Lipopolysaccharide - Wikipedia, The Free Encyclopedia

Lipopolysaccharide - Wikipedia, the free encyclopedia
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Lipopolysaccharide - Wikipedia, the

free encyclopedia
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Structure of a lipopolysaccharide
Lipopolysaccharides (LPS), also known as lipoglycans and
endotoxins, are large molecules consisting of a lipid and a
polysaccharide 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 ("LOS") is used to refer to a
low-molecular-weight form of bacterial lipopolysaccharides.
Discovery[edit]
The toxic activity of LPS was first discovered and termed
"endotoxin" by Richard Friedrich Johannes Pfeiffer, who
distinguished between exotoxins, which he classified as a toxin
that is released by bacteria into the surrounding environment, and
endotoxins, which he considered to be a toxin kept "within" the
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 does not necessarily require the
destruction of the bacterial cell wall, but rather, LPS is secreted as
part of the normal physiological activity of membrane vesicle
trafficking in the form of bacterial outer membrane vesicles
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(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[edit]
LPS is the major component of the outer membrane of
Gram-negative bacteria, contributing greatly to the structural
integrity 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 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 sensitivity, and
interactions with predators such as amoebae.
LPS is required for the proper conformation of Omptin activity;
however, smooth LPS will sterically hinder omptins.
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Composition[edit]
The saccharolipid Kdo2-Lipid A. Glucosamine residues in blue,

Kdo residues in red, acyl chains in black and phosphate groups in
green.
It comprises three parts:
1. O antigen (or O polysaccharide)
2. Core oligosaccharide
3. Lipid A
O-antigen[edit]
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A repetitive glycan polymer contained within an LPS is referred to

as the O antigen, O polysaccharide, or O 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[edit]
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
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phosphate, amino acids, and ethanolamine substituents.

Lipid A[edit]
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[edit]
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
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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[edit]
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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. A different enzyme may detoxify LPS when it
enters, or is produced in, animal tissues. Neutrophils,
macrophages, and dendritic cells produce a lipase, acyloxyacyl
hydrolase (AOAH), that inactivates LPS by removing the two
secondary acyl chains from lipid A. If they are given LPS
parenterally, mice 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.[12]
Biosynthesis and transport[edit]
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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).[13]
LPS Transport: Completed LPS molecules are transported
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across the periplasm and outer membrane by the proteins LptA,

B, C, D, E, F, and G[14]
Biological effects on hosts infected with

gram-negative bacteria[edit]
Immune response[edit]
LPS acts as the prototypical 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.[15]
As part of the cellular stress response, superoxide is one of the
major ROS species induced by LPS in various TLR expressing cell
types.
LPS is also an exogenous pyrogen (external fever-inducing
substance).
Being of crucial importance to Gram-negative bacteria, these
molecules make candidate targets for new antimicrobial agents.
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Some researchers doubt reports of generalized toxic effects

attributed to all lipopolysaccharides, in particular, for
cyanobacteria.[16]
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 g/kg induces shock in humans, but mice will
tolerate a dose up to a thousand times higher.[17] This may relate
to differences in the level of circulating natural antibodies between
the two species.[18][19] Said et al. showed that LPS causes an
IL-10-dependent inhibition of CD4 T-cell expansion and function
by up-regulating PD-1 levels on monocytes which leads to IL-10
production by monocytes after binding of PD-1 by PD-L1.[20]
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, WaterhouseFriderichsen syndrome, and meningitis.
Bruce Beutler was awarded a portion of the 2011 Nobel Prize in
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Physiology or Medicine for his work demonstrating that TLR4 is

the LPS receptor.[21][22]
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 mimicry.[23] For example,
in Neisseria meningitidis L2,3,5,7,9, the terminal tetrasaccharide
portion of the oligosaccharide (lacto-N-neotetraose) is the same
tetrasaccharide as that found in paragloboside, a precursor for
ABH glycolipid antigens found on human erythrocytes.[9] 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.[9]
Most meningococci from groups B and C, as well as gonococci,
have been shown to have this trisaccharide as part of their LOS
structure.[9] 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.[9]
Effect of variability on immune response[edit]
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O-antigens (the outer carbohydrates) are the most variable portion

of the LPS molecule, imparting the 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,
Rhodobacter sphaeroides diphosphoryl lipid A (RsDPLA) is a
potent antagonist of LPS in human cells, but is an agonist in
hamster and equine cells.[citation needed]
It has been speculated that conical Lipid A (e.g., from E. coli) are
more agonistic, less conical lipid A like those of Porphyromonas
gingivalis may activate a different signal (TLR2 instead of TLR4),
and completely cylindrical lipid A like that of Rhodobacter
sphaeroides is antagonistic to TLRs.[24][25]
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LPS gene clusters are highly variable between different strains,

