疫反应;以及促进获得性免疫的产生。     

肠道病毒感染诱导宿主细胞自噬的研究进展

细胞自噬是一种高度保守的生理代谢途径,是维持细胞稳态的重要过程。一些病毒已经进化出逃逸自噬依赖性降解的方法,甚至进化出利用自噬以促进自身复制的机制。肠道病毒感染细胞时,能激活自噬途径,诱导自噬体的形成。本文对肠道病毒感染与细胞自噬的研究概况与进展作一综述,为进一步解析肠道病毒感染与细胞自噬之间相互作用的机制提供参考。     

细胞自噬与病毒感染

自噬是广泛存在于真核细胞内的一种溶酶体依赖性降解途径,在维持细胞存活、更新、物质再利用和内环境稳定中起着重要作用。目前已经发现大量新的自噬相关基因,同时发现自噬在病毒感染过程中发挥着重要的抗病毒作用:自噬可以将胞质中的病毒转运到溶酶体中,降解病毒;也可以将病毒核酸转运至胞内感受器上激活天然免疫;还可以将病毒抗原递呈给MHCⅡ类分子激活适应性免疫。自噬参与胞内微生物感染具有双重作用。一方面,自噬能够降解入侵的微生物,即以异源吞噬(xenophagy)的方式清除胞内的病原体;另一方面,有些微生物能够通过某些机制逃避自噬而利于自身存活。本文就细胞自噬及其与不同病毒感染关系的最新研究进展进行综述。     

细菌与自噬的抗争——死亡或重生

自噬是一种高度保守的细胞内成分的降解过程,不仅维持细胞的代谢稳定,还与机体对抗各种病原菌感染有着密切关系。自噬能协助机体清除病原体,但有些细菌进化出多种策略干扰自噬信号通路或抑制自噬体与溶酶体融合形成自噬溶酶体来逃避自噬的降解,甚至利用自噬来促进其生长增殖。文中从自噬的分子机制出发,讨论多种致病菌与宿主细胞自噬关系的最新进展,以及自噬与病原菌感染的作用和意义,以期为病原菌感染导致的自噬研究提供参考。     

自噬对胞内感染病原菌的清除及促进增殖作用

自噬作为一种新的程序性细胞死亡,其在病原体感染中的地位日益受到广泛关注。自噬在病原体感染中具有"双刃剑"样作用,一方面,机体可利用自噬清除感染入侵的病原体;另一方面,自噬可被某些病原体利用、修饰或干扰,以促进自身在宿主细胞内的存活与增殖。本文拟就近年来自噬与人类疾病关系密切的胞内病原菌感染中的作用及地位进行综述,同时结合本室研究进行一定深入探讨,为探索通过调控及合理利用自噬途径预防和控制感染性疾病的发生发展提供理论依据。     

自噬在结核分枝杆菌感染中作用的研究进展

结核病是一种由结核分枝杆菌感染引发的全球致死性传染病。结核分枝杆菌感染巨噬细胞后其在胞内的命运与细胞自噬的发生息息相关。但是,由于结核分枝杆菌与细胞自噬之间的博弈过程十分复杂且机制尚未完全阐明。因此,该文以结核分枝杆菌感染巨噬细胞后经典自噬和LAP对结核病发生发展的作用为切入点,从自噬抗结核分枝杆菌感染与结核分枝杆菌破坏自噬发生两个方面阐述了自噬与结核分枝杆菌之间的相互作用,从而为结核病发病机制的研究提供新的思路和视角。     

猪丁型冠状病毒感染引致细胞自噬的研究进展

细胞自噬是利用溶酶体对细胞内多余、受损、死亡的蛋白质和细胞器进行降解的一种过程。细胞受到病毒等刺激时,为了维持内环境稳态,细胞自噬常有发生,虽然细胞自噬可以有效抵抗病毒入侵,但这个过程也会对病毒感染产生负作用。猪丁型冠状病毒(porcine deltacoronavirus,PDCoV)感染细胞时会引发细胞发生自噬现象。本文从自噬的种类和发生流程、自噬与PDCoV互作及相关检测方法等方面,对细胞自噬在PDCoV感染中如何抵抗和促进病毒复制进行了阐述,对进一步研究PDCoV致病机制和防控具有积极意义。     

Autophagy differentially controls plant basal immunity to biotrophic and necrotrophic pathogens

