Bacterial adaptation to host innate immunity responses

Several recent reports show that different bacterial components trigger innate and inflammatory responses in host organisms. In parallel, selected bacterial virulence factors have been identified that interfere with corresponding responses. In many cases, this involves interference with host proinflammatory signal transduction pathways, whereas in selected cases bacterial virulence factors interfere with host antibacterial mechanisms. This indicates that bacteria, besides activating cellular responses, also have the capacity to directly interact with branches of the innate defence.     

Sendai virus proteins counteracting the host innate immunity

The nucleotide sequence of Sendai virus (SeV) genome was determined in the 1980's. During the analysis of its cDNA, two mRNAs were found to be transcribed from the P gene; one encoding P protein, the other encoding V protein. In addition, C protein was found to be translated from both/ mRNAs. Though the function of V and C proteins was being unknown for a while, the reverse-genetic technique of paramyxoviruses developed at the latter half of the 1990's gave the light on studying them. The V or C protein-knockout-SeV can be made successfully, indicating that the V and C proteins are nonessential for virus growth, However, V knockout-SeV was cleared from the mouse lungs at the one day post inoculation, and C knockout-SeV was cleared immediately after the inoculation. Both V and C proteins were thus appeared to be important for counteracting host innate immunity generated in the early phase of viral infection.     

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

The present paradigms of selective autophagy in mammalian cells cannot fully explain the specificity and selectivity of autophagic degradation. In this paper, we report that a subset of tripartite motif (TRIM) proteins act as specialized receptors for highly specific autophagy (precision autophagy) of key components of the inflammasome and type I interferon response systems. TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro–caspase 1, for autophagic degradation, whereas TRIM21 targets IRF3. TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation. The autophagic function of TRIM20 is affected by mutations associated with familial Mediterranean fever. These findings broaden the concept of TRIMs acting as autophagic receptor regulators executing precision autophagy of specific cytoplasmic targets. In the case of TRIM20 and TRIM21, precision autophagy controls the hub signaling machineries and key factors, inflammasome and type I interferon, directing cardinal innate immunity response systems in humans.     

The role of innate immunity activation in house dust mite allergy

House dust mite (HDM) allergy is a frequent inflammatory disease found worldwide. Although allergen-specific CD4(+) Th2 cells orchestrate the HDM allergic response, notably through induction of IgE directed towards mite allergens, recent studies have demonstrated that innate immunity activation also plays a critical role in HDM-induced allergy pathogenesis. HDM allergens can not only be considered proteins that induce adaptive Th2-biased responses in susceptible subjects but also as strong activators of innate immune cells, including skin keratinocytes and airway epithelial cells. The contribution of microbial adjuvant factors, derived from HDM carriers or the environment, is also essential in such cell stimulation. This review highlights how HDM allergens, together with microbial compounds, promote allergic responses through pattern recognition receptor-dependent pathways.     

Trained immunity: a memory for innate host defense

Immune responses in vertebrates are classically divided into innate and adaptive, with only the latter being able to build up immunological memory. However, although lacking adaptive immune responses, plants and invertebrates are protected against reinfection with pathogens, and invertebrates even display transplant rejection. In mammals, past "forgotten" studies demonstrate cross-protection between infections independently of T and B cells, and more recently memory properties for NK cells and macrophages, prototypical cells of innate immunity, have been described. We now posit that mammalian innate immunity also exhibits an immunological memory of past insults, for which we propose the term "trained immunity." Understanding trained immunity will revolutionize our view of host defense and immunological memory, and could lead to defining a new class of vaccines and immunotherapies.     

Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity.

In the present study, we investigated in vivo the infection and APC functions of dendritic cells (DC) and macrophages (Mphi) after administration of live mycobacteria to mice. Experiments were conducted with Mycobacterium bovis bacillus Calmette-Guerin (BCG) or a rBCG expressing a reporter Ag. Following infection of mice, DC and Mphi were purified and the presence of immunogenic peptide/MHC class II complexes was detected ex vivo on sorted cells, as was the secretion of IL-12 p40. We show in this study that DC is a host cell for mycobacteria, and we provide an in vivo detailed picture of the role of Mphi and DC in the mobilization of immunity during the early stages of a bacterial infection. Strikingly, BCG bacilli survive but remain stable in number in the DC leukocyte subset during the first 2 wk of infection. As Ag presentation by DC is rapidly lost, this suggests that DC may represent a hidden reservoir for mycobacteria.     

