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.     

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.     

Shigella deploy multiple countermeasures against host innate immune responses

Although the intestinal epithelium is equipped with multiple defense systems that sense bacterial components, transmit alarms to the immune system, clear the bacteria, and renew the injured epithelial lining, mucosal bacterial pathogens are capable of efficiently colonizing the intestinal epithelium, because they have evolved systems that modulate the inflammatory and immune responses of the host and exploit the harmful environments as replicative niches. In this review we highlight current topics concerning Shigella's tactics that interfere with the innate immune systems.     

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.     

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.     

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。     

Regulation of innate immunity by the molecular machinery of macroautophagy

Innate immune responses are the first line of defence for an organism to restrict invading pathogens. They fulfil two main functions, namely detection of the pathogen to successively alarm the appropriate components of the immune system and early inhibition of the infection to prevent demise of the infected organism before a more tailored immune response, usually mediated by the adaptive immune system, can be mounted. Autophagy and phagocytosis, modified by the autophagic core machinery, contribute to these functions by regulating pathogen detection, influencing the production of innate immune mediators and directly restricting intracellular and extracellular pathogens as an effector mechanism of innate immunity. These aspects of the involvement of mainly macroautophagy in innate immune responses will be discussed in this review.     

Salmonella typhimurium outer membrane remodeling: role in resistance to host innate immunity.

Resistance to innate immunity is essential for salmonellae pathogenesis. The salmonellae PhoP/PhoQ regulators sense host environments to promote remodeling of the bacterial envelope. This remodeling includes enzymes that modify lipopolysaccharide (LPS). Modified LPS promotes bacterial survival by increasing resistance to cationic antimicrobial peptides and by altered host recognition of LPS.     

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.     

Manipulation of the host cell death pathway by Shigella

Host cells deploy multiple defences against microbial infection. One prominent host defence mechanism, the death of infected cells, plays a pivotal role in clearing damaged cells, eliminating pathogens, removing replicative niches, exposing intracellular bacterial pathogens to extracellular immune surveillance and presenting bacteria‐derived antigens to the adaptive immune system. Although cell death can occur under either physiological or pathophysiological conditions, it acts as an innate defence mechanism against bacterial pathogens by limiting their persistent colonization. However, many bacterial pathogens, including Shigella, have evolved mechanisms that manipulate host cell death for their own benefit.     

Interaction of viral proteins with host cell death machinery

In recent years, intense research has been directed towards understanding molecular mechanisms involved in viral pathogenesis. It is now known that many viruses manipulate host defense mechanisms to prevent apoptosis in order to maximize viral replication. Towards the end of their replication cycle, certain viruses direct the synthesis of proteins that induce apoptosis or cell lysis thereby facilitating viral release from the cell. The present review summarizes the current understanding of interactions between viral proteins and the host cell death machinery.     

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。     

RIP kinases: key decision makers in cell death and innate immunity

Innate immunity represents the first line of defence against invading pathogens. It consists of an initial inflammatory response that recruits white blood cells to the site of infection in an effort to destroy and eliminate the pathogen. Some pathogens replicate within host cells, and cell death by apoptosis is an important effector mechanism to remove the replication niche for such microbes. However, some microbes have evolved evasive strategies to block apoptosis, and in these cases host cells may employ further countermeasures, including an inflammatory form of cell death know as necroptosis. This review aims to highlight the importance of the RIP kinase family in controlling these various defence strategies. RIP1 is initially discussed as a key component of death receptor signalling and in the context of dictating whether a cell triggers a pathway of pro-inflammatory gene expression or cell death by apoptosis. The molecular and functional interplay of RIP1 and RIP3 is described, especially with respect to mediating necroptosis and as key mediators of inflammation. The function of RIP2, with particular emphasis on its role in NOD signalling, is also explored. Special attention is given to emphasizing the physiological and pathophysiological contexts for these various functions of RIP kinases.     

The grateful dead: calcium and cell death in plant innate immunity

Plant cells sensing pathogenic microorganisms evoke defence systems that can confer resistance to infection. This innate immune reaction can include triggering of basal defence responses as well as programmed cell death, or hypersensitive response (HR). In both cases (basal defence and HR), pathogen perception is translated into elevated cytosolic Ca(2+) (mediated by plasma membrane and intracellular channels) as an early step in a signalling cascade. Cyclic nucleotide-gated channels contribute to this influx of Ca(2+) into the cell. The molecular nature of other transport proteins contributing to the Ca(2+) elevation is unclear. Pathogen recognition occurs at two levels: the perception of pathogen-associated molecular pattern (PAMP) molecules widely present in microorganisms, and an interaction between pathogen avirulence gene products (if present) and corresponding plant R (resistance) gene products. The Ca(2+) elevation occurring in response to PAMP perception or R gene interactions could occur due to phosphorylation events, G-protein signalling and/or an increase in cyclic nucleotides. Downstream from the initial Ca(2+) rise, the signalling cascade includes: activation of calmodulin and protein kinases, and nitric oxide and reactive oxygen species generation. Some of these downstream events amplify the Ca(2+) signal by further activation of Ca(2+) transporters.     

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.