Lipopolysaccharide

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Endotoxins
)
Not to be confused with glycolipid.
Structure of a lipopolysaccharide (LPS)

Lipopolysaccharides (LPS) are large

delta endotoxin proteins produced by Bacillus thuringiensis.[3]

Lipopolysaccharides can have substantial impacts on human health, primarily through interactions with the immune system. LPS is a potent activator of the immune system and

pyrogen (agent that causes fever).[4] In severe cases, LPS can play a role in causing septic shock.[5] In lower levels and over a longer time period, there is evidence LPS may play an important and harmful role in autoimmunity, obesity, depression, and cellular senescence.[6][7][8][9]

Discovery

The toxic activity of LPS was first discovered and termed endotoxin by

bacterial outer membrane vesicles (OMVs), which may also contain other virulence factors and proteins.[11][1]

Functions in bacteria

LPS is a major component of the outer membrane of

amoebae. LPS is also required for the functioning of omptins, a class of bacterial protease.[13]

Composition

The saccharolipid Kdo2-Lipid A. Kdo residues in red (core), glucosamine residues in blue, acyl chains in black and phosphate groups in green.

Lipopolysaccharides are composed of three parts: the O antigen (or O polysaccharide), the core oligosaccharide, and Lipid A.

O-antigen

The repetitive

hydrophobic.[16] 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-manno-oct-2-ulosonic acid (also known as KDO, keto-deoxyoctulosonate).[17] The LPS cores of many bacteria also contain non-carbohydrate components, such as phosphate, amino acids, and ethanolamine substituents.

Lipid A

Main article: Lipid A

Lipid A is, in normal circumstances, a

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.[18] However Lipid A structure varies among bacterial species. Lipid A structure largely defines the degree and nature of the overall host immune activation.[19]

Lipooligosaccharides

The "rough form" of LPS has a lower molecular weight due to the absence of the O polysaccharide. In its place is a short oligosaccharide: this form is known as Lipooligosaccharide (LOS), and is a glycolipid found in the outer membrane of some types of

Gram negative cell envelope. LOS play an important role in the pathogenesis of certain bacterial infections because they are capable of acting as immunostimulators and immunomodulators.[6] 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. 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.[6][20]

LPS detoxification

A highly conserved host enzyme called acyloxyacyl hydrolase (AOAH) may detoxify LPS when it enters, or is produced in, animal tissues. It may also convert LPS in the intestine into an LPS inhibitor. Neutrophils, macrophages and dendritic cells produce this lipase, which inactivates LPS by removing the two secondary acyl chains from lipid A to produce tetraacyl LPS. If mice are given LPS parenterally, those that lack AOAH develop high titers of non-specific antibodies, develop prolonged hepatomegaly, and experience prolonged endotoxin tolerance. LPS inactivation may be required for animals to restore homeostasis after parenteral LPS exposure.[21] Although mice have many other mechanisms for inhibiting LPS signaling, none is able to prevent these changes in animals that lack AOAH.

Dephosphorylation of LPS by

Salmonella tryphimurium and Clostridioides difficile infection restoring normal gut microbiota.[22] Alkaline phosphatase
prevents intestinal inflammation (and "leaky gut") from bacteria by dephosphorylating the Lipid A portion of LPS.[23][24][25]

Biosynthesis and transport

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).[26]
LPS transport: Completed LPS molecules are transported across the periplasm and outer membrane by the lipopolysaccharide transport (Lpt) proteins A, B, C, D, E, F, and G.[27]

The entire process of making LPS starts with a molecule called lipid A-Kdo2, which is first created on the surface of the bacterial cell's inner membrane. Then, additional sugars are added to this molecule on the inner membrane before it's moved to the space between the inner and outer membranes (

periplasmic space) with the help of a protein called MsbA. The O-antigen, another part of LPS, is made by special enzyme complexes on the inner membrane. It is then moved to the outer membrane through three different systems: one is Wzy-dependent, another relies on ABC transporters, and the third involves a synthase-dependent process.[28]

Ultimately, LPS is transported to the outer membrane by a membrane-to-membrane bridge of lipolysaccharide transport (Lpt) proteins.[27][29] This transporter is a potential antibiotic target.[30][31]

Biological effects on hosts infected with Gram-negative bacteria

Immune response

LPS acts as the prototypical endotoxin because it binds the

TLR4 is the LPS receptor.[33][34]

As part of the cellular

pyrogen (fever-inducing substance).[4]

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 involved in septic shock. 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.[36] This may relate to differences in the level of circulating natural antibodies between the two species.[37][38] Said et al. showed that LPS causes an

monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L1.[39]

Endotoxins are in large part responsible for the dramatic clinical manifestations of infections with pathogenic Gram-negative bacteria, such as

meningococcemia, Waterhouse–Friderichsen syndrome, and meningitis
.

