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Experimental & Molecular Medicine Dec 2013Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. Minute amounts of LPS released from infecting pathogens can initiate... (Review)
Review
Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. Minute amounts of LPS released from infecting pathogens can initiate potent innate immune responses that prime the immune system against further infection. However, when the LPS response is not properly controlled it can lead to fatal septic shock syndrome. The common structural pattern of LPS in diverse bacterial species is recognized by a cascade of LPS receptors and accessory proteins, LPS binding protein (LBP), CD14 and the Toll-like receptor4 (TLR4)-MD-2 complex. The structures of these proteins account for how our immune system differentiates LPS molecules from structurally similar host molecules. They also provide insights useful for discovery of anti-sepsis drugs. In this review, we summarize these structures and describe the structural basis of LPS recognition by LPS receptors and accessory proteins.
Topics: Amino Acid Sequence; Animals; Binding Sites; Carbohydrate Sequence; Humans; Immunity, Innate; Lipopolysaccharides; Molecular Sequence Data; Toll-Like Receptor 4
PubMed: 24310172
DOI: 10.1038/emm.2013.97 -
FEMS Microbiology Reviews Jul 2016The Gram-negative bacterial lipopolysaccharide (LPS) is a major component of the outer membrane that plays a key role in host-pathogen interactions with the innate... (Review)
Review
The Gram-negative bacterial lipopolysaccharide (LPS) is a major component of the outer membrane that plays a key role in host-pathogen interactions with the innate immune system. During infection, bacteria are exposed to a host environment that is typically dominated by inflammatory cells and soluble factors, including antibiotics, which provide cues about regulation of gene expression. Bacterial adaptive changes including modulation of LPS synthesis and structure are a conserved theme in infections, irrespective of the type or bacteria or the site of infection. In general, these changes result in immune system evasion, persisting inflammation and increased antimicrobial resistance. Here, we review the modifications of LPS structure and biosynthetic pathways that occur upon adaptation of model opportunistic pathogens (Pseudomonas aeruginosa, Burkholderia cepacia complex bacteria, Helicobacter pylori and Salmonella enterica) to chronic infection in respiratory and gastrointestinal sites. We also discuss the molecular mechanisms of these variations and their role in the host-pathogen interaction.
Topics: Chronic Disease; Gastrointestinal Diseases; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Host-Pathogen Interactions; Humans; Lipopolysaccharides; Respiratory Tract Infections
PubMed: 27075488
DOI: 10.1093/femsre/fuw007 -
Frontiers in Immunology 2023Macrophages manifest as various subtypes that play diverse and important roles in immunosurveillance and the maintenance of immunological homeostasis in various tissues....
Macrophages manifest as various subtypes that play diverse and important roles in immunosurveillance and the maintenance of immunological homeostasis in various tissues. Many studies divide macrophages into two broad groups: M1 macrophages induced by lipopolysaccharide (LPS), and M2 macrophages induced by interleukin 4 (IL-4). However, considering the complex and diverse microenvironment , the concept of M1 and M2 is not enough to explain diversity of macrophages. In this study, we analyzed the functions of macrophages induced by simultaneous stimulation with LPS and IL-4 (termed LPS/IL-4-induced macrophages). LPS/IL-4-induced macrophages were a homogeneous population showing a mixture of the characteristics of M1 and M2 macrophages. In LPS/IL-4-induced macrophages, expression of cell-surface M1 markers (I-A) was higher than in M1 macrophages, but lower expression of iNOS, and expression of M1-associated genes ( and ) were decreased in comparison to expression in M1 macrophages. Conversely, expression of the cell-surface M2 marker CD206 was lower on LPS/IL-4-induced macrophages than on M2 macrophages and expression of M2-associated genes (, , and ) varied, with being greater than, being lower than, and being comparable to that in M2 macrophages. Glycolysis-dependent phagocytic activity of LPS/IL-4-induced macrophages was strongly enhanced as was that of M1 macrophages; however, the energy metabolism of LPS/IL-4-induced macrophages, such as activation state of glycolytic and oxidative phosphorylation, was quite different from that of M1 or M2 macrophages. These results indicate that the macrophages induced by LPS and IL-4 had unique properties.
