BCG-induced protection: Effects on innate immune memory

The Bacille Calmette–Guerin (BCG) vaccine is the only vaccine proved to be effective against tuberculosis and it remains the most commonly used vaccine worldwide. In addition to its effects on mycobacterial diseases, an increasing body of epidemiological evidence accumulated since its introduction in 1921 shows that BCG also exerts beneficial non-specific effects ranging from protection against non-mycobacterial diseases, decreased incidence of allergic diseases, and treatment of certain malignancies. The biological substrate of these effects is mediated partly by heterologous effects on adaptive immunity, but also on the potentiation of innate immune responses through epigenetic mechanisms, a process termed ‘trained immunity’. The process of trained immunity may also play a role in the beneficial effects of BCG against tuberculosis and Mycobacterium tuberculosis infection, and this could have important consequences for our quest for improving vaccination strategies.     

Promotion of trained innate immunity by nanoparticles

The dogma that immunological memory is an exclusive trait of adaptive immunity has been recently challenged by studies showing that priming of innate cells can also result in modified long-term responsiveness to secondary stimuli, once the cells have returned to a non-activated state. This phenomenon is known as ‘innate immune memory’, ‘trained immunity’ or ‘innate training’. While the main known triggers of trained immunity are microbial-derived molecules such as β-glucan, endogenous particles such as oxidized low-density lipoprotein and monosodium urate crystals can also induce trained phenotypes in innate cells. Whether exogenous particles can induce trained immunity has been overlooked. Our exposure to particulates has dramatically increased in recent decades as a result of the broad medical use of particle-based drug carriers, theragnostics, adjuvants, prosthetics and an increase in environmental pollution. We recently showed that pristine graphene can induce trained immunity in macrophages, enhancing their inflammatory response to TLR agonists, proving that exogenous nanomaterials can affect the long-term response of innate cells. The consequences of trained immunity can be beneficial, for instance, enhancing protection against unrelated pathogens; however, they can also be deleterious if they enhance inflammatory disorders. Therefore, studying the ability of particulates and biomaterials to induce innate trained phenotypes in cells is warranted.Here we analyse the mechanisms whereby particles can induce trained immunity and discuss how physicochemical characteristics of particulates could influence the induction of innate memory. We review the implications of trained immunity in the context of particulate adjuvants, nanocarriers and nanovaccines and their potential applications in medicine. Finally, we reflect on the unanswered questions and the future of the field.     

BCG-induced trained immunity in NK cells: Role for non-specific protection to infection

Adaptive features of innate immunity, also termed ‘trained immunity’, have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens via epigenetic reprogramming of monocytes. Recently, memory-like properties were also observed in NK cells during viral infections, but it is unknown if memory properties of NK cells contribute to trained immunity due to BCG vaccination.     

Trained innate immunity and resistance to Mycobacterium tuberculosis infection

BackgroundSome individuals, even when heavily exposed to an infectious tuberculosis patient, develop neither active nor latent tuberculosis infection (LTBI). This ‘early clearance’ of Mycobacterium tuberculosis is associated with a history of bacillus Calmette–Guérin (BCG) vaccination. As BCG vaccination can boost innate immune responses through a process termed ‘trained immunity’, we hypothesize that BCG-induced trained innate immunity contributes to early clearance of M. tuberculosis.ObjectivesWe describe the epidemiological evidence and biological concepts of early clearance and trained immunity, and the possible relation between these two processes through BCG vaccination.SourcesRelevant data from published reports up to November 2018 were examined in the conduct of this review.ContentSeveral observational studies and one recent randomized trial support the concept that boosting innate immunity contributes to protection against M. tuberculosis infection, with BCG vaccination providing approximately 50% protection. The molecular mechanisms mediating early clearance remain largely unknown, but we propose that trained immunity, characterized by epigenetic and metabolic reprogramming of innate immune cells such as monocytes or macrophages, is at least partially responsible for eliminating the mycobacteria and inducing early clearance.ImplicationsFuture studies should examine if BCG revaccination increases early clearance of M. tuberculosis through induction of trained immunity. Epigenetic or metabolic modulation may further boost BCG-induced trained innate immunity to promote tuberculosis prevention. New tuberculosis vaccine candidates should also be examined for their capacity to improve protection against M. tuberculosis infection and induce trained immunity.     