Portions of the LPS from several bacterial strains have been shown to be chemically similar to human host cell surface molecules; the ability of some bacteria to present molecules on their surface which are chemically identical or similar to the surface molecules of some types of host cells is termed molecular

erythrocytes.[6] In another example, the terminal trisaccharide portion (lactotriaose) of the oligosaccharide from pathogenic Neisseria spp. LOS is also found in lactoneoseries glycosphingolipids from human cells.[6] Most meningococci from groups B and C, as well as gonococci, have been shown to have this trisaccharide as part of their LOS structure.[6] The presence of these human cell surface 'mimics' may, in addition to acting as a 'camouflage' from the immune system, play a role in the abolishment of immune tolerance when infecting hosts with certain human leukocyte antigen (HLA) genotypes, such as HLA-B35.[6]

LPS can be sensed directly by hematopoietic stem cells (HSCs) through the bonding with TLR4, causing them to proliferate in reaction to a systemic infection. This response activate the TLR4-TRIF-ROS-p38 signaling within the HSCs and through a sustained TLR4 activation can cause a proliferative stress, leading to impair their competitive repopulating ability.[41] Infection in mice using S. typhimurium showed similar results, validating the experimental model also in vivo.

Effect of variability on immune response

Toll-like receptors of the innate immune system recognize LPS and trigger an immune response.

O-antigens (the outer carbohydrates) are the most variable portion of the LPS molecule, imparting antigenic specificity. In contrast, lipid A is the most conserved part. However, lipid A composition also may vary (e.g., in number and nature of

acyl chains even within or between genera). Some of these variations may impart antagonistic properties to these LPS. For example, diphosphoryl lipid A of Rhodobacter sphaeroides (RsDPLA) is a potent antagonist of LPS in human cells, but is an agonist in hamster and equine cells.[42]

It has been speculated that conical lipid A (e.g., from

TLR2 instead of TLR4), and completely cylindrical lipid A like that of Rhodobacter sphaeroides is antagonistic to TLRs.[43][44] In general, LPS gene clusters are highly variable between different strains, subspecies, species of bacterial pathogens of plants and animals.[45][46]

Normal human blood serum contains anti-LOS antibodies that are bactericidal and patients that have infections caused by serotypically distinct strains possess anti-LOS antibodies that differ in their specificity compared with normal serum.[47] These differences in humoral immune response to different LOS types can be attributed to the structure of the LOS molecule, primarily within the structure of the oligosaccharide portion of the LOS molecule.[47] In

bovine host immune defenses.[48]
Taken together, these observations suggest that variations in bacterial surface molecules such as LOS can help the pathogen evade both the humoral (antibody and complement-mediated) and the cell-mediated (killing by neutrophils, for example) host immune defenses.

Non-canonical pathways of LPS recognition

Recently, it was shown that in addition to

TLR4 mediated pathways, certain members of the family of the transient receptor potential ion channels recognize LPS.[49] LPS-mediated activation of TRPA1 was shown in mice[50] and Drosophila melanogaster flies.[51] At higher concentrations, LPS activates other members of the sensory TRP channel family as well, such as TRPV1, TRPM3 and to some extent TRPM8.[52]
LPS is recognized by TRPV4 on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.[53]

Testing

Lipopolysaccharide is a significant factor that makes bacteria harmful, and it helps categorize them into different groups based on their structure and function. This makes LPS a useful marker for telling apart various Gram-negative bacteria. Swiftly identifying and understanding the types of pathogens involved is crucial for promptly managing and treating infections. Since LPS is the main trigger for the immune response in our cells, it acts as an early signal of an acute infection. Therefore, LPS testing is more specific and meaningful than many other serological tests.[54]

The current methods for testing LPS are quite sensitive, but many of them struggle to differentiate between different LPS groups. Additionally, the nature of LPS, which has both water-attracting and water-repelling properties (amphiphilic), makes it challenging to develop sensitive and user-friendly tests.[54]

The typical detection methods rely on identifying the lipid A part of LPS. However, this method has limitations because Lipid A is very similar among different bacterial species and serotypes. LPS testing techniques fall into six categories, and they often overlap: in vivo tests, in vitro tests, modified immunoassays, biological assays, and chemical assays.[54]

Pathophysiology

LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood can lead to endotoxemia, potentially causing a harmful condition called septic shock. This condition includes symptoms like rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction.[54]

Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems.[54]

LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems.[54]

Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.[54]

Health effects

In general the health effects of LPS are due to its abilities as a potent activator and modulator of the immune system, especially its inducement of inflammation.

