Contributions to microbiology最新文献

Chemotaxis is the process by which cells sense chemical gradients in their environment and then move towards more favorable conditions. In the case of Escherichia coli, the paradigm organism for chemotaxis, the pathway is now arguably the best characterized in all of biology. If one broadens their perspective to include other species of bacteria, then our knowledge of chemotaxis is far less developed. In particular, the chemotaxis pathways in unrelated species are quite different despite the conservation of many core signaling proteins. Here, we summarize the current state of knowledge regarding the chemotaxis pathways in E. coli and Bacillus subtilis, with a specific focus on the mechanisms for excitation and adaptation. The mechanisms vary widely, and the B. subtilis process, similar to those found in Thermotoga maritima and many archaea, may represent a new paradigm for bacterial chemotaxis. For instance, B. subtilis has three interacting means for restoring prestimulus behavior after stimulation, including one involving CheYp feedback. The one shared with E. coli, the receptor methylation system, is vastly different, as is the mechanism for conveying signals across the membrane.

The important human pathogen Staphylococcus aureus is able to satisfy its nutrient iron requirement by acquiring heme from host hemoglobin in the context of infection. However, heme acquisition exposes S. aureus to heme toxicity. In order to detect the presence of toxic levels of exogenous heme, S. aureus is able to sense heme through the heme sensing system (HssRS) two-component system. Upon sensing heme, HssRS directly regulates the expression of the heme-regulated ABC transporter HrtAB, which alleviates heme toxicity. Importantly, the inability to sense or respond to heme alters the virulence of S. aureus, highlighting the importance of heme sensing and detoxification to staphylococcal pathogenesis. Furthermore, potential orthologues of the Hss and Hrt systems are found in many species of Gram-positive bacteria, a possible indication that heme stress is a challenge faced by bacteria whose habitats include host tissues rich in heme.

Infectious agents threaten any organism. Therefore, mammals and insects have evolved a complex network of cells and humoral factors termed immune system able to control and eliminate pathogens. Immunity varies between different groups of animals but always contains an innate immune system that can act fast and often effectively against a wide range of distinct pathogens (i.e. viruses, bacteria, fungi, and eukaryotic parasites). In mammals and insects, the communication between and regulation of immune cells is carried out by cytokines which orchestrate the defense against the invaders. The major challenge to recognize and to fight pathogens is the same for any host. In insects and mammals, the pathogens are recognized as non-self by recognition of pathogen-associated molecular patterns. In addition, similar pathogen recognition receptors and signaling pathways activate the immune response in insects and mammals. The pathogens have to be opsonized and/or ingested and controlled/eliminated by antimicrobial peptides or small effector molecules (reactive oxygen and nitrogen intermediates). Interestingly, even invertebrates have evolved certain forms of adaptive immunity, i.e. specific immune priming, and in some invertebrates alternative splicing of pathogen recognition receptors allows for a more specific recognition of a wide variety of pathogens. This enhanced specificity of pattern recognition conveys a special form of memory to their invertebrate hosts. In this chapter, we also consider gut immunity of insects and compare it with the response in mammals.

Phagocytosis in unicellular animals represents the most ancient and ubiquitous form of defense against foreign material. Unicellular invertebrates can phagocytose for food and defense. Multicellular invertebrates and vertebrates possess phagocytic cells and have evolved more complex functions attributed to immunodefense cells that specialized into cellular and humoral immune responses. Thus all animals possess: innate, natural, nonspecific (no memory) nonanticipatory, nonclonal, germline (hard wired) host defense functions. In addition, all vertebrates possess: adaptive, induced, specific (memory), anticipatory, clonal, somatic (flexible) immune responses. A similar situation exists with respect to components of the signaling system, immunity and development. With multicellularity, clearly numerous immune response characteristics are not possible in unicellular forms or even those that straddle the divide between unicellularity and multicellularity, beginning with colonial/social protozoans. Still, it is instructive to elucidate a hierarchy of animals based upon immunologic characteristics and how they parallel other physiological traits. Evidence is presented that the most primitive of invertebrates prior to the evolution of multicellular organisms possess varying degrees of complexity at the molecular level of those hallmarks that now characterize the immune system.