天然免疫记忆研究进展

经典免疫学理论认为只有获得性免疫能建立免疫记忆.现研究发现天然免疫细胞包括NK细胞、单核细胞、巨噬细胞等经过驯化后能在再次刺激后产生增强的免疫反应,这种现象被称为天然免疫记忆或训练免疫.天然免疫记忆主要由代谢及表观遗传重编程而存储记忆.天然免疫记忆为感染性疾病、癌症及炎症等疾病的发病机理及治疗提供了新的研究视角.     

Immunometabolic circuits in trained immunity

The classical view that only adaptive immunity can build immunological memory has recently been challenged. Both in organisms lacking adaptive immunity as well as in mammals, the innate immune system can adapt to mount an increased resistance to reinfection, a de facto innate immune memory termed trained immunity. Recent studies have revealed that rewiring of cellular metabolism induced by different immunological signals is a crucial step for determining the epigenetic changes underlying trained immunity. Processes such as a shift of glucose metabolism from oxidative phosphorylation to aerobic glycolysis, increased glutamine metabolism and cholesterol synthesis, play a crucial role in these processes. The discovery of trained immunity opens the door for the design of novel generations of vaccines, for new therapeutic strategies for the treatment of immune deficiency states, and for modulation of exaggerated inflammation in autoinflammatory diseases.     

自噬与固有免疫应答相互调节研究进展

自噬在细胞分化、肿瘤、炎症、免疫等多方面发挥关键作用.近年来,随着分子生物学、细胞生物学、免疫学等学科的发展,研究发现细胞自噬与固有免疫应答有着重要的相互调控作用.自噬是固有免疫的重要组成成分,可以通过溶酶体直接降解被自噬体包裹的病原体.自噬参与众多固有免疫信号的调控.固有免疫信号也诱导或抑制自噬.自噬在抗胞内病原体感染中发挥重要作用.     

The role of the interleukin-1 family in trained immunity

Immunological memory was long considered a trait exclusive to cells of the adaptive immune system. However, recent studies have shown that after activation of the innate immune system, innate immune cells may undergo long-term functional reprogramming characterized by the ability to mount either a stronger or attenuated inflammatory response upon reactivation. This phenomenon, which has been termed trained immunity and is a de facto innate immune memory, is regulated by a network of integrated metabolic and epigenetic rewiring. The endogenous mediators that modulate trained immunity in the host are only partially understood, but increasing evidence supports the concept that the interleukin (IL)-1 family of cytokines plays an important role. In this review, we will highlight key findings from studies that provide insight into the multifaceted roles of members of the IL-1 family for trained immunity. Finally, we will discuss how the recent advances of our understanding on the role of IL-1 cytokines in this field may lead to new therapeutic strategies for treatment of common conditions, such as IL-1-driven autoinflammatory diseases.     

自噬相关蛋白对固有免疫调控的研究进展

模式识别受体（PPRs）识别病原微生物成分,诱导机体产生固有免疫应答。固有免疫应答异常,可导致超强的炎症反应,并可引起自身免疫性疾病。因此,必须对固有免疫应答进行严格的调控,才能维持机体生理平衡稳定。近年来,研究发现细胞自噬（autophagy）对固有免疫应答有着重要的调控作用。     

Trained immunity from the perspective of Plasmodium infection

The immune system of vertebrates includes innate immunity and adaptive immunity, and the network between them enables the host to fight against invasions of various pathogens. Recently, studies discovered that immune memory is one of the features of innate immunity, breaking the previous opinion that immune memory exists only in adaptive immunity. Immune memory supports innate immune cells to respond efficiently upon reinfection or restimulation. During the Plasmodium infection, the innate immune system is the first to be triggered, and innate immune cells are activated by components from Plasmodium or Plasmodium-infected red blood cells. Innate immune cells could be induced to develop memory after the activation and may play an important role in the subsequent infection of Plasmodium or other pathogens and stimulation. This review will discuss the recent findings relevant to trained immunity and Plasmodium infection, facilitating the understanding of the role of trained immunity in malaria and other diseases and the development of therapeutic strategies based on trained immunity.     