subspecies, species of bacterial pathogens of plants and animals.
[26][27]
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.[28] 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.[28] In Neisseria gonorrhoeae it has been demonstrated
that the antigenicity of LOS molecules can change during an
infection due to the ability of these bacteria to synthesize more
than one type of LOS,[28] a characteristic known as phase
variation. Additionally, Neisseria gonorrhoeae, as well as
Neisseria meningitidis and Haemophilus influenzae,[9] are
capable of further modifying their LOS in vitro, for example
through sialylation (modification with sialic acid residues), and as
a result are able to increase their resistance to complementmediated killing [28] or even down-regulate complement
activation[9] or evade the effects of bactericidal antibodies.[9]
Sialylation may also contribute to hindered neutrophil attachment
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and phagocytosis by immune system cells as well as a reduced

oxidative burst.[9] Haemophilus somnus, a pathogen of cattle, has
also been shown to display LOS phase variation, a characteristic
which may help in the evasion of bovine host immune
defenses.[29] Taken together, these observations suggest that
variations in bacterial surface molecules such as LOS can help the
pathogen evade both the humoral (antibody and complementmediated) and the cell-mediated (killing by neutrophils, for
example) host immune defenses.
Health effects[edit]
Endotoxemia[edit]
The presence of endotoxins in the blood is called endotoxemia. It
can lead to septic shock, if the immune response is severely
pronounced.[30]
Moreover, endotoxemia of intestinal origin, especially, at the
host-pathogen interface, is considered to be an important factor in
the development of alcoholic hepatitis,[31] which is likely to
develop on the basis of the small bowel bacterial overgrowth
syndrome and an increased intestinal permeability.[32]
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Lipid A may cause uncontrolled activation of mammalian immune

systems with production of inflammatory mediators that may lead
to septic shock.[10] This inflammatory reaction is mediated by
Toll-like receptor 4 which is responsible for immune system cell
activation.[10] Damage to the endothelial layer of blood vessels
caused by these inflammatory mediators can lead to capillary leak
syndrome, dilation of blood vessels and a decrease in cardiac
function and can lead to septic shock.[33] Pronounced complement
activation can also be observed later in the course as the bacteria
multiply in the blood.[33] High bacterial proliferation triggering
destructive endothelial damage can also lead to disseminated
intravascular coagulation (DIC) with loss of function of certain
internal organs such as the kidneys, adrenal glands and lungs due
to compromised blood supply. The skin can show the effects of
vascular damage often coupled with depletion of coagulation
factors in the form of petechiae, purpura and ecchymoses. The
limbs can also be affected, sometimes with devastating
consequences such as the development of gangrene, requiring
subsequent amputation.[33] Loss of function of the adrenal glands
can cause adrenal insufficiency and additional hemorrhage into
the adrenals causes 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.[28]
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Auto-immune disease[edit]
The molecular mimicry of some LOS molecules is thought to cause
autoimmune-based host responses, such as flareups of multiple
sclerosis.[9][23] 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-Barr syndrome and a
variant of Guillain-Barr called Miller-Fisher syndrome.[9]
Link to obesity[edit]
Epidemiological studies have previously 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.[34][35][36] Other
studies have shown that purified endotoxin from Escherichia coli
can induce obesity and insulin-resistance phenotypes when
injected into germ-free mouse models.[37] A more recent study has
uncovered a potentially contributing role for Enterobacter cloacae
B29 toward obesity and insulin resistance in a human patient.[38]
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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.[37]There is a correlation between plasma LPS and
insulin resistance.[39]
Bacterial genera associated with endotoxin-related obesity effects:
Escherichia, Enterobacter
Laboratory research and biotechnology

production systems[edit]
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.[40]
Also, 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 hyperresponsiveness (AHR). Commercially available ovalbumin that is
contaminated with LPS can fully activate endothelial cells in an
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in-vitro assay of the first step of inflammation, and it falsifies

research results, as it does not accurately reflect the effect of sole
protein antigen on animal physiology.[citation needed]
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 break down this substance. A defined endotoxin
reduction rate is a correlation between time and temperature.
Based on primary packaging material as syringes or vials, a glass
temperature of 250 C and a holding time of 30 minutes is typical
to achieve a reduction of endotoxin levels by a factor of 1000.[41]
The standard assay for detecting presence of endotoxin is the
Limulus Amebocyte Lysate (LAL) assay, utilizing blood from the
Horseshoe crab.[42] Very low levels of LPS can cause coagulation
of the limulus lysate due to a powerful amplification through an
enzymatic cascade. However, due to the dwindling population of
horseshoe crabs, and the fact that there are factors that interfere
with the LAL assay, efforts have been made to develop alternative
assays, with the most promising ones being ELISA tests using a
recombinant version of a protein in the LAL assay, Factor C.[43]
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See also[edit]
Bioaerosol
Depyrogenation
Exotoxin
Mucopolysaccharide
Nesfatin-1
Schwartzman reaction
Host-pathogen interface
Membrane vesicle trafficking
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External links[edit]
Lipopolysaccharides at the US National Library of Medicine
Medical Subject Headings (MeSH)
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