蛋白质组学技术在感染研究中的应用

蛋白质组学的目标在于阐明特定生物体、组织、细胞或亚细胞结构中全部蛋白质的表达模式和功能模式,其技术平台由高通量的蛋白质分离技术、鉴定技术和生物信息学组成。在许多研究领域,蛋白质组学技术为阐明疾病过程和生命现象的分子机制提供了全面、网络和动态的蛋白质组信息。感染是重要的基本致病因素之一,蛋白质组学的研究策略和技术方法有利于快速分离鉴定病原体蛋白质组、宿主免疫细胞蛋白质组、感染相关蛋白、疫苗候：选抗原蛋白、生物标志物和药物靶标,从而明显加快病原体、宿主反应、感染发病机制以及感染预防、诊断和治疗等相关研究的进程。     

人体肠道微生物多样性和功能研究进展

人体肠道中庞大而复杂的微生物群落对人体自身代谢表型有深远的影响.肠道微生物群落在亚种或菌株水平上表现出极大的多样性.利用微生物分子生态学、元基因组学和代谢组学研究方法,发现肠道微生物与宿主表现出共进化的特点,肠道微生物群落及其基因组为宿主提供了互补的遗传和代谢功能,表现出互惠共生关系.但是,肠道微生物群落中影响宿主代谢表型的关键功能菌鉴定及其作用模式问题仍然悬而未决,综合运用多种高通量研究方法和多维数据分析方法可能成为解决这个问题的突破口.     

宿主遗传背景与肠道微生物互作研究进展

“微生物”这一名词指非常小的生物，如古菌、细菌、原生生物、真菌和病毒，肠道“微生物组”表示的是肠道微生物集合体。它们实际上共享宿主的身体空间，但作为宿主健康和疾病的决定因素却几乎被忽视。作为信息的集合，微生物组包括微生物的基因组数据、结构元件、代谢物和环境条件。最近对肠道微生物组的研究表明，微生物群落在维持宿主稳态和调节宿主表型上发挥着重要作用。随着包括二代测序(next-generation sequencing, NGS)在内的新技术的出现以及微生物群落序列谱等深入测定技术出现，人们对肠道微生物组与宿主遗传背景之间的关系有了许多见解。本文通过肠道微生物组学的概述，基于全基因组关联分析技术建立肠道微生物组学与宿主遗传之间联系，并对宿主遗传学与肠道微生物组的关系及未来发展前景进行探讨。     

酰基辅酶A结合结构域蛋白3在病原微生物复制中的作用

病毒及细菌等病原微生物侵入细胞后,复制过程离不开宿主细胞内的宿主蛋白.近年来研究表明,酰基辅酶A结合结构域蛋白3(ACBD3)可以与一些病原体的蛋白质相互作用,影响病原体微生物在宿主细胞的复制.本文通过总结爱知病毒、柯萨奇病毒、脊髓灰质炎病毒、丙肝病毒、人类鼻病毒以及沙门氏菌侵染宿主细胞时,病毒蛋白质与ACBD3及磷脂酰肌醇4-激酶B(PI4KB)相互作用的研究进展,探讨ACBD3在病原微生物中的作用.     

糖组学研究技术及其进展

多细胞生物机体内,蛋白质糖基化是一个重要后修饰事件 . 蛋白质的糖链不仅仅是区别细胞种类的标志,且与众多的生物现象有关,如细胞发育、分化、形态、肿瘤转移、微生物感染等 . 糖组学的内容主要涉及单个个体的全部糖蛋白结构分析,确定编码糖蛋白的基因和蛋白质糖基化的机制 . 综述了糖组学的分离和结构鉴定技术及其最新进展 .     

