PM2RA: A Framework for Detecting and Quantifying Relationship Alterations in Microbial Community

The dysbiosis of gut microbiota is associated with the pathogenesis of human diseases.However, observing shifts in the microbe abundance cannot fully reveal underlying perturbations.Examining the relationship alterations(RAs) in the microbiome between health and disease statuses provides additional hints about the pathogenesis of human diseases, but no methods were designed to detect and quantify the RAs between different conditions directly. Here, we present profile monitoring for microbial relationship alteration(PM2 RA), an analysis framework to identify and quantify the microbial RAs. The performance of PM2 RA was evaluated with synthetic data, and it showed higher specificity and sensitivity than the co-occurrence-based methods. Analyses of real microbial datasets showed that PM2 RA was robust for quantifying microbial RAs across different datasets in several diseases. By applying PM2 RA, we identified several novel or previously reported microbes implicated in multiple diseases. PM2 RA is now implemented as a web-based application available at http://www.pm2 ra-xingyinliulab.cn/.     

群体感应及其在动物病原菌致病中的作用

摘要: 群体感应是指微生物群体某些基因的表达受到与群体密度相关的信号分子调控的现象。微生物以酰基高丝氨酸内酯化合物,某些短肽分子,呋喃酮类化合物,以及一些小分子物质为信号分子,介导不同的群体感应系统。各群体感应系统之间以平行协同或层次串连的方式组织起来调控微生物各种基因。众多病原菌致病基因的表达与群体感应密切相关,主要表现在：群体感应帮助微生物对宿主的侵袭和定殖;调控毒力因子的产生和作用于宿主;以及介导病原菌对宿主的免疫能力和药物抗性。进行群体感应对微生物致病过程调控的研究,将有利于从群体感应入手进行病原菌防控新策略的探索。     

The use of animal infection models to study the pathogenesis of melioidosis and glanders

The use of animal infection models is central to the study of microbial pathogenesis. In combination with genetic, immunological and antigen purification techniques, much can be learned regarding the pathogenesis of diseases caused by microorganisms. This update focuses on the recent use of animal infection models to study the pathogenesis of melioidosis and glanders.     

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.     

口腔微生物多样性研究进展

口腔微生物多样性的改变是口腔常见感染性疾病的发病机制之一,随着分子生物学技术的普遍应用,研究者能够不通过纯培养技术即可对人类口腔不同生态系的微生物组成及变化进行研究。本文综述了当前口腔微生物多样性研究的常用方法及各自的特点,从而为口腔微生物生态方面的进一步深入研究提供参考。     

感染组学 (infectomics) ———对感染性疾病的总体性和综合性研究

在感染性疾病的范畴内,目前急需一个能有效地、精确地和综合性地研究微生物感染的结构性和功能性基因组学和蛋白质组学 ( 感染组学 ) 的全面方法. 新的方法 ( 如 DNA 和蛋白质微阵列 ) 和传统方法 ( 如分子克隆、 PCR 、基因敲除,加进 (knockin) 和反义术等 ) 的结合将有助于克服今天的困难. 在感染时,微生物及其宿主的全部表型改变 ( 感染组 ) 均由微生物病原体及其宿主的基因组所编码,并在特异的微生物 - 宿主相互作用时的某些环境条件下表达. 微生物及其宿主的全部药物反应 ( 药理组 ) 可用基因组或蛋白质组的方法检出. 分析基因型和表型或表达形式的全基因组方法将最终导致对微生物的发病机理、感染性疾病的快速诊断和控制感染的新策略的全面研究. 感染性疾病中最基本的问题是,如何全面地和综合性地应用感染组学,来了解微生物病原体及其宿主的相互作用.     

Cellular microbiology: can we learn cell physiology from microorganisms?

Cellularmicrobiology is a new discipline that is emerging at the interfacebetween cell biology and microbiology. The application of moleculartechniques to the study of bacterial pathogenesis has made possiblediscoveries that are changing the way scientists view thebacterium-host interaction. Today, research on the molecular basis ofthe pathogenesis of infective diarrheal diseases of necessity transcends established boundaries between cell biology, bacteriology, intestinal pathophysiology, and immunology. The use of microbial pathogens to address questions in cell physiology is just now yieldingpromising applications and striking results.     

