Lipoteichoic acid
Encyclopedia
Lipoteichoic acid is a major constituent of the cell wall
of Gram-positive
bacteria. These organisms have an inner (or cytoplasmic) membrane and, external to it, a thick (up to 80 nanometer) peptidoglycan layer. It consists of teichoic acids, long chains of ribitol
phosphate and is anchored to the lipid bilayer
via a glyceride
. It acts as regulator of autolytic wall enzymes (muramidases). It has antigenic properties being able to stimulate specific immune response and is released from the bacterial cells mainly after bacteriolysis
induced by lysozyme
, cationic peptides from leucocytes, or beta-lactam
antibiotics.
LTA may bind to target cells non-specifically through membrane phospholipids, or specifically to CD14
and to Toll-like receptors. Binding to TLR-2 has shown to induce NF-κB expression(a central transcription factor
), elevating expression of both pro- and anti-apoptotic genes. Its activation also induces mitogen-activated protein kinases (MAPK) activation along with Phosphoinositide 3-kinase
activation.
LTA bound to targets can interact with circulating antibodies and activate the complement cascade to induce a passive immune kill phenomenon. It also triggers the release from neutrophils and macrophage
s of reactive oxygen
and nitrogen species, acid hydrolases, highly cationic proteinases, bactericidal cationic peptides, growth factors, and cytotoxic cytokines, which may act in synergy to amplify cell damage. Therefore, LTA shares many pathogenic similarities with endotoxin
s (lipopolysaccharide).
, nephritis
, uveitis
, encephalomyelitis
, meningitis
, and periodontal
lesions, and also triggered cascades resulting in septic shock
and multiorgan failure
. Binding of LTA to targets can be inhibited by phospholipids and antibodies directed at LTA, CD14, or Toll-like receptors. In vitro, LTA release can be inhibited by non-bacteriolytic antibiotics and by polysulfates such as heparin
.
LTA can be considered a virulence factor
that has an important role in infections and in postinfectious sequelae caused by Gram-positive bacteria. The development of effective antibiotics killing the bacteria without lysing them and multidrug strategies to attenuate LTA-induced secretion of proinflammatory agonists is of great importance to combat septic shock and multiorgan failure caused by Gram-positive bacteria.
LTA's molecular structure has been found to have the strongest hydrophobic bonds of an entire bacteria.
Said et al. showed that LTA 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-L.
Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...
of Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria. These organisms have an inner (or cytoplasmic) membrane and, external to it, a thick (up to 80 nanometer) peptidoglycan layer. It consists of teichoic acids, long chains of ribitol
Ribitol
Ribitol or adonitol is a crystalline pentose alcohol formed by the reduction of ribose. It occurs naturally in the plant Adonis vernalis, as well as in the cell walls of Gram positive bacteria . It also contributes to the chemical structure of riboflavin.-External links:**...
phosphate and is anchored to the lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
via a glyceride
Glyceride
Glycerides, more correctly known as acylglycerols, are esters formed from glycerol and fatty acids.Glycerol has three hydroxyl functional groups, which can be esterified with one, two, or three fatty acids to form monoglycerides, diglycerides, and triglycerides.Vegetable oils and animal fats...
. It acts as regulator of autolytic wall enzymes (muramidases). It has antigenic properties being able to stimulate specific immune response and is released from the bacterial cells mainly after bacteriolysis
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
induced by lysozyme
Lysozyme
Lysozyme, also known as muramidase or N-acetylmuramide glycanhydrolase, are glycoside hydrolases, enzymes that damage bacterial cell walls by catalyzing hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between...
, cationic peptides from leucocytes, or beta-lactam
Beta-lactam
A β-lactam ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl...
antibiotics.
LTA may bind to target cells non-specifically through membrane phospholipids, or specifically to CD14
CD14
Cluster of differentiation 14 also known as CD14 is a human gene.The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms. Either it is anchored into the membrane by a glycosylphosphatidylinositol tail or it appears in a soluble form...
and to Toll-like receptors. Binding to TLR-2 has shown to induce NF-κB expression(a central transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
), elevating expression of both pro- and anti-apoptotic genes. Its activation also induces mitogen-activated protein kinases (MAPK) activation along with Phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
activation.
LTA bound to targets can interact with circulating antibodies and activate the complement cascade to induce a passive immune kill phenomenon. It also triggers the release from neutrophils and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s of reactive oxygen
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
and nitrogen species, acid hydrolases, highly cationic proteinases, bactericidal cationic peptides, growth factors, and cytotoxic cytokines, which may act in synergy to amplify cell damage. Therefore, LTA shares many pathogenic similarities with endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
s (lipopolysaccharide).
Studies
In animal studies, LTA has induced arthritisArthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
, nephritis
Nephritis
Nephritis is inflammation of the nephrons in the kidneys. The word "nephritis" was imported from Latin, which took it from Greek: νεφρίτιδα. The word comes from the Greek νεφρός - nephro- meaning "of the kidney" and -itis meaning "inflammation"....
, uveitis
Uveitis
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....
, encephalomyelitis
Encephalomyelitis
Encephalomyelitis is a general term for inflammation of the brain and spinal cord, describing a number of disorders:* Acute disseminated encephalomyelitis or postinfectious encephalomyelitis, a demyelinating disease of the brain and spinal cord, possibly triggered by vaccination or viral...
, meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
, and periodontal
Periodontium
Periodontium refers to the specialized tissues that both surround and support the teeth, maintaining them in the maxillary and mandibular bones. The word comes from the Greek terms peri-, meaning "around" and -odons, meaning "tooth." Literally taken, it means that which is "around the tooth"...
lesions, and also triggered cascades resulting in septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
and multiorgan failure
Organ failure
Organ dysfunction is a condition where an organ does not perform its expected function. Organ failure is organ dysfunction to such a degree that normal homeostasis cannot be maintained without external clinical intervention.It is not a diagnosis...
. Binding of LTA to targets can be inhibited by phospholipids and antibodies directed at LTA, CD14, or Toll-like receptors. In vitro, LTA release can be inhibited by non-bacteriolytic antibiotics and by polysulfates such as heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
.
LTA can be considered a virulence factor
Virulence factor
Virulence factors are molecules expressed and secreted by pathogens that enable them to achieve the following:* colonization of a niche in the host...
that has an important role in infections and in postinfectious sequelae caused by Gram-positive bacteria. The development of effective antibiotics killing the bacteria without lysing them and multidrug strategies to attenuate LTA-induced secretion of proinflammatory agonists is of great importance to combat septic shock and multiorgan failure caused by Gram-positive bacteria.
LTA's molecular structure has been found to have the strongest hydrophobic bonds of an entire bacteria.
Said et al. showed that LTA 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-L.