Lipopolysaccharide
Lipopolysaccharides (LPS), also known as lipoglycans and endotoxin, are large molecules consisting of a lipid and a polysaccharide（多糖） composed of O-antigen, outer core and inner core joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, and elicit strong immune responses in animals. The term lipooligosaccharide (\ is used to refer to a low molecular weight form of bacterial lipopolysaccharide
Structure of a lipopolysaccharide Discovery
The toxic activity of LPS was first discovered and termed \内毒素) by Richard Friedrich Johannes Pfeiffer, who distinguished between exotoxins（外毒素）, which he classified as a toxin that is released by bacteria into the environment when bacteria are killed, and endotoxins, which he considered to be a toxin kept \bacterial cell and released only after destruction of the bacterial cell wall.[1]:84 Subsequent work showed that release of LPS from gram negative microbes（细菌） does not require the necessity of destruction of the bacterial cell wall, but rather, LPS is secreted as part of the normal physiological activity of membrane vesicle （膜囊泡）trafficking in the form of bacterial outer membrane vesicles (OMVs), which may also contain other virulence factors and proteins.[2]
Today, the term 'endotoxin' is mostly used synonymously with LPS,[3] although there are a few molecules secreted by other bacteria that are not related to LPS, such as the so-called delta endotoxin proteins secreted by Bacillus thuringiensis.
Functions in bacteria
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LPS is the major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity（n.完整） of the bacteria, and protecting the membrane from certain kinds of chemical attack. LPS also increases the negative charge of the cell membrane and helps stabilize the overall membrane structure. It is of crucial importance to gram-negative bacteria, whose death results if it is mutated or removed. LPS is an endotoxin, and induces a strong response from
normal animal immune systems. It has also been implicated in non-pathogenic aspects of bacterial ecology, including surface adhesion, bacteriophage（n. [病毒] 噬菌体；抗菌素） sensitivity, and interactions with predators（捕食者） such as amoebae(变形虫).
LPS is required for the proper conformation of Omptin activity; however, smooth
LPS will sterically hinder omptins.
Composition It comprises three parts: 1. O antigen (or O antigen| O polysaccharide) 2. Core oligosaccharide 3. Lipid A O-antigen A repetitive glycan polymer contained within an LPS is referred to as the O antigen, O polysaccharide, or O The saccharolipid Kdo2-Lipid A. Glucosamine(氨基葡萄糖) residues in blue, Kdo residues in red, acyl chains in black and phosphate groups in green. side-chain of the bacteria. The O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The composition of the O chain varies from strain to strain. For example, there are over 160 different O antigen structures produced by different E. coli strains.[4] The presence or absence of O chains determines whether the LPS is considered rough or smooth. Full-length O-chains would render the LPS smooth, whereas the absence or reduction of O-chains would make the LPS rough.[5] Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics, since a rough LPS is more hydrophobic.[6] O antigen is exposed on the very outer surface of the bacterial cell, and, as a consequence, is a target for recognition by host antibodies. Core
Main article: Core oligosaccharide The Core domain always contains an oligosaccharide component that attaches directly to lipid A and commonly contains sugars such as heptose and
3-deoxy-D-mannooctulosonic Acid (also known as KDO, keto-deoxyoctulosonate).[7] The LPS Cores of many bacteria also contain non-carbohydrate components, such as phosphate, amino acids, and ethanolamine substituents. Lipid A
Lipid A is, in normal circumstances, a phosphorylated glucosamine disaccharide decorated with multiple fatty acids. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane, and the rest of the LPS projects from the cell
surface. The lipid A domain is responsible for much of the toxicity of Gram-negative bacteria. When bacterial cells are lysed by the immune system, fragments of
membrane containing lipid A are released into the circulation, causing fever, diarrhea, and possible fatal endotoxic shock (also called septic shock). The Lipid A moiety is a very conserved component of the LPS.[8]
Lipooligosaccharides
Lipooligosaccharides (LOS) are glycolipids found in the outer membrane of some types of Gram negative bacteria, such as Neisseria spp. and Haemophilus spp. The term is synonymous with the low molecular weight form of bacterial LPS.[9] LOS plays a central role in maintaining the integrity and functionality of the outer membrane of the Gram negative cell envelope. Lipooligosaccharides play an important role in the pathogenesis of certain bacterial infections because they are
capable of acting as immunostimulators and immunomodulators.[9] Furthermore, LOS molecules are responsible for the ability of some bacterial strains to display molecular mimicry and antigenic diversity, aiding in the evasion of host immune defenses and thus contributing to the virulence of these bacterial strains.