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。     

The Mycobacterium tuberculosis cell wall component mycolic acid elicits pathogen-associated host innate immune responses

Recognition of conserved pathogen-associated molecular patterns constitutes a crucial step in the initiation of innate immune responses. We studied the contribution to the host-pathogen interaction of mycolic acid (MA), a major lipid component of the cell envelope of the macrophage intracellular pathogen Mycobacterium tuberculosis and other mycobacteria. MA administered to the peritoneal cavity or to the airways induced a unique macrophage morphotype, similar to the foamy macrophage derivatives observed in tuberculous granulomas and characterized by intracellular accumulation of neutral lipids and entry into mitosis. When assayed for production of inflammatory mediators, a conditioning rather than a direct activation of the MA-elicited foamy macrophages was observed. MA enabled production of IFN-gamma and myeloperoxidase, enhanced TNF-alpha production and suppressed IL-10 upon renewed exposure to innate triggers. Intratracheal instillation of MA mimicked additional features of the airway response to M. tuberculosis infection, namely a rapid but transient neutrophil influx and IL-6 production and a chronic IL-12 production. These MA-elicited cellular innate defenses and the accompanying formation of foamy macrophages identify for the first time the foamy macrophage morphotype as part of the host response to a pathogen-associated structure. Furthermore, these results characterize MA as a direct trigger of innate immunity, distinct from Toll-like receptor ligands.     

Long-term activation of the innate immune system in atherosclerosis

Efforts to reverse the pathologic consequences of vulnerable plaques are often stymied by the complex treatment resistant pro-inflammatory environment within the plaque. This suggests that pro-atherogenic stimuli, such as LDL cholesterol and high fat diets may impart longer lived signals on (innate) immune cells that persist even after reversing the pro-atherogenic stimuli. Recently, a series of studies challenged the traditional immunological paradigm that innate immune cells cannot display memory characteristics. Epigenetic reprogramming in these myeloid cell subsets, after exposure to certain stimuli, has been shown to alter the expression of genes upon re-exposure. This phenomenon has been termed trained innate immunity or innate immune memory. The changed responses of ‘trained’ innate immune cells can confer nonspecific protection against secondary infections, suggesting that innate immune memory has likely evolved as an ancient mechanism to protect against pathogens. However, dysregulated processes of immunological imprinting mediated by trained innate immunity may also be detrimental under certain conditions as the resulting exaggerated immune responses could contribute to autoimmune and inflammatory diseases, such as atherosclerosis. Pro-atherogenic stimuli most likely cause epigenetic modifications that persist for prolonged time periods even after the initial stimulus has been removed. In this review we discuss the concept of trained innate immunity in the context of a hyperlipidemic environment and atherosclerosis. According to this idea the epigenome of myeloid (progenitor) cells is presumably modified for prolonged periods of time, which, in turn, could evoke a condition of continuous immune cell over-activation.     

蚯蚓与固有免疫

动物的免疫系统包括固有免疫和适应性免疫.固有免疫是指动物机体与生具有的抵御微生物或者外来异物侵袭的能力,包括组织屏障作用、细胞免疫作用和体液免疫作用.固有免疫细胞识别病原体表面的模式分子而活化,经特殊信号转导途径产生免疫效应.蚯蚓属无脊椎动物,其免疫系统缺乏免疫球蛋白,适应性免疫不发达,主要依赖固有免疫机制来抵御微生物的感染.     