Topics: Lipopolysaccharides; Interleukin-4; Macrophages
PubMed: 37180123
DOI: 10.3389/fimmu.2023.1111729 -
Nature Communications Feb 2023Lipopolysaccharide is essential for most Gram-negative bacteria as it is a main component of the outer membrane. In the pathogen Brucella abortus, smooth...
Lipopolysaccharide is essential for most Gram-negative bacteria as it is a main component of the outer membrane. In the pathogen Brucella abortus, smooth lipopolysaccharide containing the O-antigen is required for virulence. Being part of the Rhizobiales, Brucella spp. display unipolar growth and lipopolysaccharide was shown to be incorporated at the active growth sites, i.e. the new pole and the division site. By localizing proteins involved in the lipopolysaccharide transport across the cell envelope, from the inner to the outer membrane, we show that the lipopolysaccharide incorporation sites are determined by the inner membrane complex of the lipopolysaccharide transport system. Moreover, we identify the main O-antigen ligase of Brucella spp. involved in smooth lipopolysaccharide synthesis. Altogether, our data highlight a layer of spatiotemporal organization of the lipopolysaccharide biosynthesis pathway and identify an original class of bifunctional O-antigen ligases.
Topics: Brucella abortus; Lipopolysaccharides; O Antigens; Carbohydrate Metabolism; Cell Membrane
PubMed: 36806059
DOI: 10.1038/s41467-023-36442-y -
Cellular and Molecular Gastroenterology... 2023Hepatic immune system disorder plays a critical role in the pathogenesis of acute liver injury. The intrinsic signaling mechanisms responsible for dampening excessive...
BACKGROUND & AIMS
Hepatic immune system disorder plays a critical role in the pathogenesis of acute liver injury. The intrinsic signaling mechanisms responsible for dampening excessive activation of liver macrophages are not completely understood. The Notch and Hippo-YAP signaling pathways have been implicated in immune homeostasis. In this study, we investigated the interactive cell signaling networks of Notch1/YAP pathway during acute liver injury.
METHODS
Myeloid-specific Notch1 knockout (Notch1) mice and the floxed Notch1 (Notch1) mice were subjected to lipopolysaccharide/D-galactosamine toxicity. Some mice were injected via the tail vein with bone marrow-derived macrophages transfected with lentivirus-expressing YAP. Some mice were injected with YAP siRNA using an in vivo mannose-mediated delivery system.
RESULTS
We found that the activated Notch1 and YAP signaling in liver macrophages were closely related to lipopolysaccharide/D-galactosamine-induced acute liver injury. Macrophage/neutrophil infiltration, proinflammatory mediators, and hepatocellular apoptosis were markedly ameliorated in Notch1 mice. Importantly, myeloid Notch1 deficiency depressed YAP signaling and facilitated M2 macrophage polarization in the injured liver. Furthermore, YAP overexpression in Notch1 livers exacerbated liver damage and shifted macrophage polarization toward the M1 phenotype. Mechanistically, macrophage Notch1 signaling could transcriptionally activate YAP gene expression. Reciprocally, YAP transcriptionally upregulated the Notch ligand Jagged1 gene expression and was essential for Notch1-mediated macrophage polarization. Finally, dual inhibition of Notch1 and YAP in macrophages further promoted M2 polarization and alleviated liver damage.
CONCLUSIONS
Our findings underscore a novel molecular insight into the Notch1-YAP circuit for controlling macrophage polarization in acute liver injury, raising the possibility of targeting macrophage Notch1-YAP circuit as an effective strategy for liver inflammation-related diseases.
