Lipoarabinomannan
Encyclopedia
Lipoarabinomannan, also called LAM
, is a glycolipid
, and a virulence factor
associated with Mycobacterium tuberculosis
, the bacteria
responsible for tuberculosis
. Its primary function is to inactivate macrophage
s and scavenge oxidative radicals.
The inactivation of macrophages allows for the dissemination of mycobacteria to other parts of the body. The destruction of oxidative radicals allows for the survival of the bacteria, as oxidative free radicals are an important mechanism by which our bodies try to rid ourselves of infection.
Additional functions of lipoarabinommanan are thought to include the neutralization of cytotoxic oxygen free radicals produced by macrophages, inhibition of protein kinase C
, and induction of early response genes.
There are many proposed mechanisms behind ManLAM function. Activation of a PI3K pathway is sufficient to trigger phosphorylation of the Bcl-2 family member Bad by ManLAM. ManLAM is able to activate the serine/threonine kinase Akt via phosphorylation which is then able to phosphorylate Bad. Dephosphorylated Bad serves as a pro-apoptotic protein and its activation allows for cell survival. This demonstrates one virulence-associated mechanism by which bacteria are able to up-regulate signaling pathways to control host cell apoptosis.
ManLAM may also directly activate SHP-1, a phosphotyrosine phosphatase known to be involved in terminating activation signals. SHP-1 negatively regulates pathways related to the actions of IFN-γ and insulin. LAM may regulate SHP-1 by multiple mechanisms including direct interactions, phosphorylation, and subcellular localization. Once activated, SHP-1 translocates from the cytosol to the membrane. By activating a phosphatase, LAM can inhibit LPS
and IFN-γ induced protein tyrosine phosphorylation in monocytes. This decreases production of TNF-α, a molecule necessary in forming granulomas against M. tuberculosis and important in macrophage defense against bacterium via nitrogen oxide production. LAM's activation of SHP-1 also works to deactivate IL-12. IL-12 is important for innate resistance to M. tuberculosis infections. It activates natural killer cells which produce IFN-γ to activate macrophages. By impairing the function of these two molecules by SHP-1 activation, ManLAM may promote intracellular survival.
Other models suggest that ManLAM acts to mediate immunosuppressive effects through suppression of LPS-induced IL-12 p40 protein production. ManLAM is thought to inhibit the IL-1 receptor-associated kinase (IRAK)-TRAF6 interaction, IκB-α phosphorylation, and nuclear translocation of c-Rel and p50 which causes reduced IL-12 p40 production.
, a recognition receptor present on macrophages, associate with toll-like receptor 2 (TLR2) is described to be a receptor for PILAM. Binding of PILAM to the receptor elicits the activation of an intracellular signaling cascade which activates transcription factors that initiate transcription of proinflammatory cytokine genes. This may lead to TNF-α, IL-8, and IL-12 activation and apoptosis of macrophages.
, KC, and JE, AraLAM induces transcription of the mRNA for cytokines (such as TNF-α, IL 1-α, IL 1-β, IL-6, IL-8, and IL-10) characteristically produced by macrophages. Proto-oncogenes c-fos and c-myc are involved in the regulation of gene transcription while JE and KC are peptide cytokines that serve as specific chemoattractants for neutrophils and monocytes. Activation of TNF-α creates pathologic manifestations of disease such as tissue necrosis, nerve damage, and protective immunity.
O-acyl groups of the arabinomannan moiety may be responsible for TNF-inducing activity which causes the tuberculosis symptoms of fever, weight loss, and necrosis. However, the presence of ManLAMs decreases AraLAM activity, suppressing an immune response.
Lam
-Lam:*Mor lam, an ancient Lao form of song in Laos and Isan*Lam saravane, a music genre*Lam luang, a music genre*Lam, Germany, a town in Bavaria-LAM:*Lactational amenorrhea method, a contraceptive method...
, is a glycolipid
Glycolipid
Glycolipids are lipids with a carbohydrate attached. Their role is to provide energy and also serve as markers for cellular recognition.-Metabolism:...
, and 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...
associated with Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
, the bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
responsible for tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
. Its primary function is to inactivate 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 and scavenge oxidative radicals.
The inactivation of macrophages allows for the dissemination of mycobacteria to other parts of the body. The destruction of oxidative radicals allows for the survival of the bacteria, as oxidative free radicals are an important mechanism by which our bodies try to rid ourselves of infection.
Background
Lipoarabinomannan is a lipoglycan and major virulence factor in the bacteria genus Mycobacterium. In addition to serving as a major cell wall component, it is thought to serve as a modulin with immunoregulatory and anti-inflammatory effects. This allows the bacterium maintain survival in the human reservoir by undermining host resistance and acquired immune responses. These mechanisms include the inhibition of T-cell proliferation and of macrophage microbicidal activity via diminished IFN-γ response.Additional functions of lipoarabinommanan are thought to include the neutralization of cytotoxic oxygen free radicals produced by macrophages, inhibition of protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
, and induction of early response genes.