Chemically, lipooligosaccharides lack O-antigens and possess only the a lipid A-based outer membrane-anchoring moiety, and an oligosaccharide core.[10] In the case of Neisseria meningitidis, the lipid A portion of the molecule has a symmetrical structure and the inner core is composed of 3-deoxy-D-manno-2-octulosonic acid (KDO) and heptose (Hep) moieties. The outer core oligosaccharide chain varies
depending on the bacterial strain.[9][10] The term lipooligosaccharide is used to refer to the low molecular weight form of bacterial lipopolysaccharides, which can be categorized into two forms: the high molecular weight (Mr, or smooth) form
possesses a high molecular weight, repeating polysaccharide O-chain, while the low molecular weight (low-Mr or rough) form, lacks the O-chain but possesses a short oligosaccharide in its place.[9]
LPS modifications（修饰） The making of LPS can be modified in order to present a specific sugar structure. Those can be recognised by either other LPS (which enables to inhibit LPS toxins) or glycosyltransferases that use those sugar structure to add more specific sugars. It has recently been shown that a specific enzyme in the intestine (alkaline phosphatase) can detoxify LPS by removing the two phosphate groups found on LPS carbohydrates.[11] This may function as an adaptive mechanism to help the host manage potentially toxic effects of gram-negative bacteria normally found in the small intestine.
Biosynthesis and transport
LPS Final Assembly: O-antigen subunits are translocated across the inner membrane (by Wzx) where they are polymerized (by Wzy, chain length determined by Wzz) and ligated (by WaaL) on to complete Core-Lipid A molecules (which were translocated by MsbA).[12] LPS Transport: Completed LPS molecules are transported across the periplasm and outer membrane by the proteins LptA, B, C, D, E, F, and G[13] Biological effects on hosts infected with gram-negative bacteria
Immune response
LPS acts as the prototypical（典型的） endotoxin because it binds the
CD14/TLR4/MD2 receptor complex in many cell types, but especially in
monocytes, dendritic cells, macrophages and B cells, which promotes the secretion of pro-inflammatory cytokines, nitric oxide, and eicosanoids（类花生酸）.[14]
LPS is also an exogenous pyrogen (external fever-inducing substance，外源性致热源） Being of crucial importance to Gram-negative bacteria, these molecules make candidate targets for new antimicrobial（抗菌的） agents.
Some researchers doubt reports of generalized toxic effects attributed to（归因于） all lipopolysaccharides, in particular, for cyanobacteria（蓝藻菌）.[15]
LPS function has been under experimental research for several years due to its role in activating many transcription factors. LPS also produces many types of mediators （介质）involved in septic shock（感染性休克）. Humans are much more sensitive to LPS than other animals (e.g., mice). A dose of 1 μg/kg induces shock in humans, but mice will tolerate a dose up to a thousand times higher.[16] This may relate to differences in the level of circulating natural antibodies between the two species.[17][18] Said （上述）et al. showed that LPS causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1（progressed cell death-1，a kind of protein in human） levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.[19]
Endotoxins are in large part responsible for the dramatic clinical manifestations of infections with pathogenic Gram-negative bacteria, such as Neisseria meningitidis, the pathogens that causes meningococcal disease, including meningococcemia, Waterhouse-Friderichsen syndrome, and meningitis.