Natural type I interferon-producing cells as a link between innate and adaptive immunity

Type I interferons (IFNs) are promptly produced upon invasion of pathogens, and activate a broad range of effector cells in the innate and adaptive immune system. Lin⁻CD4⁺CD11c⁻ plasmacytoid dendritic cell precursors (plasmacytoid pre-DCs) produce enormous amounts of type I IFNs in response to viruses and CpG DNA, thus corresponding to the previously described but not fully defined natural type I IFN-producing cells (IPCs). Plasmacytoid pre-DCs strongly express toll-like receptor (TLR) 7 and TLR9, in contrast to monocytes, which mainly express TLR1, 2, 4, 5, and 8, suggesting that these two DC precursors recognize different microbial molecules and that they may have developed through different evolutionary trails. Three different stimuli, CpG DNA plus CD40 ligand, interleukin-3 (IL-3), and herpes simplex virus, stimulate plasmacytoid pre-DCs to differentiate into DCs that induce distinct types of T helper cells, i.e., Th1, Th2, and IFN-γ- and IL-10-producing T cells, respectively. The remarkable versatility of plasmacytoid pre-DCs distinguishes them from other cell types in the immune system that have only limited functions, and suggests that these cells may play a key role in integrating the innate and adaptive aspects of various immune responses.     

Autophagy as an emerging dimension to adaptive and innate immunity

Autophagy is an evolutionary conserved cellular process during which cytoplasmic material is engulfed in double membrane vacuoles that then fuse with lysosomes, ultimately degrading their cargo. Emerging evidence, however, now suggests that autophagy can form part of our innate and adaptive immune defense programs. Recent studies have identified pattern recognition molecules as mediators of this process and shown that intracellular pathogens can interact with and even manipulate autophagy. Recent translational evidence has also implicated autophagy in the pathogenesis of several immune-mediated diseases, including Crohn disease. In this review, we present autophagy in the context of its role as an immune system component and effector and speculate on imminent and future research directions in this field.     

结核分支杆菌重组BCG疫苗研究进展

结核分支杆菌引起的结核病是一种人兽共患的慢性传染病,短程督导化疗是治疗该病的主要措施,卡介苗是预防该病的唯一疫苗,但其免疫效果极不稳定.文章介绍了7种结核分支杆菌重组BCG疫苗构建及其免疫机制等方面的研究进展.     

The occurrence and mechanisms of innate immunity against parasites in fish

Parasitic infections in teleost fish are limited by constitutive innate defence mechanisms that render the host refractory or reduce the severity of infection. Controlled challenge trials using naive animals provide indirect evidence of innate immunity as well as identifying the host range or specificity of a parasite, often when specific details of defence mechanism(s) are lacking. Examples of parasites for which innate immunity may be inferred from cross-infectivity studies include Gyrodactylus spp., Lepeophtheirus salmonis, Cryptobia spp., Trypanosoma spp., Ceratomyxa shasta, Myxobolus cerebralis and Kudoa thyrsites. Recent studies however, have begun to clarify the relative roles of innate and acquired immunity against parasitic infection in teleosts by recognizing the presence and significance of specific innate effector mechanisms. The physico-chemical characeristics of skin mucus, the presence of bioactive substances including lysozyme, complement, C-reactive protein, haemolysins and lectins and the epidermal migration of inflammatory cells and their secretions may affect the establishment and proliferation of ectoparasitic copepods, ciliates or monogenea. Similarly in refractory species, haematozoic parasites are lysed via the alternative complement pathway and in susceptible and refractory hosts, protease inhibitors associated with the plasma neutralize proteolytic virulence factors. Detailed knowledge of innate resistance mechanisms against histiozoic parasites are lacking although non-specific cytotoxic lymphoid cells and macrophages probably play a role. The demonstration in certain disease models that innate resistance traits are under genetic control and may be inherited in a simple Mendelian fashion suggests opportunities for selective breeding for resistance against parasitic disease. Beyond a small number of well-described models however, research programs focussing on innate immunity against parasites in fish are lacking. Given the relative importance of innate immunity in fish, particularly as disease losses continue to have an economic impact in aquaculture, this area deserves considerable attention.     

巨噬细胞移动抑制因子对固有免疫的调节作用

长期以来,巨噬细胞移动抑制因子(MIF)一直是一种功能不明的细胞因子.最近几年的研究发现,MIF是宿主抗微生物预警系统和应急反应(可以促进免疫细胞促炎症功能)的一个必要组成成份,是一种对固有免疫反应具有关键性调节作用的重要分子.研究表明,MIF参与了包括脓毒症、炎症和自身免疫性炎症疾病在内的一系列疾病的发病机制,这为未来使用靶向MIF疗法治疗相关的人类疾病提供了全新的思路.