Zoonoses

The numbers of microbial species that can infect human beings are shown to be 1415, of which 868 species (61%) are zoonotic. Since most of the emerging pathogens (75%) are originated from other animals, public health sectors should be vigilant against the emergence of new zoonotic diseases. Only 33% of zoonoses can spread from human to human after introduction into human population. Various factors such as human demography, ecological change, global transportation and climate change are responsible for the emergence of zoonoses. Even a slight change in the ecological niche where pathogenic organisms thrive would result in the increase of the incidence of the disease.     

Perspectives and hopes in infectious pathology]

Over the last few decades, changes in socio-economic conditions and social practices as well as aggressive therapy of many diseases have led to the emergence of new infectious pathologies. These new pathologies are either associated with newly identified microbial species or the emergence of known microbes which have encountered new environments in which they are able to cause disease. Recent progress has allowed us to understand the mechanisms by which these pathogens express their virulence and will certainly allow us to diagnose and treat these infections more efficiently in the future.     

Environmental variation enables invasions of environmental opportunist pathogens

Emerging infectious diseases are a persistent threat to humans and food production but the mechanisms promoting the emergence of novel pathogens are not fully understood. The widely discussed explanations for pathogen emergence include range shifts, coincidental evolution of virulence, and host immunity variation. Here we propose a novel mechanism of virulence evolution that relies on environmental variability. Our model combines an environmental community experiencing random or periodic variability, to a classical SIR epidemiological model. We assume that environmentally growing, potentially infective variants arise at low frequency from a resident, non‐infective (benign microbial) strain through random variation on genetic material. We found that environmental perturbations commonly promote establishment of sporadic infections or persistent epidemics, by creating transient periods of low competition, which can in turn be exploited by an infective strain. Given the ubiquitous nature of potentially pathogenic environmental micro‐organisms and environmental variability, this mechanism provides a plausible explanation for emerging diseases.     

Microorganisms and man. Various characteristics of their coexistence at present

Modern data of literature on microbial associations and their role in human health and diseases are presented. As pointed out in this work, the characteristic feature of the XX century is the emergence and the re-emergence of 36 new infections. The emergence of many infections is associated with such factors as the increased migration of the population, ecological environmental disasters, etc. Grounds for a new view on the etiology of a number of chronic somatic diseases are given. The task of preparation development for the immunoprophylaxis of 25-30 infections has been set by WHO as its target for the year 2025. Prospects of new approaches to the development of new generation vaccines against bacterial, viral and parasitic infections, including HIV/AIDS, tuberculosis, virus hepatitides, malaria, etc., are shown.     

Microbial pathogenesis and type III interferons

The innate immune system possesses a multitude of pathways to sense and respond to microbial pathogens. One such family are the interferons (IFNs), a family of cytokines that are involved in several cellular functions. Type I IFNs are appreciated to be important in several viral and bacterial diseases, while the recently identified type III IFNs (IFNL1, IFNL2, IFNL3, IFNL4) have been studied primarily in the context of viral infection. Viral and bacterial infections however are not mutually exclusive, and often the presence of a viral pathogen increases the pathogenesis of bacterial infection. The role of type III IFN in bacterial and viral-bacterial co-infections has just begun to be explored. In this mini review we discuss type III IFN signaling and its role in microbial pathogenesis with an emphasis on the work that has been conducted with bacterial pathogens.     

Negative regulation of Toll-like receptor signaling pathway

TLRs are primary sensors of invading pathogens, recognizing conserved microbial molecules and activating signaling pathways that are pivotal to innate and adaptive immune responses. However, a TLR signaling pathway must be tightly controlled because its excessive activation can contribute to the pathogenesis of many human diseases. This review provides a summary of the different mechanisms that are involved in the negative regulation of TLR signaling pathways.     

Why should cell biologists study microbial pathogens?

One quarter of all deaths worldwide each year result from infectious diseases caused by microbial pathogens. Pathogens infect and cause disease by producing virulence factors that target host cell molecules. Studying how virulence factors target host cells has revealed fundamental principles of cell biology. These include important advances in our understanding of the cytoskeleton, organelles and membrane-trafficking intermediates, signal transduction pathways, cell cycle regulators, the organelle/protein recycling machinery, and cell-death pathways. Such studies have also revealed cellular pathways crucial for the immune response. Discoveries from basic research on the cell biology of pathogenesis are actively being translated into the development of host-targeted therapies to treat infectious diseases. Thus there are many reasons for cell biologists to incorporate the study of microbial pathogens into their research programs.     

