Painful interactions: Microbial compounds and visceral pain

Visceral pain, characterized by abdominal discomfort, originates from organs in the abdominal cavity and is a characteristic symptom in patients suffering from irritable bowel syndrome, vulvodynia or interstitial cystitis. Most organs in which visceral pain originates are in contact with the external milieu and continuously exposed to microbes. In order to maintain homeostasis and prevent infections, the immune- and nervous system in these organs cooperate to sense and eliminate (harmful) microbes. Recognition of microbial components or products by receptors expressed on cells from the immune and nervous system can activate immune responses but may also cause pain. We review the microbial compounds and their receptors that could be involved in visceral pain development.     

Drosophila eiger mutants are sensitive to extracellular pathogens

We showed previously that eiger, the Drosophila tumor necrosis factor homolog, contributes to the pathology induced by infection with Salmonella typhimurium. We were curious whether eiger is always detrimental in the context of infection or if it plays a role in fighting some types of microbes. We challenged wild-type and eiger mutant flies with a collection of facultative intracellular and extracellular pathogens, including a fungus and Gram-positive and Gram-negative bacteria. The response of eiger mutants divided these microbes into two groups: eiger mutants are immunocompromised with respect to extracellular pathogens but show no change or reduced sensitivity to facultative intracellular pathogens. Hence, eiger helps fight infections but also can cause pathology. We propose that eiger activates the cellular immune response of the fly to aid clearance of extracellular pathogens. Intracellular pathogens, which can already defeat professional phagocytes, are unaffected by eiger.     

Mechanisms of microbial traversal of the blood-brain barrier

Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality. Microbial invasion and traversal of the blood-brain barrier is a prerequisite for CNS infections. Pathogens can cross the blood-brain barrier transcellularly, paracellularly and/or in infected phagocytes (the so-called Trojan-horse mechanism). Consequently, pathogens can cause blood-brain barrier dysfunction, including increased permeability, pleocytosis and encephalopathy. A more complete understanding of the microbial-host interactions that are involved in microbial traversal of the blood-brain barrier and the associated barrier dysfunction should help to develop new strategies to prevent CNS infections.     

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.     

How do extracellular pathogens cross the blood-brain barrier?

Bacterial invasion of the meninges can occur as a consequence of bloodstream invasion by some bacterial pathogens. Bacteria enter the central nervous system following a direct interaction with the luminal side of the cerebral endothelium, which constitutes the blood-brain barrier. To breach the barriers protecting the brain, extracellular pathogens must cross a monolayer of tight junction-expressing endothelial or epithelial cells. The limited number of pathogens capable of crossing these tight barriers and invading the meninges suggests that they display very specific attributes. For Neisseria meningitidis, type IV pili have been identified as being essential for meningeal invasion and it is believed other, as-yet-unidentified factors are also involved.     

Evasive maneuvers by secreted bacterial proteins to avoid innate immune responses

To cause disease, bacterial pathogens must first breach physical barriers, such as the mucous membrane that lines organs, and then successfully replicate and disseminate while avoiding destruction by the immune system. Many bacterial pathogens accomplish this by secreting proteins into their host environment, which act to subvert or dampen the expanding immune response. Here, we discuss how bacterial pathogens use an arsenal of secreted virulence proteins to modify the outcome of innate immune activation by altering how the immune system recognizes microbial invaders.     

Native microbiota shape insect vector competence for human pathogens

The resident microbiota of insect vectors can impede transmission of human pathogens. Recent studies have highlighted the capacity of endogenous bacteria to decrease viral and parasitic infections in mosquito and tsetse fly vectors by activating their immune responses or directly inhibiting pathogen development. These microbes may prove effective agents for manipulating the vector competence of malaria and other important human pathogens.     

Glutamate utilization promotes meningococcal survival in vivo through avoidance of the neutrophil oxidative burst

Polymorphonuclear neutrophil leucocytes (PMNs) are a critical part of innate immune defence against bacterial pathogens, and only a limited subset of microbes can escape killing by these phagocytic cells. Here we show that Neisseria meningitidis, a leading cause of septicaemia and meningitis, can avoid killing by PMNs and this is dependent on the ability of the bacterium to acquire L-glutamate through its GltT uptake system. We demonstrate that the uptake of available L-glutamate promotes N. meningitidis evasion of PMN reactive oxygen species produced by the oxidative burst. In the meningococcus, L-glutamate is converted to glutathione, a key molecule for maintaining intracellular redox potential, which protects the bacterium from reactive oxygen species such as hydrogen peroxide. We show that this mechanism contributes to the ability of N. meningitidis to cause bacteraemia, a critical step in the disease process during infections caused by this important human pathogen.     

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.     

