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ManLAM structure. ManLAM biosynthesis follows a pathway from phosphatidyl-myo-inositol (PI)→PIM→LM→LAM→ ManLAM. ManLAM contains three domains: an MPI anchor, a polysaccharide backbone and mannose caps. The MPI anchor comprises a PI unit with Manp units. PI acts as an anchor inserted into the cell membrane. The MPI anchor is recognized by CD1b, CD1d, TLR2, DCAR, MBP and lactosylceramide enriched lipid rafts. The polysaccharide backbone includes a mannan core and an arabinan domain. In the mannan backbone of LAM/ManLAM, PIM 2 is linked to another 17-19 residues of Manp. The arabinan core consists of a branched linear α (1→5) linked Araf. Mature LAM/ManLAM is further linked via an arabinan domain made up of approximately 70 Araf residues. Two arrangements or motifs can be found at the non-reducing end: a branched hexaarabinofuranoside (Ara 6 ) and a linear tetraarabinofuranoside (Ara 4 ). The mannose caps consist of one to three Manp residues linked to the terminal β-linked Araf unit. The mannose caps are recognized by MR, DC-SIGN and surfactant protein D.
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Mannose-capped lipoarabinomannan (ManLAM) is a high molecular mass amphipathic lipoglycan identified in pathogenic Mycobacterium tuberculosis (M. tb) and M. bovis Bacillus Calmette-Guérin (BCG). ManLAM, serves as both an immunogen and a modulator of the host immune system, and its critical role in mycobacterial survival during infection has been we...
Contexts in source publication
Context 1
... consists of three domains (Figure 1): an MPI anchor, a polysaccharide backbone and mannose caps. The MPI anchor is based on an sn-glycero-3-phospho-(1-D-myo-inositol) unit with α-D-mannopyranosyl (Manp) units linked at O-2 and O-6 of the myo-inositol [3]. ...
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... can be recognized by multiple receptors and soluble molecules because of its structural complexity. The mannose caps of ManLAM are recognized by mannose receptor (MR), the dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and surfactant protein D (Figure 1) [6- 9]. The MPI anchors of ManLAM are recognized by CD1 (including CD1b and CD1d), Toll like receptor 2 (TLR2), dendritic cell immunoactivating receptor (DCAR), mannose-binding protein (MBP), and lactosylceramide enriched lipid rafts in the plasma membrane ( Figure 1) [10][11][12][13][14][15][16]. ...
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... mannose caps of ManLAM are recognized by mannose receptor (MR), the dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and surfactant protein D (Figure 1) [6- 9]. The MPI anchors of ManLAM are recognized by CD1 (including CD1b and CD1d), Toll like receptor 2 (TLR2), dendritic cell immunoactivating receptor (DCAR), mannose-binding protein (MBP), and lactosylceramide enriched lipid rafts in the plasma membrane ( Figure 1) [10][11][12][13][14][15][16]. Other receptors and molecules that bind to ManLAM include pulmonary surfactant protein A (PS-A), Dectin 2 and CD44 [17- 21], however, the ManLAM binding domains that interact with these molecules remain unknown. ...
Citations
... M.tb-induced Man-Lam acts as an anti-inflammatory molecule by inhibiting IL-12 and TNF-α production and increasing IL-10 production by dendritic cells (DCs). Furthermore, LM activates macrophage type 2 (M2), which is dependent on the presence of TLR2 and has a significant inhibitory effect on the production of TNF-α, IL-12p40, and NO by lipopolysaccharide (LPS)-activated macrophages (M1) [24]. Some M.tb glycolipoproteins such as LpqH (Rv3763) and LprG (Rv1441c) induce the expression of TNF-α, IL-10, IL-12, and apoptosis in differentiated THP-1 cells, and monocyte-derived macrophages, while this effect is TLR2-mediated. ...
... In Myco bacterium tuberculosis, where the role of LAM in infection has been better defined, this lipoglycan modulates key aspects of the host innate and adaptive immune responses. In addition to mediating the binding and entry of M. tuberculosis inside phagocytic cells through C-type lectins and modulating phagosome maturation inside mac rophages, LAM and its biosynthetic precursor, lipomannan (LM), contribute to driving proinflammatory or anti-inflammatory res ponses depending on the fine details of their structures (24)(25)(26)(27)(28). The fact that mutations in embC were reported in M. abscessus subsp. ...
Mycobacterium abscessus is increasingly recognized as the causative agent of chronic pulmonary infections in humans. One of the genes found to be under strong evolutionary pressure during adaptation of M. abscessus to the human lung is embC which encodes an arabinosyltransferase required for the biosynthesis of the cell envelope lipoglycan, lipoarabinomannan (LAM). To assess the impact of patient-derived embC mutations on the physiology and virulence of M. abscessus , mutations were introduced in the isogenic background of M. abscessus ATCC 19977 and the resulting strains probed for phenotypic changes in a variety of in vitro and host cell-based assays relevant to infection. We show that patient-derived mutational variations in EmbC result in an unexpectedly large number of changes in the physiology of M. abscessus, and its interactions with innate immune cells. Not only did the mutants produce previously unknown forms of LAM with a truncated arabinan domain and 3-linked oligomannoside chains, they also displayed significantly altered cording, sliding motility, and biofilm-forming capacities. The mutants further differed from wild-type M. abscessus in their ability to replicate and induce inflammatory responses in human monocyte–derived macrophages and epithelial cells. The fact that different embC mutations were associated with distinct physiologic and pathogenic outcomes indicates that structural alterations in LAM caused by nonsynonymous nucleotide polymorphisms in embC may be a rapid, one-step, way for M. abscessus to generate broad-spectrum diversity beneficial to survival within the heterogeneous and constantly evolving environment of the infected human airway.