Subunits of human condensins are potential therapeutic targets for cancers

The main role of condensins is to regulate chromosome condensation and segregation during cell cycles. Recently, it has been suggested in the literatures that subunits of condensin I and condensin II are involved in some human cancers. This paper will first briefly discuss discoveries of human condensins, their components and structures, and their multiple cellular functions. This will be followed by reviews of most recent studies on subunits of human condensins and their dysregulations or mutations in human cancers. It can be concluded that many of these subunits have potentials to be novel targets for cancer therapies. However, hCAP-D2, a subunit of human condensin I, has not been directly documented to be associated with any human cancers to date. This review hypothesizes that hCAP-D2 can also be a potential therapeutic target for human cancers, and therefore that all subunits of human condensins are potential therapeutic targets for human cancers.     

肠道病毒调控固有免疫的分子机制研究进展

肠道病毒属于小核糖核酸病毒科,包括脊髓灰质炎病毒等多种重要人类病原体,已成为全球公共卫生安全的重大威胁之一。固有免疫是机体早期抵御病毒感染的重要防线。不同肠道病毒在进化中已经具备了多种途径躲避免疫识别或诱导固有免疫系统失活。本文重点对肠道病毒调控宿主固有免疫的相关分子机制进行综述,系统整理了肠道病毒逃避干扰素依赖与干扰素非依赖的抗病毒固有免疫防御的分子特征与作用规律,为肠道病毒致病机制的探究和抗病毒药物的研发提供参考。     

猪δ冠状病毒感染及其对宿主先天免疫功能的影响

猪δ冠状病毒(porcine deltacoronavirus,PDCoV)是目前新发现的唯一一种感染哺乳动物的δ冠状病毒。PDCoV主要感染猪的小肠,特别是空肠和回肠,造成小肠绒毛上皮细胞萎缩,引起严重的萎缩性肠炎,临床症状主要表现为新生仔猪水样腹泻、呕吐和脱水死亡,给养猪业造成很大的经济损失。2014年以来全球暴发的仔猪腹泻中,PDCoV单一感染检出率占有一定的比例,还与其他猪冠状病毒存在较高比例的共感染现象。随着PDCoV毒株的基因组测序完成和病毒的分离成功,以及病毒与宿主互作研究的推进,对该病毒有了更多的认知。本文根据现有的文献报道,结合本课题组的研究进展,对猪δ冠状病毒的流行、基因组结构的遗传多样性、病毒感染受体和对宿主先天免疫应答调控机制的研究进展进行了综述,以帮助相关人员对PDCoV有全面和深入的了解。     

Molecular battle between host and bacterium: recognition in innate immunity

During infection, our innate immune system is the first line of defense and has evolved to clear invading bacteria immediately. To do so, recognition is the key element. However, how does the innate immune system distinguish self from nonself, and how does it recognize all bacteria (estimated to be far over a million species)? The answer lies in the recognition of evolutionary conserved structures. In this review, we approach this phenomenon from the bacterial perspective. What are the evolutionary conserved structures in bacteria, and what strategies are there in the human innate immune system to sense these structures? We illustrate most examples both at the functional as well as at the molecular level. Furthermore, we highlight how pathogenic bacteria can evade this recognition to survive better in the human host which in turn can result in life‐threatening diseases. Copyright © 2011 John Wiley & Sons, Ltd.     