Topics: Animals; Mice; Galactosamine; Lipopolysaccharides; Liver; Macrophages; Signal Transduction
PubMed: 36706917
DOI: 10.1016/j.jcmgh.2023.01.002 -
Biosensors Dec 2019Lipopolysaccharides (LPS) are endotoxins, hazardous and toxic inflammatory stimulators released from the outer membrane of Gram-negative bacteria, and are the major... (Review)
Review
Lipopolysaccharides (LPS) are endotoxins, hazardous and toxic inflammatory stimulators released from the outer membrane of Gram-negative bacteria, and are the major cause of septic shock giving rise to millions of fatal illnesses worldwide. There is an urgent need to identify and detect these molecules selectively and rapidly. Pathogen detection has been done by traditional as well as biosensor-based methods. Nanomaterial based biosensors can assist in achieving these goals and have tremendous potential. The biosensing techniques developed are low-cost, easy to operate, and give a fast response. Due to extremely small size, large surface area, and scope for surface modification, nanomaterials have been used to target various biomolecules, including LPS. The sensing mechanism can be quite complex and involves the transformation of chemical interactions into amplified physical signals. Many different sorts of nanomaterials such as metal nanomaterials, magnetic nanomaterials, quantum dots, and others have been used for biosensing of LPS and have shown attractive results. This review considers the recent developments in the application of nanomaterials in sensing of LPS with emphasis given mainly to electrochemical and optical sensing.
Topics: Biosensing Techniques; Lipopolysaccharides; Nanostructures
PubMed: 31877825
DOI: 10.3390/bios10010002 -
FEBS Letters Apr 2022Systemic inflammation is associated with chronic disease and is purported to be a main pathogenic mechanism underlying metabolic conditions. Microbes harbored in the... (Review)
Review
Systemic inflammation is associated with chronic disease and is purported to be a main pathogenic mechanism underlying metabolic conditions. Microbes harbored in the host gastrointestinal tract release signaling byproducts from their cell wall, such as lipopolysaccharides (LPS), which can act locally and, after crossing the gut barrier and entering circulation, also systemically. Defined as metabolic endotoxemia, elevated concentrations of LPS in circulation are associated with metabolic conditions and chronic disease. As such, measurement of LPS is highly prevalent in animal and human research investigating these states. Indeed, LPS can be a potent stimulant of host immunity, but this response depends on the microbial species' origin, a parameter often overlooked in both preclinical and clinical investigations. Indeed, the lipid A portion of LPS is mutable and comprises the main virulence and endotoxic component, thus contributing to the structural and functional diversity among LPSs from microbial species. In this review, we discuss how such structural differences in LPS can induce differential immunological responses in the host.
Topics: Animals; Endotoxemia; Endotoxins; Gastrointestinal Microbiome; Inflammation; Lipopolysaccharides
PubMed: 35262962
DOI: 10.1002/1873-3468.14328 -
Helicobacter Dec 2016This review covers the current knowledge and gaps in Helicobacter pylori lipopolysaccharide (LPS) structure and biosynthesis. H. pylori is a Gram-negative bacterium... (Review)
Review
This review covers the current knowledge and gaps in Helicobacter pylori lipopolysaccharide (LPS) structure and biosynthesis. H. pylori is a Gram-negative bacterium which colonizes the luminal surface of the human gastric epithelium. Both a constitutive alteration of the lipid A preventing TLR4 elicitation and host mimicry of the Lewis antigen decorated O-antigen of H. pylori LPS promote immune escape and chronic infection. To date, the complete structure of H. pylori LPS is not available, and the proposed model is a linear arrangement composed of the inner core defined as the hexa-saccharide (Kdo-LD-Hep-LD-Hep-DD-Hep-Gal-Glc), the outer core composed of a conserved trisaccharide (-GlcNAc-Fuc-DD-Hep-) linked to the third heptose of the inner core, the glucan, the heptan and a variable O-antigen, generally consisting of a poly-LacNAc decorated with Lewis antigens. Although the glycosyltransferases (GTs) responsible for the biosynthesis of the H. pylori O-antigen chains have been identified and characterized, there are many gaps in regard to the biosynthesis of the core LPS. These limitations warrant additional mutagenesis and structural studies to obtain the complete LPS structure and corresponding biosynthetic pathway of this important gastric bacterium.
