Introduction to Lipoarabinomannan

Mycobacterium tuberculosis Structure

Mycobacterium tuberculosis (MTB) represents a Gram-positive bacterium that is acid-fast and requires oxygen to survive as an obligate aerobic bacillus. The organism shows a long rod-shaped structure which can occasionally display slight curves and lacks any flagella or spores. Polysaccharides and lipids with distinctive and unusual structures form the primary composition of MTB cell walls. During infection Mycobacterium tuberculosis depends on its cell wall components to shield against environmental factors and control the host immune response which makes these components vital in tuberculosis pathogenesis. The MTB cell wall's lipid components determine its pathogenicity because increased lipid content strengthens its virulence.

The MTB cell wall, from inside to outside, consists of the cell membrane, peptidoglycan layer, outer membrane layer, and capsule. PG is covalently linked to arabinogalactan (AG), which is esterified at its non-reducing end with α-alkyl, β-hydroxy long-chain mycolic acids. The outer membrane is an asymmetric bilayer mainly composed of MA and phospholipids, with non-covalently embedded lipids and lipopolysaccharides such as phosphatidylinositol mannoside, phthiocerol dimycocerosate, phenolic glycolipid, mannose-capped lipoarabinomannan (ManLAM), and various acyl trehaloses. ManLAM is anchored to the bacterial cell membrane through the PIM anchor and extends through the cell wall to the outer membrane surface. The outermost layer is a loosely attached capsule mainly composed of α-D-glucan, proteins, and a small amount of lipids. The capsule also contains D-arabino-D-mannan.

Figure 1. M. tuberculosis cell wall
(Source: Jacobo-Delgado YM, et al. 2023)

LAM Function

Mycobacterium tuberculosis has strong adaptability under stress conditions and can undergo proteome and lipidome rearrangements. During different stages of infection, the distribution of glycolipids and the ratio of LAM to lipomannan (LM) can change. Low concentrations of LAM can induce negative feedback regulation of the immune system, possibly because LAM has multiple epitopes that interact with cell surface receptors with varying affinities. For example, the lectin domain of CR3 exposed on eosinophils can interact with mannose, mediating bacterial uptake. The variety of mannose units in LAM influences dendritic cell maturation and function as their concentration increases. LAM extracted from Mycobacterium tuberculosis and Mycobacterium leprae functions by suppressing T cell multiplication while also interfering with interferon-gamma-driven macrophage activation and protein kinase activity and by triggering tumor necrosis factor production in monocytes and complement activation.

The virulence factors of MTB such as LAM modulate innate immune responses by altering the functions of immune cells including alveolar epithelial cells, macrophages and dendritic cells. The production of IL-37 in human type II alveolar epithelial cells is triggered by LAM through TLR-2 initiated signaling pathways which result in p38 upregulation and ERK1/2 phosphorylation. IL-37 binds to Smad3 and moves into the nucleus to block pro-inflammatory cytokine signals. LAM can block activation and differentiation of immune cell subsets. In vitro, monocytes exposed to LAM fail to differentiate into mature macrophages, showing reduced expression of CD86, TLR2, and TLR4. These macrophages have impaired tumor necrosis factor (TNF) signaling and defective PAR2 pathway function, weakening control of intracellular MTB growth. LAM targets neutrophils through insertion into lactosylceramide-enriched lipid rafts on their membranes which disrupts tyrosine kinase signaling and blocks hematopoietic cell kinase recruitment while reducing granule trafficking. The production of myeloperoxidase and NADPH oxidase decreases while calcium flux becomes impaired which restricts phagolysosome formation and cytokine production as well as degranulation and respiratory burst. LAM binds to CD11b/CD18 receptors on eosinophils which stops TLR-2 activation and restricts the release of inflammatory cytokines. LAM inhibits phagosome maturation, further impairing innate immune activation. Genetic polymorphisms such as TLR1 1805G/T are associated with increased susceptibility to MTB due to altered LAM recognition. Tuberculosis patients have circulating LAM which attaches to high-density lipoprotein to enhance macrophage vulnerability to mycobacteria while reducing TNF production substantially. The presence of LAM modifies innate immune cells in a way that slows down their response to MTB infection and reduces their effectiveness.

Figure 3. Schematic illustration of MTB-host interactions with and inside of the alveolar macrophage
(Source: Naeem MA, et al. 2021)

In regulating adaptive immunity, LAM promotes an increase in the number of IL-10-producing B cell subsets. An IL-10-rich environment allows Mycobacterium tuberculosis to survive by suppressing the host's pro-inflammatory immune defenses. LAM suppresses T cell activation through its effect on reducing antigen-presenting molecule expression including MHC-II and CD80/CD86. When dendritic cells undergo treatment with LAM they display diminished ability to cross-present tuberculosis antigens which leads to CD4+ T cell proliferation dropping by 40% to 60%.

LAM Antibodies

LAM Antigens