甲型流感病毒感染过程中干扰素介导的天然免疫应答机制

甲型流感病毒作为引起人类和动物急性呼吸道传染病的一个主要病原体,在世界范围内广泛流行。研究表明,甲型流感病毒感染宿主后会诱导宿主的天然免疫应答。甲型流感病毒感染可引起Toll样受体(Toll like receptors,TLRs)和RIG-Ⅰ样受体(RIG-Ⅰ like receptors,RLRs)等宿主模式识别受体介导的抗病毒信号通路的活化,并在多种机制调控下诱导干扰素和其他细胞因子的表达,如Ⅰ型干扰素、Ⅲ型干扰素等,从而启动干扰素刺激基因(Interferon stimulated genes,ISGs)的转录及其抗病毒蛋白的表达,进而实现抗病毒作用。本文就甲型流感病毒感染与干扰素介导的天然免疫应答相关的信号通路和调控机制进行综述。     

BAFF and innate immunity: new therapeutic targets for systemic lupus erythematosus

Recently, the B cell has emerged as a cornerstone of systemic lupus erythematosus (SLE) pathogenesis. This has been highlighted by studies of the cytokine B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF), a crucial factor regulating B-cell maturation, survival and function. Overexpression of BAFF in mice leads to the development of an SLE-like disease, independent of T cells but instead relying on innate immunity mechanisms. Moreover, BAFF has been shown to be elevated in the serum of patients suffering from autoimmune conditions, especially SLE, and may correlate with disease activity. These findings challenge the previous notion that T:B-cell collaboration is the sole driver of SLE. In recent years, controlled trials have for the first time tested targeted therapeutics for SLE. However, agents designed to target B cells failed to meet primary endpoints in clinical trials in SLE, suggesting that a more complex role for B cells in SLE awaited elucidation. By contrast, on 9 March 2011, the US Food and Drug Administration approved belimumab, a fully human anti-BAFF monoclonal antibody, as a new B-cell-specific treatment for SLE. This article will review over 10 years of research on the BAFF system, key findings that led to this recent positive clinical outcome and propose a model potentially explaining why this B-cell-specific therapy has yielded positive results in clinical trials. We will also review promising therapies presently in clinical trials targeting innate immunity, which are likely to revolutionize SLE management towards a personalized and targeted therapy approach.     

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.     

The potential of effector-target genes in breeding for plant innate immunity

Increasing numbers of infectious crop diseases that are caused by fungi and oomycetes urge the need to develop alternative strategies for resistance breeding. As an alternative for the use of resistance (R) genes, the application of mutant susceptibility (S) genes has been proposed as a potentially more durable type of resistance. Identification of S genes is hampered by their recessive nature. Here we explore the use of pathogen-derived effectors as molecular probes to identify S genes. Effectors manipulate specific host processes thereby contributing to disease. Effector targets might therefore represent S genes. Indeed, the Pseudomonas syringae effector HopZ2 was found to target MLO2, an Arabidopsis thaliana homologue of the barley S gene Mlo. Unfortunately, most effector targets identified so far are not applicable as S genes due to detrimental effects they have on other traits. However, some effector targets such as Mlo are successfully used, and with the increase in numbers of effector targets being identified, the numbers of S genes that can be used in resistance breeding will rise as well.     

An alloy of zinc and innate immunity: Galvanising host defence against infection

Innate immune cells such as macrophages and neutrophils initiate protective inflammatory responses and engage antimicrobial responses to provide frontline defence against invading pathogens. These cells can both restrict the availability of certain transition metals that are essential for microbial growth and direct toxic concentrations of metals towards pathogens as antimicrobial responses. Zinc is important for the structure and function of many proteins, however excess zinc can be cytotoxic. In recent years, several studies have revealed that innate immune cells can deliver toxic concentrations of zinc to intracellular pathogens. In this review, we discuss the importance of zinc status during infectious disease and the evidence for zinc intoxication as an innate immune antimicrobial response. Evidence for pathogen subversion of this response is also examined. The likely mechanisms, including the involvement of specific zinc transporters that facilitate delivery of zinc by innate immune cells for metal ion poisoning of pathogens are also considered. Precise mechanisms by which excess levels of zinc can be toxic to microorganisms are then discussed, particularly in the context of synergy with other antimicrobial responses. Finally, we highlight key unanswered questions in this emerging field, which may offer new opportunities for exploiting innate immune responses for anti‐infective development.