Listeria monocytogenes: epidemiology, human disease, and mechanisms of brain invasion

Listeria monocytogenes is a facultative intracellular bacterium that has predilection for causing central nervous systemic infections in humans and domesticated animals. This pathogen can be found worldwide in the food supply and most L. monocytogenes infections are acquired through ingestion of contaminated food. The main clinical syndromes caused by L. monocytogenes include febrile gastroenteritis, perinatal infection, and systemic infections marked by central nervous system infections with or without bacteremia. Experimental infection of mice has been used for over 50 years as a model system to study the pathogenesis of this organism including the mechanisms by which it invades the brain. Data from this model indicate that a specific subset of monocytes, distinguished in part by high expression of the Ly-6C antigen, become parasitized in the bone marrow and have a key role in transporting intracellular bacteria across the blood-brain barriers and into the central nervous system. This Minireview will summarize recent epidemiologic and clinical information regarding L. monocytogenes as a human pathogen and will discuss current in vitro and in vivo data relevant to the role of parasitized monocytes and the pathogenetic mechanisms that underlie its formidable ability to invade the central nervous system.     

Entry of pathogens into the central nervous system

Abstract: The blood-brain barrier (BBB) is formed by the tight junctions of the cerebral capillary endothelium and the choroid plexus epithelium. The molecular anatomy of the tight junction resembles that of a polarized, transporting epithelium, suggesting some model cell culture systems can provide insight into traffic into the central nervous system. Pathogens target both the endothelium, causing encephalitis, and the choroid plexus, leading to meningitis. Routes of entry are diverse including paracellular and transcellular penetration. In addition, circulating microbial products can induce loss of BBB function. Understanding the heterogeneous molecular interactions between pathogens and the BBB may provide avenues to interrupt the devastating neurological sequelae that accompany central nervous system infections.     

Understanding neuroinflammation through central nervous system infections

Neuroinflammation is now recognized to compound many central nervous system (CNS) pathologies, from stroke to dementia. As immune responses evolved to handle infections, studying CNS infections can offer unique insights into the CNS immune response and address questions such as: What defenses and strategies do CNS parenchymal cells deploy in response to a dangerous pathogen? How do CNS cells interact with each other and infiltrating immune cells to control microbes? What pathways are beneficial for the host or for the pathogen? Here, we review recent studies that use CNS-tropic infections in combination with cutting-edge techniques to delve into the complex relationships between microbes, immune cells, and cells of the CNS.     

Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea

Among the many genera of free-living amoebae that exist in nature, members of only four genera have an association with human disease: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri and Sappinia diploidea. Acanthamoeba spp. and B. mandrillaris are opportunistic pathogens causing infections of the central nervous system, lungs, sinuses and skin, mostly in immunocompromised humans. Balamuthia is also associated with disease in immunocompetent children, and Acanthamoeba spp. cause a sight-threatening infection, Acanthamoeba keratitis, mostly in contact-lens wearers. Of more than 30 species of Naegleria, only one species, N. fowleri, causes an acute and fulminating meningoencephalitis in immunocompetent children and young adults. In addition to human infections, Acanthamoeba, Balamuthia and Naegleria can cause central nervous system infections in animals. Because only one human case of encephalitis caused by Sappinia diploidea is known, generalizations about the organism as an agent of disease are premature. In this review we summarize what is known of these free-living amoebae, focusing on their biology, ecology, types of disease and diagnostic methods. We also discuss the clinical profiles, mechanisms of pathogenesis, pathophysiology, immunology, antimicrobial sensitivity and molecular characteristics of these amoebae.     

Beneficial microbes going underground of root immunity

Plant roots interact with an enormous diversity of commensal, mutualistic, and pathogenic microbes, which poses a big challenge to roots to distinguish beneficial microbes from harmful ones. Plants can effectively ward off pathogens following immune recognition of conserved microbe‐associated molecular patterns (MAMPs). However, such immune elicitors are essentially not different from those of neutral and beneficial microbes that are abundantly present in the root microbiome. Recent studies indicate that the plant immune system plays an active role in influencing rhizosphere microbiome composition. Moreover, it has become increasingly clear that root‐invading beneficial microbes, including rhizobia and arbuscular mycorrhiza, evade or suppress host immunity to establish a mutualistic relationship with their host. Evidence is accumulating that many free‐living rhizosphere microbiota members can suppress root immune responses, highlighting root immune suppression as an important function of the root microbiome. Thus, the gate keeping functions of the plant immune system are not restricted to warding off root‐invading pathogens but also extend to rhizosphere microbiota, likely to promote colonization by beneficial microbes and prevent growth‐defense tradeoffs triggered by the MAMP‐rich rhizosphere environment.     

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.     