In plants, autophagy has been assigned 'pro-death' and 'pro-survival' roles in controlling programmed cell death associated with microbial effector-triggered immunity. The role of autophagy in basal immunity to virulent pathogens has not been addressed systematically, however. Using several autophagy-deficient (atg) genotypes, we determined the function of autophagy in basal plant immunity. Arabidopsis mutants lacking ATG5, ATG10 and ATG18a develop spreading necrosis upon infection with the necrotrophic fungal pathogen, Alternaria brassicicola, which is accompanied by the production of reactive oxygen intermediates and by enhanced hyphal growth. Likewise, treatment with the fungal toxin fumonisin B1 causes spreading lesion formation in atg mutant genotypes. We suggest that autophagy constitutes a 'pro-survival' mechanism that controls the containment of host tissue-destructive microbial infections. In contrast, atg plants do not show spreading necrosis, but exhibit marked resistance against the virulent biotrophic phytopathogen, Pseudomonas syringae pv. tomato. Inducible defenses associated with basal plant immunity, such as callose production or mitogen-activated protein kinase activation, were unaltered in atg genotypes. However, phytohormone analysis revealed that salicylic acid (SA) levels in non-infected and bacteria-infected atg plants were slightly higher than those in Col-0 plants, and were accompanied by elevated SA-dependent gene expression and camalexin production. This suggests that previously undetected moderate infection-induced rises in SA result in measurably enhanced bacterial resistance, and that autophagy negatively controls SA-dependent defenses and basal immunity to bacterial infection. We infer that the way in which autophagy contributes to plant immunity to different pathogens is mechanistically diverse, and thus resembles the complex role of this process in animal innate immunity.     

Cell type-dependent requirement of autophagy in HSV-1 antiviral defense

Type I interferons (IFNs) are induced during most viral infections and are considered to be the primary and universal means of innate viral control. However, several other innate mechanisms, including autophagy, have recently been shown to play an important role in antiviral defense. In our recent study, we utilized a herpes simplex virus 1 (HSV-1) infection model to investigate the relationship between cell type and innate antiviral immune mechanisms. Our study demonstrates that dorsal root ganglion (DRG) neurons undergo an innate antiviral response to HSV-1 that differs from the antiviral program induced in mitotic cells in three distinct ways. First, DRG neurons produce less type I IFN and undergo a less effective IFN antiviral program vs. mitotic cells in response to HSV-1 infection. Second, the type I IFN program initiated in DRG neurons induces less cell death than in mitotic cells. Third, in the absence of a robust type I IFN response, DRG neurons, but not mitotic cells, repy on autophagy in HSV-1 defense. Our findings reveal a cell type-specific requirement for autophagy in defense against HSV-1, and offer insight into the cell-appropriate antiviral defense mechanism employed by neurons.     

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.     

细胞自噬发生的表观遗传调节

细胞自噬是一种进化上保守的, 通过吞噬降解自身大分子物质或细胞器来维持细胞生存的活动。自噬与多种生命活动息息相关, 其功能的紊乱往往会导致肿瘤发生、神经退行性疾病、微生物感染等疾病。研究表明, 表观遗传修饰可以调控细胞自噬的发生, 并在细胞自噬的生物学功能调节过程中发挥重要作用, 但具体调控机制尚需进一步探究。文章综述了细胞自噬发生过程中存在的表观遗传效应, 包括组蛋白乙酰化对细胞自噬激活或抑制的负反馈调控, 通过DNA甲基化调节自噬相关基因活性来影响细胞自噬的发生, miRNA通过靶向调节自噬相关基因表达来影响组蛋白修饰, 从而调控细胞自噬的发生及作用过程等, 旨在为人们进一步研究细胞自噬发生过程中的表观遗传修饰及其机制提供信息依据。     

Autophagy in sepsis: Degradation into exhaustion?

Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro- and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers.     

Interactions of pathogenic bacteria with autophagy systems

Autophagy is a conserved cellular degradative pathway that is now established to be a vital part of the host immune response to microbial infection. Autophagy can directly eliminate intracellular pathogens by mediating their delivery to lysosomes. Canonical autophagy is characterized by the formation of a double-membrane autophagosome and the involvement of over 35 autophagy-related proteins (Atgs), including a commonly used autophagosome marker in mammalian cells, LC3. Recent studies have shown that a subset of autophagy components can lead to LC3 conjugation onto phagosomes. This process of LC3-associated phagocytosis (LAP) results in the degradation of the cargo by promoting phagosome fusion with lysosomes. Other components of the autophagy machinery also play roles in immunity that are distinct from the canonical autophagy and LAP pathways. This minireview highlights the complicated relationship between autophagy components and intracellular bacteria, including bacterial targeting mechanisms and the interaction between autophagy and effectors/toxins secreted by bacteria.     

iTRAQ-based proteomics analysis of autophagy-mediated immune responses against the vascular fungal pathogen Verticillium dahliae in Arabidopsis