Endotoxemia

The presence of endotoxins in the blood is called endotoxemia. High level of endotoxemia can lead to septic shock,[55] while lower concentration of endotoxins in the bloodstream is called metabolic endotoxemia.[56] Endotoxemia is associated with obesity, diet,[57] cardiovascular diseases,[57] and diabetes,[56] while also host genetics might have an effect.[58]

Moreover, endotoxemia of intestinal origin, especially, at the

small bowel bacterial overgrowth syndrome and an increased intestinal permeability.[60]

Waterhouse-Friderichsen syndrome
, both of which can be life-threatening.

It has also been reported that gonococcal LOS can cause damage to human fallopian tubes.[47]

Auto-immune disease

The molecular mimicry of some LOS molecules is thought to cause autoimmune-based host responses, such as flareups of multiple sclerosis.[6][40] Other examples of bacterial mimicry of host structures via LOS are found with the bacteria Helicobacter pylori and Campylobacter jejuni, organisms which cause gastrointestinal disease in humans, and Haemophilus ducreyi which causes chancroid. Certain C. jejuni LPS serotypes (attributed to certain tetra- and pentasaccharide moieties of the core oligosaccharide) have also been implicated with Guillain–Barré syndrome and a variant of Guillain–Barré called Miller-Fisher syndrome.[6]

Link to obesity

Epidemiological studies have shown that increased endotoxin load, which can be a result of increased populations of endotoxin-producing bacteria in the intestinal tract, is associated with certain obesity-related patient groups.

mouse models.[64] A more recent study has uncovered a potentially contributing role for Enterobacter cloacae B29 toward obesity and insulin resistance in a human patient.[65] The presumed mechanism for the association of endotoxin with obesity is that endotoxin induces an inflammation-mediated pathway accounting for the observed obesity and insulin resistance.[64] Bacterial genera associated with endotoxin-related obesity effects include Escherichia and Enterobacter
.

Depression

There is experimental and observational evidence that LPS might play a role in depression. Administration of LPS in mice can lead to depressive symptoms, and there seem to be elevated levels of LPS in some people with depression. Inflammation may sometimes play a role in the development of depression, and LPS is pro-inflammatory.[8]

Cellular senescence

Inflammation induced by LPS can induce

neurodegeneration).[9]

Role as contaminant in biotechnology and research

Lipopolysaccharides are frequent contaminants in plasmid DNA prepared from bacteria or proteins expressed from bacteria, and must be removed from the DNA or protein to avoid contaminating experiments and to avoid toxicity of products manufactured using industrial fermentation.[66]

Ovalbumin is frequently contaminated with endotoxins. Ovalbumin is one of the extensively studied proteins in animal models and also an established model allergen for airway hyper-responsiveness (AHR). Commercially available ovalbumin that is contaminated with LPS can falsify research results, as it does not accurately reflect the effect of the protein antigen on animal physiology.[67]

In pharmaceutical production, it is necessary to remove all traces of endotoxin from drug product containers, as even small amounts of endotoxin will cause illness in humans. A depyrogenation oven is used for this purpose. Temperatures in excess of 300 °C are required to fully break down LPS.[68]

The standard

recombinant version of a protein in the LAL assay, Factor C.[70]

Testing
Lipopolysaccharide, is a significant factor that makes bacteria harmful, and it helps categorize them into different groups based on their structure and function. This makes LPS a useful marker for telling apart various Gram-negative bacteria. Swiftly identifying and understanding the types of pathogens involved is crucial for promptly managing and treating infections. Since LPS is the main trigger for the immune response in our cells, it acts as an early signal of an acute infection. Therefore, LPS testing is more specific and meaningful than many other serological tests. The current methods for testing LPS are quite sensitive, but many of them struggle to differentiate between different LPS groups. Additionally, the nature of LPS, which has both water-attracting and water-repelling properties (amphiphilic), makes it challenging to develop sensitive and user-friendly tests. The typical detection methods rely on identifying the lipid A part of LPS. However, this method has limitations because Lipid A is very similar among different bacterial species and serotypes. LPS testing techniques fall into six categories, and they often overlap: in vivo tests, in vitro tests, modified immunoassays, biological assays, and chemical assays. [54]
Pathophysiology
LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood can lead to endotoxemia, potentially causing a harmful condition called septic shock. This condition includes symptoms like rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction. Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems. LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems. Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.[54]

See also

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External links
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