病原微生物感染破坏上皮细胞黏附连接的研究进展

上皮细胞具有高度规则的结构并为下层组织提供保护层,以防病原微生物侵入。上皮细胞排列整齐的结构基础是细胞间连接,一般是细胞间黏附分子形成的有规律连接复合物,如黏附连接(adherens junctions, AJs)。然而,为了破坏或穿越上皮屏障引起宿主感染,病原体通常采取各种策略靶向作用和调控黏附连接,如细菌通过靶向E-cadherin (E-钙黏蛋白)、β-catenin (β-连环蛋白)或细胞内信号通路破坏AJs,而病毒通过靶向E-cadherin或与nectin (黏连蛋白)相互作用侵入细胞。对病原微生物与黏附连接相互作用的机制研究,不仅能在细胞水平解释上皮屏障的基本生理特性,而且能阐明病原体侵入宿主的机制,为防治病原体感染提供新的思路和理论基础。     

基因组学、蛋白质组学、抗原组学与疫苗的发展

疫苗免疫是机体抵御微生物和寄生虫感染的有效措施,然而还有许多病原体缺乏有效的疫苗,疫苗研究任重而道远。随着许多病原体基因组测序的完成,利用基因组字筛选疫苗抗原显示了强大的优势。同时由于近年来比较基因组学、蛋白质组学、抗原组学等的发展,病原体毒力相关蛋白、分泌性蛋白和膜表面结合蛋白基因可以被分离出来,从而可以更加准确地分析候选抗原,极大地提高了疫苗抗原分析的效率。总之,利用基因组和蛋白质组进行疫苗抗原筛选是疫苗研究的革命,将极大地推动疫苗的研究和开发。     

DNA微阵列技术在细菌感染后宿主反应研究中的应用

感染性疾病是病原微生物和宿主紧密相互作用的结果。深入理解宿主对病原微生物感染发生反应的分子基础是预防感染性疾病发生和组织损伤的必要条件。本文通过介绍体内、体外2种感染模型中宿主对细胞内和细胞外致病菌感染后的基因表达谱变化,简述了DNA微阵列技术在病原菌一宿主相互作用中宿主反应研究中的应用。     

病原微生物毒力因子与宿主细胞信号通路相互作用研究进展

病原微生物与宿主的相互作用是感染性疾病发生的基础,涉及病原微生物在宿主体内的生存、复制、传播及致病等多个过程。病原菌在进化过程中发展了多种策略以攻击宿主,其中最重要的一种方式就是通过毒力蛋白影响宿主细胞信号通路,病原菌可以通过多种方式阻断宿主信号通路的激活,如乙酰化、β消除等。研究病原体与宿主细胞相互作用的规律,有望发现具有广谱作用的传染病防治药物。我们就病原体通过信号转导影响细胞功能的研究进展做简要综述。     

病毒-宿主蛋白相互作用组学研究进展

病毒和宿主之间的蛋白相互作用贯穿其整个生命周期.对病毒-宿主蛋白相互作用组的研究不仅可以阐明病毒的感染过程和机体的防御机制,而且还可以揭示潜在的抗病毒治疗靶点.本文回顾了病毒-宿主蛋白相互作用组学常用的研究方法,并探讨了每种方法的优点及局限性.     

Infectomics: genomics and proteomics of microbial infections

The completion of genomic sequences is the greatest triumph of molecular reductionism since the discovery of the DNA double helix in 1953. However, the utility of reductionism is becoming limited and holistic approaches, including theories and techniques, are desperately needed in the postgenomic era. In the field of infectious diseases there is an urgent need for global approaches that can efficiently, precisely and integratively study structural and functional genomics and proteomics of microbial infections (infectomics). The combination of new (e.g. DNA and protein microarrays) and traditional approaches (e.g. cloning, PCR, gene knockout and knockin, and antisense) will help overcome the challenges we are facing today. We assume that the global phenotypic changes (infectomes) in microbes and their host during infections are encoded by the genomes of microbial pathogens and their hosts, expressed in certain environmental conditions devoted to specific microbe-host interactions. Global drug responses (pharmacomes) in microbes and their host can be detected by genomic and proteomic approaches. Genome-wide approaches to genotyping and phenotyping or expression profiling will eventually lead to global dissection of microbial pathogenesis, efficient and rapid diagnosis of infectious diseases, and the development of novel strategies to control infections. The key fundamental issue of infectious diseases is how to globally and integratively understand the interactions between microbial pathogens and their hosts by using infectomics. In this review, we focus on the events that are considered important in infectomics. Electronic Publication     