The mechanisms underlying the functional link between autophagy and plant innate immunity remain largely unknown. In this study, we investigated the autophagy-mediated plant defense responses against Verticillium dahliae (V. dahliae) infection by comparative proteomics and cellular analyses. An assessment of the autophagy activity and disease development showed that autophagic processes were tightly related to the tolerance of Arabidopsis plant to Verticillium wilt. An isobaric tags for relative and absolute quantification (iTRAQ)-based proteomics analysis was performed, and we identified a total of 780 differentially accumulated proteins (DAPs) between wild-type and mutant atg10-1 Arabidopsis plants upon V. dahliae infection, of which, 193 ATG8-family-interacting proteins were identified in silico and their associations with autophagy were verified for several selected proteins. Three important aspects of autophagy-mediated defense against V. dahliae infection were revealed: 1) autophagy is required for the activation of upstream defense responses; 2) autophagy-mediated mitochondrial degradation (mitophagy) occurs and is an important player in the defense process; and 3) autophagy promotes the transdifferentiation of perivascular cells and the formation of xylem hyperplasia, which are crucial for protection against this vascular disease. Together, our results provide several novel insights for understanding the functional association between autophagy and plant immune responses.     

Autophagy: An overlooked mechanism of HIV-1 pathogenesis and NeuroAIDS?

Human immunodeficiency virus type 1 (HIV-1) establishes a persistent infection characterized by progressive depletion of CD4⁺ lymphocytes and immunosuppression. Although extensive research has examined the importance of apoptosis as a cause of cell death associated with HIV-1 infection, the role of autophagy has been largely ignored. Our laboratory has examined the autophagic process in HIV-1-infected cells. Following infection of human peripheral blood CD4+ T-cells or U937 cells with HIV-1 for 48 hours, the autophagy proteins Beclin 1 and LC3-II were found to be markedly decreased. Beclin 1 mRNA expression and autophagosomes were also reduced in HIV-1 infected cells. Thus, our data indicate that HIV-1 infection inhibits autophagy in infected cells in contrast to the previously described induction of autophagy by gp120 in uninfected bystander cells. It is likely that HIV-1 has evolved this mechanism as part of an elaborate attempt to evade the immune system while promoting its own replication. We believe that autophagy is an overlooked mechanism in HIV-1 pathogenesis and plays a particularly important role in the early cognitive impairment and dementia often associated with advanced AIDS. A model is presented that describes the potential role of autophagy in NeuroAIDS.

Addendum to: Zhou D, Spector SA. Human immunodeficiency virus type-1 infection inhibits autophagy. Aids 2008;22:695-9.     

Porcine reproductive and respiratory syndrome virus induces autophagy to promote virus replication

An increasing number of studies demonstrate that autophagy, an intrinsic mechanism that can degrade cytoplasmic components, is involved in the infection processes of a variety of pathogens. It can be hijacked by various viruses to facilitate their replication. In this study, we found that PRRSV infection significantly increases the number of double- or single-membrane vesicles in the cytoplasm of host cells in ultrastructural analysis. Our results showed the LC3-I was converted into LC3-II after virus infection, suggesting the autophagy machinery was activated. We further used pharmacological agents and shRNAs to confirm that autophagy promoted the replication of PRRSV in host cells. Confocal microscopy analysis showed that PRRSV inhibited the fusion between autophagosomes and lysosomes, suggesting that PRRSV induced incomplete autophagy. This suppression caused the accumulation of autophagosomes which may serve as replication site to enhance PRRSV replication. It has been shown that NSP2 and NSP3 of arterivirus are two components of virus replication complex. We also found in our studies that NSP2 colocalized with LC3 in MARC-145 cells by performing confocal microscopy analysis and continuous density gradient centrifugation. Our studies presented here indicated that autophagy was activated during PRRSV infection and enhanced PRRSV replication in host cells by preventing autophagosome and lysosome fusion.     

Autophagy and toll-like receptors: a new link in cancer cells

In addition to its clean-up function, autophagy is considered as an innate immunity mechanism due to its role in the removal of intracellular pathogens. Toll-like receptors (TLRs) are crucial components of innate immunity involved in the recognition of a diverse array of microbial products. Recent works demonstrated that different pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and single-strand RNA are able to induce autophagy via different TLRs in immune cells. In a recent report, we showed that bacterial CpG motifs, another PAMP, can induce autophagy in rodent and human tumor cell lines and that this process is TLR9-dependent. In addition, an increase in the number of autophagosomes can also be observed in vivo after the intratumoral injection of CpG motifs. These results extend the link between TLRs and autophagy to non-immune tumor cells and may be relevant for cancer treatment and more generally for gene therapy approaches in TLR9-positive tissues. In this addendum, we discuss the potential mechanisms and the consequences of the CpG-induced autophagy in tumor cells.