Lipoarabinomannan
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Lipoarabinomannan, also called LAM, is a
glycolipid Glycolipids are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the connec ...
, and a
virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...
associated with ''
Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...
'', the
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
responsible for
tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
. Its primary function is to inactivate
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
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 to 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 Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
response. Additional functions of Lipoarabinomannan are thought to include the neutralization of cytotoxic oxygen free radicals produced by macrophages, inhibition of
protein kinase C In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
, and induction of early response genes.


Structure

Lipoarabinomannan is synthesized via addition of mannose residues to phosphoinositol by a series of mannosyltransferases 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 Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
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 Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
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 Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene. Function The protein encoded by this gene is a member ...
, 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.


PILAM

LAMS capped with phosphoinositol are typically found in nonpathogenic species including
M. smegmatis ''Mycobacterium smegmatis'' is an acid-fast bacterium, bacterial species in the phylum ''Actinomycetota'' and the genus ''Mycobacterium''. It is 3.0 to 5.0 µm long with a bacillus (shape), bacillus shape and can be stained by Ziehl–Neels ...
. In contrast to ManLAMs, PILAMs are pro-inflammatory.
CD14 CD14 (cluster of differentiation 14) is a human protein made mostly by macrophages as part of the innate immune system. It helps to detect bacteria in the body by binding lipopolysaccharide (LPS), a pathogen-associated molecular pattern (PAMP). C ...
, a recognition receptor present on macrophages, associate with
toll-like receptor 2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune sys ...
(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-fos Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkin ...
, 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.


Point-of-care TB Diagnosis

Fujifilm SILVAMP TB LAM is a LAM based urine
point-of-care Clinical point of care (POC) is the point in time when clinicians deliver healthcare products and services to patients at the time of care. Clinical documentation Clinical documentation is a record of the critical thinking and judgment of a health ...
test, using
silver halide A silver halide (or silver salt) is one of the chemical compounds that can form between the element silver (Ag) and one of the halogens. In particular, bromine (Br), chlorine (Cl), iodine (I) and fluorine (F) may each combine with silver to prod ...
amplification technology. Up to 60% of people with
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
are unable to produce a sputum sample, leading to delays in TB diagnosis for these patients, which often proves deadly.
Foundation for Innovative New Diagnostics The Foundation for Innovative New Diagnostics (FIND) is a global health non-profit based in Geneva, Switzerland. FIND functions as a product development partnership, engaging in active collaboration with over 150 partners to facilitate the develo ...
(FIND) and
Fujifilm , trading as Fujifilm, or simply Fuji, is a Japanese multinational conglomerate headquartered in Tokyo, Japan, operating in the realms of photography, optics, office and medical electronics, biotechnology, and chemicals. The offerings from th ...
developed the test, which is particularly useful in low-income settings, where the burden of HIV and TB is the highest. It takes an hour, doesn’t rely on electricity, and requires limited training for health workers. A study with 968 HIV+ hospital inpatients found the Fujifilm SILVAMP TB LAM test to have a 28.1% higher sensitivity than the Alere Determine TB LAM Ag and the Fujifilm SILVAMP TB LAM could diagnose 65% of patients with active TB within 24 h. A meta-analysis with 1,595 inpatients and outpatients showed 70.7% sensitivity and 90.9% specificity for TB diagnosis in people living with HIV for Fujifilm SILVAMP TB LAM. Further, FujiLAM showed good sensitivity for the detection of extrapulmonary TB (EPTB) ranging from 47 to 94% across different forms of ETB and could have rapidly diagnosed TB in up to 89% of HIV-positive inpatients who died within 12 weeks. The test showed a high positive predictive value (95.2%) in HIV-negative outpatients and has the potential to improve rapid, urine-based TB diagnosis in general populations at the point-of-care. Large prospective studies are on the way.


References


Further reading

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