Unraveling the role of membrane microdomains during microbial infections

Infectious diseases pose major socioeconomic and health-related threats to millions of people across the globe. Strategies to combat infectious diseases derive from our understanding of the complex interactions between the host and specific bacterial, viral, and fungal pathogens. Lipid rafts are membrane microdomains that play important role in life cycle of microbes. Interaction of microbial pathogens with host membrane rafts influences not only their initial colonization but also their spread and the induction of inflammation. Therefore, intervention strategies aimed at modulating the assembly of membrane rafts and/or regulating raft-directed signaling pathways are attractive approaches for the. management of infectious diseases. The current review discusses the latest advances in terms of techniques used to study the role of membrane microdomains in various pathological conditions and provides updated information regarding the role of membrane rafts during bacterial, viral and fungal infections.     

低龄婴幼儿龋微生物群落的研究进展

低龄婴幼儿龋(early childhood caries,ECC)是影响全世界儿童最常见的疾病之一,然而龋病并不是由单一致龋细菌引起,而是由微生物、宿主、饮食和时间,即"龋病病因四因素"之间复杂的相互作用所引起,其中微生物因素起着主要作用。口腔微生物之间存在着一种稳定关系,与宿主保持着和谐的生态平衡,一旦受到某种特殊环境改变的影响,这种平衡则可能被打破。到目前为止,国内外关于ECC的微生物群落研究方法很多,结果不尽相同,因此了解ECC的组成及动态变化对于儿童龋病的预防和防治极其重要。本文就ECC微生物群落的研究进展作一详细综述。     

Microbial subversion of heparan sulfate proteoglycans

The interactions between the host and microbial pathogen largely dictate the onset, progression, and outcome of infectious diseases. Pathogens subvert host components to promote their pathogenesis and, among these, cell surface heparan sulfate proteoglycans are exploited by many pathogens for their initial attachment and subsequent cellular entry. The ability to interact with heparan sulfate proteoglycans is widespread among viruses, bacteria, and parasites. Certain pathogens also use heparan sulfate proteoglycans to evade host defense mechanisms. These findings suggest that heparan sulfate proteoglycans are critical in microbial pathogenesis, and that heparan sulfate proteoglycan-pathogen interactions are potential targets for novel prophylactic and therapeutic approaches.     

Shared themes of antigenic variation and virulence in bacterial, protozoal, and fungal infections.

Pathogenic microbes have evolved highly sophisticated mechanisms for colonizing host tissues and evading or deflecting assault by the immune response. The ability of these microbes to avoid clearance prolongs infection, thereby promoting their long-term survival within individual hosts and, through transmission, between hosts. Many pathogens are capable of extensive antigenic changes in the face of the multiple constitutive and dynamic components of host immune defenses. As a result, highly diverse populations that have widely different virulence properties can arise from a single infecting organism (clone). In this review, we consider the molecular and genetic features of antigenic variation and corresponding host-parasite interactions of different pathogenic bacterial, fungal, and protozoan microorganisms. The host and microbial molecules involved in these interactions often determine the adhesive, invasive, and antigenic properties of the infecting organisms and can dramatically affect the virulence and pathobiology of individual infections. Pathogens capable of such antigenic variation exhibit mechanisms of rapid mutability in confined chromosomal regions containing specialized genes designated contingency genes. The mechanisms of hypermutability of contingency genes are common to a variety of bacterial and eukaryotic pathogens and include promoter alterations, reading-frame shifts, gene conversion events, genomic rearrangements, and point mutations.     