Polymorphonuclear neutrophils (PMNs) and monocyte/macrophages (MMs) are professional phagocytic cells that are able to phagocytose and destroy infectious agents. Therefore, they are key anti-infectious actors in host defense but can mediate tissue damages. In addition, it is now clear that the role of these cells goes far beyond phagocytosis and pathogen killing. PMNs and MMs are essential cells for immunity, absolutely required to build and modulate the innate response. The respective roles of PMNs and MMs in the inflammatory process are discussed: their common features and their differences are reviewed, both in terms of origins and functions with special emphasis on novel concepts about neutrophil survival and resolution of inflammation. The recognition and the subsequent engulfment of apoptotic PMNs by macrophages is a key event of the resolution of inflammation, which can be associated with autoimmunity or inflammatory diseases. During the past years, significant efforts have been made to dissect the molecular mechanisms governing phagocytosis and pathogen killing. Although these effector functions are crucial, more work has to be done to understand the respective role of PMNs and MMs to regulate and inhibit the inflammatory process as well as the immune response. This might be the future challenge for the next years in phagocyte research and this will presumably open new avenues of research in the modulation of inflammation.

Several antibacterial proteins and peptides of the human innate immune system have additional roles in the regulation of adaptive immune responses. Among peptides with innate and adaptive immune functions are chemokines, a family of structurally related peptides with conserved amino-terminal motifs. Chemokines regulate leukocyte trafficking during both health and disease. In recent years, some chemokines have been shown to exert direct antibacterial activity. On the other hand, several granulebound antibacterial proteins of granulocytes, and epithelium-expressed antibacterial polypeptides, possess chemotactic activity and stimulate cells of the adaptive immune system. It is likely that during evolution, some antimicrobial peptides and proteins of innate immunity have diverged to coordinate the actions of the innate immune system and the evolutionary younger, adaptive immunity. This review aims to describe antibacterial chemokines and antibacterial peptides possessing chemotactic activity, biologic properties that link innate and adaptive immunity.

Antigen-presenting cells, such as macrophages and dendritic cells, represent a central and important part of the immune defence against invading microorganisms, as they participate in initial capture and processing of microbial antigens (innate immunity) and then activation of specific T and B cell effector mechanisms (acquired immunity). Recognition of microbial molecules by antigen-presenting cells occurs through so called pattern recognition receptors (PRRs), which recognize conserved structures, or pathogen-associated molecular patterns, in pathogenic microbes. The Toll-like receptors are the most extensively studied of these receptors, but accumulating evidence shows that other PRRs, such as scavenger receptors, C-type lectin receptors and NOD-like receptors, also play important roles in the innate immune defence. Here, we summarize current knowledge of the role of various PRRs in the defence against pathogenic microorganisms and we report recent advances in studies of different receptor-ligand interactions. In particular, we focus on the importance of microbial proteins as ligands for PRRs.

The importance of reactive oxygen species (ROS) in innate immunity was first recognized in professional phagocytes undergoing a 'respiratory burst'upon activation. This robust oxygen consumption is related to a superoxide-generating enzyme, the phagocytic NADPH oxidase (Nox2-based or phox). The oxidase is essential for microbial killing, since patients lacking a functional oxidase suffer from enhanced susceptibility to microbial infections. ROS derived from superoxide attack bacteria in the isolated niche of the neutrophil phagosome. The oxidase is electrogenic, alters ion currents across membranes, induces apoptosis, regulates cytokine production, influences gene expression, and promotes formation of extracellular traps. Recently, new homologues of Nox2 were discovered establishing the Nox family of NADPH oxidases that encompasses seven members. Nox1 is highly expressed in the colon epithelium, and can be induced by LPS or IFN- gamma. Nox4 was implicated in innate immunity since LPS induces Nox4-dependent ROS generation. Duox1 and Duox2 localize to the apical plasma membrane of epithelial cells in major airways, salivary glands, and the gastrointestinal tract, and provide extracellular hydrogen peroxide to lactoperoxidase to produce antimicrobial hypothiocyanite ions. Th1 and Th2 cytokines regulate expression of dual oxidases in human airways and may thereby act in host defense or in proinflammatory responses.

The epithelium of the respiratory tract forms a large surface area that maintains intimate contact with the environment. Through the act of breathing, this mucosal surface encounters an array of pathogens and toxic particulates. In response to these challenges many strategies have evolved to protect the host. These include the barrier functions of the epithelium, cough, mucociliary clearance, resident professional phagocytes, and the secretion of a number of proteins and peptides with host defense functions. Thus, the surface and submucosal gland epithelium of the conducting airways is a constitutive primary participant in innate immunity. In addition, this tissue may serve the function of a secondary amplifier of innate immune responses following neurohumoral input, stimulation with cytokines from cells such as alveolar macrophages, or engagement of pattern recognition receptors. Here, we provide an overview of the airway epithelium's role in pulmonary innate immunity, especially in the context of bacterial and viral infections, emphasizing findings from human cells and selected animal models. We also provide examples of human disease states caused by impaired epithelial defenses in the lung.