The immune response to agents that cause acute and chronic diseases

Recent advances in lymphocyte technology allow production of large amounts of homogenous T cells which create immunoregulatory peptides. This means that it is now possible to define and purify nontoxic peptides that either specifically turn off or turn on immune responses. For example, monoclonal peptides synthesized by inducer cells each activates a different target cell to divide or differentiate. One activates stem cells to differentiate into red cells and white cells [27], another stimulates B cells to secrete antibody [21], and another induces mast cells to divide [26] and perhaps to differentiate. More recent work has shown that some inducer peptides may "fine tune" the immune response: Certain types of inducer clones, for example, selectively stimulate production of IgA. Peptides that mediate the activity of these clones are the subject of intense analysis of because these monoclonal substances offer the possibility of stimulating rapid induction of IgA after infection by microbes that enter through mucosal of the gut, bladder or lungs. This type of antibody (IgA) is the body's key defense against infections by these microbes: Development of a rapid and specific IgA response is the most important factor in the outcome of infections by viruses such as genital herpes type II and infections by intracellular bacterial pathogens that are currently resistant to treatment by antibiotics. Perhaps the most informative point that has come from these studies is that each peptide that has been isolated from T cell clones exerts powerful regulatory effects on either the intensity or type of the immune response. The hope is that some of these immunoregulatory molecules or their analogs can be used as potent therapeutic agents for some chronic diseases. Since purified inducer and suppressive peptides will be available in large amounts within the next several years, it will not be long before this strategy can be thoroughly evaluated.     

Database mining of plant peptide homologues

In plant-pathogen interactions, pathogens employ secreted molecules, known as effectors to overcome physical barriers, modulate plant immunity, and facilitate colonization. Among these diverse effectors, some are found to mimic the plant peptides, to target host’s peptide receptors, and intervene in the peptide-regulated defense pathways and/or plant development. To better understand how pathogens have co-evolved with their plant hosts in order to improve disease management, we explored the presence of plant peptide mimics in microbes by bioinformatic analysis. In total, 36 novel peptide mimics belong to five plant peptide families were detected in bacterial and fungal kingdoms. Among them, phytosulfokine homologues were widely distributed in 22 phytopathogens and one bacterium, thereby constituted the largest proportion of the identified mimics. The putative functional peptide region is well conserved between plant and microbes, while the existence of a putative signal peptide varies between species. Our findings will increase understanding of plant-pathogen interactions, and provide new ideas for future studies of pathogenic mechanisms and disease management.     

Algae as Reservoirs for Coral Pathogens

Benthic algae are associated with coral death in the form of stress and disease. It''s been proposed that they release exudates, which facilitate invasion of potentially pathogenic microbes at the coral-algal interface, resulting in coral disease. However, the original source of these pathogens remains unknown. This study examined the ability of benthic algae to act as reservoirs of coral pathogens by characterizing surface associated microbes associated with major Caribbean and Indo-Pacific algal species/types and by comparing them to potential pathogens of two dominant coral diseases: White Syndrome (WS) in the Indo-Pacific and Yellow Band Disease (YBD) in the Caribbean. Coral and algal sampling was conducted simultaneously at the same sites to avoid spatial effects. Potential pathogens were defined as those absent or rare in healthy corals, increasing in abundance in healthy tissues adjacent to a disease lesion, and dominant in disease lesions. Potentially pathogenic bacteria were detected in both WS and YBD and were also present within the majority of algal species/types (54 and 100% for WS and YBD respectively). Pathogenic ciliates were associated only with WS and not YBD lesions and these were also present in 36% of the Indo-Pacific algal species. Although potential pathogens were associated with many algal species, their presence was inconsistent among replicate algal samples and detection rates were relatively low, suggestive of low density and occurrence. At the community level, coral-associated microbes irrespective of the health of their host differed from algal-associated microbes, supporting that algae and corals have distinctive microbial communities associated with their tissue. We conclude that benthic algae are common reservoirs for a variety of different potential coral pathogens. However, algal-associated microbes alone are unlikely to cause coral death. Initial damage or stress to the coral via other competitive mechanisms is most likely a prerequisite to potential transmission of these pathogens.     

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     

An essential complementary role of NF-kappaB pathway to microbicidal oxidants in Drosophila gut immunity

In the Drosophila gut, reactive oxygen species (ROS)-dependent immunity is critical to host survival. This is in contrast to the NF-kappaB pathway whose physiological function in the microbe-laden epithelia has yet to be convincingly demonstrated despite playing a critical role during systemic infections. We used a novel in vivo approach to reveal the physiological role of gut NF-kappaB/antimicrobial peptide (AMP) system, which has been 'masked' in the presence of the dominant intestinal ROS-dependent immunity. When fed with ROS-resistant microbes, NF-kappaB pathway mutant flies, but not wild-type flies, become highly susceptible to gut infection. This high lethality can be significantly reduced by either re-introducing Relish expression to Relish mutants or by constitutively expressing a single AMP to the NF-kappaB pathway mutants in the intestine. These results imply that the local 'NF-kappaB/AMP' system acts as an essential 'fail-safe' system, complementary to the ROS-dependent gut immunity, during gut infection with ROS-resistant pathogens. This system provides the Drosophila gut immunity the versatility necessary to manage sporadic invasion of virulent pathogens that somehow counteract or evade the ROS-dependent immunity.