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     

Quorum-quenching microbial infections: mechanisms and implications

The discovery of antibiotics early in the past century marked the beginning of active control and prevention of infectious microbial diseases. However, extensive use of antibiotics has also unavoidably resulted in the emergence of ‘superbugs’ that resist conventional antibiotics. The finding that many pathogens rely on cell-to-cell communication mechanisms, known as quorum sensing, to synchronize microbial activities essential for infection and survival in the host suggests a promising disease control strategy, i.e. quenching microbial quorum sensing or in short, quorum quenching. Work over the past few years has demonstrated that quorum-quenching mechanisms are widely conserved in many prokaryotic and eukaryotic organisms. These naturally occurring quorum-quenching mechanisms appear to play important roles in microbe–microbe and pathogen–host interactions and have been used, or served as lead compounds, in developing and formulating a new generation of antimicrobials. Characterization of the crystal structures of several types of quorum-quenching enzymes has provided valuable information to elucidate the catalytic mechanisms, as well as clues for future protein tailoring and molecular improvement. The discovery of quorum-sensing signal degradation enzymes in mammalian species represents a new milestone in quorum sensing and quorum quenching research. The finding highlights the importance of investigating their roles in host innate defence against infectious diseases and to determine the factors influencing their in vivo concentrations and catalytic activities.     

Herpesvirus: an underestimated virus

Herpes simplex virus (HSV) infections are common and widespread; nevertheless, their outcome can be of unpredictable prognosis in neonates and in immunosuppressed patients. Anti-HSV therapy is effective, but the emergence of drug-resistant strains or the drug toxicity that hamper the treatment is of great concern. Vaccine has not yet shown relevant benefit; therefore, palliative prophylactic measures have been adopted to prevent diseases. This short review proposes to present concisely the history of HSV, its taxonomy, physical structure, and replication and to explore the pathogenesis of the infection, clinical manifestations, laboratory diagnosis, treatment, prophylaxis and epidemiology of the diseases.     

The biology and future prospects of antivirulence therapies

The emergence and increasing prevalence of bacterial strains that are resistant to available antibiotics demand the discovery of new therapeutic approaches. Targeting bacterial virulence is an alternative approach to antimicrobial therapy that offers promising opportunities to inhibit pathogenesis and its consequences without placing immediate life-or-death pressure on the target bacterium. Certain virulence factors have been shown to be potential targets for drug design and therapeutic intervention, whereas new insights are crucial for exploiting others. Targeting virulence represents a new paradigm to empower the clinician to prevent and treat infectious diseases.     

口腔微生物耐氟机制的研究进展

氟化物一直被当作一种有效的抗龋药物广泛应用,但长期使用氟化物可能会导致耐氟菌株的出现,使其通过表型适应或基因型改变对氟产生抗性,降低氟化物防龋效果,且长期氟干扰可能引起口腔微生态失衡,从而诱发疾病。鉴于氟与口腔疾病防治的密切关系,以及口腔微生物稳态对于口腔乃至全身健康的重要作用,本文就口腔微生物耐氟机制的研究进展作一综述。     

Identification of candidate T-cell epitopes and molecular mimics in chronic Lyme disease

Elucidating the cellular immune response to infectious agents is a prerequisite for understanding disease pathogenesis and designing effective vaccines. In the identification of microbial T-cell epitopes, the availability of purified or recombinant bacterial proteins has been a chief limiting factor. In chronic infectious diseases such as Lyme disease, immune-mediated damage may add to the effects of direct infection by means of molecular mimicry to tissue autoantigens. Here, we describe a new method to effectively identify both microbial epitopes and candidate autoantigens. The approach combines data acquisition by positional scanning peptide combinatorial libraries and biometric data analysis by generation of scoring matrices. In a patient with chronic neuroborreliosis, we show that this strategy leads to the identification of potentially relevant T-cell targets derived from both Borrelia burgdorferi and the host. We also found that the antigen specificity of a single T-cell clone can be degenerate and yet the clone can preferentially recognize different peptides derived from the same organism, thus demonstrating that flexibility in T-cell recognition does not preclude specificity. This approach has potential applications in the identification of ligands in infectious diseases, tumors and autoimmune diseases.