Structure
Lipoarabinomannan is synthesized when a mannopyranosyl adds to a phosphoinositol to produce PIMs and lipomannan(LM). PIM and LM are then glycosylated with arabinan to form LAM. LAM is known to have three primary structural domains. These include a glycosylphosphatidyl anchor which attaches the molecule to the cell wall, a D-mannan core serving as a carbohydrate skeleton, and a terminal D-arabinan, also composing the carbohydrate skeleton. Many arabinofuranosyl side chains branch off the mannose core. It is the covalent modifications to this terminal D-arabinan that creates various LAM structures with their own unique functions to mediate bacterial survival within a host. The presence and the structure of capping allow classification of LAM molecules into three major classes.ManLAM
Mannosylated LAMs (ManLAM) are characterized by the presence of mannosyl caps on the terminal D-arabinan. These types of LAMs are most commonly found in more pathogenic Mycobacterium species such as M. tuberculosis, M. leprae, and M. bovis. ManLAM has been shown to be an anti-inflammatory molecule that inhibits production of TNF-α and IL-12 production by human dendritic cells and human macrophages in vitro and to modulate M. tuberculosis-induced macrophage apoptosis via binding to host macrophage mannose receptors. This is particularly important in deactivating host macrophages to allow the bacteria to survive and multiply within them.Proposed Mechanisms
There are many proposed mechanisms behind ManLAM function. Activation of a PI3K pathway is sufficient to trigger phosphorylation of the Bcl-2 family member Bad by ManLAM. ManLAM is able to activate the serine/threonine kinase Akt via phosphorylation which is then able to phosphorylate Bad. Dephosphorylated Bad serves as a pro-apoptotic protein and its activation allows for cell survival. This demonstrates one virulence-associated mechanism by which bacteria are able to up-regulate signaling pathways to control host cell apoptosis.
ManLAM may also directly activate SHP-1, a phosphotyrosine phosphatase known to be involved in terminating activation signals. SHP-1 negatively regulates pathways related to the actions of IFN-γ and insulin. LAM may regulate SHP-1 by multiple mechanisms including direct interactions, phosphorylation, and subcellular localization. Once activated, SHP-1 translocates from the cytosol to the membrane. By activating a phosphatase, LAM can inhibit LPS
LPS
LPS can stand for more than one thing:* Lipopolysaccharide * Liters per second* Low Pressure Sodium vapor lamps* Leases per second, a speed measure for DHCP servers* Leica Photogrammetry Suite, official name was changed to "LPS" in 2008...
and IFN-γ induced protein tyrosine phosphorylation in monocytes. This decreases production of TNF-α, a molecule necessary in forming granulomas against M. tuberculosis and important in macrophage defense against bacterium via nitrogen oxide production. LAM's activation of SHP-1 also works to deactivate IL-12. IL-12 is important for innate resistance to M. tuberculosis infections. It activates natural killer cells which produce IFN-γ to activate macrophages. By impairing the function of these two molecules by SHP-1 activation, ManLAM may promote intracellular survival.
Other models suggest that ManLAM acts to mediate immunosuppressive effects through suppression of LPS-induced IL-12 p40 protein production. ManLAM is thought to inhibit the IL-1 receptor-associated kinase (IRAK)-TRAF6 interaction, IκB-α phosphorylation, and nuclear translocation of c-Rel and p50 which causes reduced IL-12 p40 production.
PILAM
LAMS capped with phosphoinositol are typically found in nonpathogenic species including M. smegmatis. In contrast to ManLAMs, PILAMs are pro-inflammatory. CD14CD14
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...
, a recognition receptor present on macrophages, associate with toll-like receptor 2 (TLR2) is described to be a receptor for PILAM. Binding of PILAM to the receptor elicits the activation of an intracellular signaling cascade which activates transcription factors that initiate transcription of proinflammatory cytokine genes. This may lead to TNF-α, IL-8, and IL-12 activation and apoptosis of macrophages.
AraLAM (CheLAM)
Certain species of rapid-growing bacterium such as M. chelonae and laboratory strains (H37Ra) contain LAMs that are absent of both mannose and phosphoinosital caps. This form of LAM is characterized by 1,3 –mannosyl side chains instead of the 1,2 commonly found in others mycobacterial species. These forms are considered to be more potent than the mannose-capped ManLAM in inducing functions associated with macrophage activation. In addition to stimulation of early genes such as c-fosC-Fos
In the field of molecular biology and Genetics, c-Fos is a protein encoded by the FOS gene.-Structure and function:c-Fos is a cellular proto-oncogene belonging to the immediate early gene family of transcription factors. c-Fos has a leucine-zipper DNA binding domain, and a transactivation domain at...
, KC, and JE, AraLAM induces transcription of the mRNA for cytokines (such as TNF-α, IL 1-α, IL 1-β, IL-6, IL-8, and IL-10) characteristically produced by macrophages. Proto-oncogenes c-fos and c-myc are involved in the regulation of gene transcription while JE and KC are peptide cytokines that serve as specific chemoattractants for neutrophils and monocytes. Activation of TNF-α creates pathologic manifestations of disease such as tissue necrosis, nerve damage, and protective immunity.
O-acyl groups of the arabinomannan moiety may be responsible for TNF-inducing activity which causes the tuberculosis symptoms of fever, weight loss, and necrosis. However, the presence of ManLAMs decreases AraLAM activity, suppressing an immune response.