Immunomodulators as an antimicrobial tool

The spectrum of infectious diseases has shifted in the past 50 years to include those caused by microbes that cause disease predominantly in immunocompromised individuals. This phenomenon has underscored the dependence of microbial virulence on the immune status of the host. The limited efficacy of the available antimicrobial armamentarium in immunocompromised individuals, combined with increasing resistance to these agents, has led to an urgent need for new therapies for infectious diseases. Immunomodulation represents a novel approach to antimicrobial therapy that depends on bolstering host immunity, rather than direct antimicrobial activity. Immunomodulators can be divided into those that are specific to pathogens (pathogen-specific) and those that are not specific to pathogens (non-specific). However, to date only a few immunomodulators have been evaluated for their efficacy as antimicrobial tools.     

Systems biology of host-fungus interactions: turning complexity into simplicity

Modeling interactions between fungi and their hosts at the systems level requires a molecular understanding both of how the host orchestrates immune surveillance and tolerance, and how this activation, in turn, affects fungal adaptation and survival. The transition from the commensal to pathogenic state, and the co-evolution of fungal strains within their hosts, necessitates the molecular dissection of fungal traits responsible for these interactions. There has been a dramatic increase in publically available genome-wide resources addressing fungal pathophysiology and host-fungal immunology. The integration of these existing data and emerging large-scale technologies addressing host-pathogen interactions requires novel tools to connect genome-wide data sets and theoretical approaches with experimental validation so as to identify inherent and emerging properties of host-pathogen relationships and to obtain a holistic view of infectious processes. If successful, a better understanding of the immune response in health and microbial diseases will eventually emerge and pave the way for improved therapies.     

Circadian orchestration of host and gut microbiota in infection

Circadian rhythms are present in almost every organism and regulate multiple aspects of biological and physiological processes (e.g. metabolism, immune responses, and microbial exposure). There exists a bidirectional circadian interaction between the host and its gut microbiota, and potential circadian orchestration of both host and gut microbiota in response to invading pathogens. In this review, we summarize what is known about these intestinal microbial oscillations and the relationships between host circadian clocks and various infectious agents (bacteria, fungi, parasites, and viruses), and discuss how host circadian clocks prime the immune system to fight pathogen infections as well as the direct effects of circadian clocks on viral activity (e.g. SARS-CoV-2 entry and replication). Finally, we consider strategies employed to realign normal circadian rhythmicity for host health, such as chronotherapy, dietary intervention, good sleep hygiene, and gut microbiota-targeted therapy. We propose that targeting circadian rhythmicity may provide therapeutic opportunities for the treatment of infectious diseases.     

Coral-associated micro-organisms and their roles in promoting coral health and thwarting diseases

Over the last decade, significant advances have been made in characterization of the coral microbiota. Shifts in its composition often correlate with the appearance of signs of diseases and/or bleaching, thus suggesting a link between microbes, coral health and stability of reef ecosystems. The understanding of interactions in coral-associated microbiota is informed by the on-going characterization of other microbiomes, which suggest that metabolic pathways and functional capabilities define the ‘core’ microbiota more accurately than the taxonomic diversity of its members. Consistent with this hypothesis, there does not appear to be a consensus on the specificity in the interactions of corals with microbial commensals, even though recent studies report potentially beneficial functions of the coral-associated bacteria. They cycle sulphur, fix nitrogen, produce antimicrobial compounds, inhibit cell-to-cell signalling and disrupt virulence in opportunistic pathogens. While their beneficial functions have been documented, it is not certain whether or how these microbes are selected by the hosts. Therefore, understanding the role of innate immunity, signal and nutrient exchange in the establishment of coral microbiota and in controlling its functions will probably reveal ancient, evolutionarily conserved mechanisms that dictate the outcomes of host–microbial interactions, and impact the resilience of the host.