Topics: Glycosyltransferases; Helicobacter pylori; Humans; Immune Evasion; Lipopolysaccharides; Metabolic Networks and Pathways
PubMed: 26934862
DOI: 10.1111/hel.12301 -
Current Topics in Microbiology and... 2015The outer membrane (OM) is the front line of leptospiral interactions with their environment and the mammalian host. Unlike most invasive spirochetes, pathogenic... (Review)
Review
The outer membrane (OM) is the front line of leptospiral interactions with their environment and the mammalian host. Unlike most invasive spirochetes, pathogenic leptospires must be able to survive in both free-living and host-adapted states. As organisms move from one set of environmental conditions to another, the OM must cope with a series of conflicting challenges. For example, the OM must be porous enough to allow nutrient uptake, yet robust enough to defend the cell against noxious substances. In the host, the OM presents a surface decorated with adhesins and receptors for attaching to, and acquiring, desirable host molecules such as the complement regulator, Factor H.Factor H. On the other hand, the OM must enable leptospires to evade detection by the host's immune system on their way from sites of invasion through the bloodstream to the protected niche of the proximal tubule. The picture that is emerging of the leptospiral OM is that, while it shares many of the characteristics of the OMs of spirochetes and Gram-negative bacteria, it is also unique and different in ways that make it of general interest to microbiologists. For example, unlike most other pathogenic spirochetes, the leptospiral OM is rich in lipopolysaccharide (LPS). Leptospiral LPS is similar to that of Gram-negative bacteria but has a number of unique structural features that may explain why it is not recognized by the LPS-specific Toll-like receptor 4 of humans. As in other spirochetes, lipoproteins are major components of the leptospiral OM, though their roles are poorly understood. The functions of transmembrane outer membrane proteins (OMPs) in many cases are better understood, thanks to homologies with their Gram-negative counterparts and the emergence of improved genetic techniques. This chapter will review recent discoveries involving the leptospiral OM and its role in leptospiral physiology and pathogenesis.
Topics: Bacterial Outer Membrane Proteins; Cell Membrane; Immunity, Innate; Leptospira; Lipopolysaccharides
PubMed: 25388136
DOI: 10.1007/978-3-662-45059-8_8 -
European Journal of Pharmaceutics and... Nov 2022Lipopolysaccharide (LPS) is a cell-wall component of Gram-negative bacteria which contributes to bacterial toxicity. During processes such as cell division, shedding of... (Review)
Review
Lipopolysaccharide (LPS) is a cell-wall component of Gram-negative bacteria which contributes to bacterial toxicity. During processes such as cell division, shedding of outer membrane vesicles, or bacterial cell death, LPS is released into the surrounding media. If such contamination got into the bloodstream, it would induce pro-inflammatory immune responses which can result in sepsis and death. Therefore, detection of LPS is essential in the pharmaceutical and food industries to prevent patients being exposed to LPS. The Limulus Amebocyte Lysate (LAL) assay is the current major assay used by industry to detect and quantify LPS contamination. However, in recent years the phenomenon of Low Endotoxin Recovery (LER) has gained significant scientific attention. The phenomenon describes the inability of LAL assays, in some cases, to detect LPS due to a masking effect caused by interaction with formulation excipients. Although the mechanism of LER has not been fully determined, it is widely thought that the origin of the effect is associated with these interactions perturbing the supramolecular formation of LPS aggregates. Whilst the phenomenon of LER is highly complex and remains to be entirely understood, herein we aim to provide a state-of-the-art review of the ongoing and, at times, controversial topics of LER research. We overview the current understanding of the relationship between LPS structure and toxicity, conditions in which the supramolecular arrangement of LPS can be altered, the hypothesised mechanisms of LER, and discuss the possible risk of masked LPS remaining biologically toxic upon administration to patients.
Topics: Humans; Endotoxins; Lipopolysaccharides; Gram-Negative Bacteria; Biological Assay; Drug Contamination
PubMed: 36272656
DOI: 10.1016/j.ejpb.2022.10.006