... Mannose-capped lipoarabinomannan (ManLAM) found on the surface of Mycobacterium tuberculosis (Mtb) is an immunomodulator of the host immune system, which plays critical roles in the survival of Mtb (Vergne et al., 2014;Zhou et al., 2019). Literature has shown that the mannose cap, composed of 1-3 units of α(1,2)-D-mannans, on the non-reducing end of ManLAM, is crucial for the binding of ManLAM to the pattern-recognizing receptors on the host cell (Koppel et al., 2004;Zheng et al., 2017). ...
... This high-affinity multivalent binding with mannose receptor (MR) or dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) has been known to generate strong downstream signaling which leads to immunosuppressive responses (Geijtenbeek et al., 2003;Nigou et al., 2001;Rajaram et al., 2010;Vergne et al., 2014). For example, the binding of ManLAM with MR could enhance the expression of peroxisome proliferator activated receptor-gamma (PPAR-g) and IL-1 receptor-associated kinase (IRAK)-M, ultimately resulting in the reduction of nitric oxide and pro-inflammatory cytokine, and induction of immunosuppressive cytokines (Pan et al., 2017;Pathak et al., 2005;Rajaram et al., 2010;Zhou et al., 2019). On the other hand, our discrete, synthetic α(1,2)-D-mannans and α(1,6)-D-mannans, which cannot form the supramolecular structure, might bind with MR and DC-SIGN (Koppel et al., 2004;Leelayuwapan et al., 2017;Zheng et al., 2017), but with much weaker affinities, compared to the supramolecular multivalent binding. ...
The mannose cap motif, which consists of short-chain α(1,2)-d-mannans located on the non-reducing end of Mycobacterium tuberculosis’ mannose-capped lipoarabinomannan (ManLAM), exhibits strong binding affinities toward the lectins on mammalian host cells. The α(1,2)-d-mannans induce the immunosuppressive effects crucial for the survival and virulence of mycobacteria. However, the biological activities of discrete α(1,2)-d-mannans with different chain lengths remain unknown. In this study, the rapid synthesis of α(1,2)-d-mannans was rationally developed to increase the accessibility of α(1,2)-d-mannans. The rapid synthesis enabled simultaneous productions of the protected α(1,2)-d-mannans with chain lengths of 2–5 units, at room temperature (25 °C), within 4 h. After hydrolysis unmasking, different sizes of α(1,2)-d-mannans, and their α(1,6)-d-mannan counterparts were obtained and biologically evaluated. In summary, this work led to the optimally-designed low-steric-hindrance bicyclic orthoester monomer suitable for the gram-scale rapid synthesis of α(1,2)-d-mannans at 25 °C. This provided a basis for further development of more efficient syntheses for glycans with (1,2)-glycosidic linkages. Notably, the improved accessibility to these glycan motifs allowed us to discover that the α(1,2)-d-mannobioside could significantly enhance LPS-induced nitric oxide production in macrophages, suggesting its potential use as an immunomodulator and implying the existence of an unknown pathway or receptor responsible for this effect.
... Mycobacterium spp also. It is hypothesized that ManLAM attaches to the Glycosylphosphatidylinositol (GPI) anchor present on the surface of the cell wall of the bacteria and reduces phagolysosomal maturation (Zhou et al. 2019;Turner & Torrelles 2018;Sweet et al. 2010;Welin et al., 2008). There are different reports depicting different modes of action of ManLAM for inhibiting phagolysosomal fusion. ...
Mycobacterium tuberculosis (Mt.b), a deadly disease causer, is a facultative parasite. This microorganism has developed several methods to defend itself, once internalized within specialised vacuoles in the macrophages. A wide array of receptors like the complement receptor mannose receptors, scavenger receptor assists the entry of the microbe within the phagocytic macrophages. However, Mt.b is clever enough to protect itself from the hostile environment of the macrophage thereby prevailing within it. The microbe can efficiently inhibit processes like phagosome-lysosome fusion, acidification of phagosomes, release of proinflammatory cytokines and stop crucial events like apoptosis. Additionally, it also adopts resistance to killing by reactive oxygen intermediates and reactive nitrogen intermediates. There are multiple genes both in host and the pathogen which are involved in this successful survival of Mt.b. The regulation of phagolysosome fusion is mediated by proteins such as Coronin, TlyA, SapM, PnkG, EsxH. The microbe has certain mechanisms to even acquire iron from the host cell, to withstand iron deprivation as a mode of host’s defence mechanism. This review focuses on the various defensive adaptations acquired by Mt.b for fighting against the deprived conditions existing within the macrophages and their capability of proliferating successfully within it, thereby resulting in a diseased condition.
... LAM and ManLAM are also involved in the escape through their interaction with DC-SIGN and the mannose receptor. The interactions with these receptors inhibit the release of pro-inflammatory cytokines such as IL-12, TNF-α, and IL-6 while boosting the release of anti-inflammatory IL-10 [51][52][53]. Importantly, ManLAM inhibits phagosome maturation once the bacteria are engulfed and allows the insertion of bacteria into macrophage membranes [54]. The binding of LAM to lactosylceramide (LacCer)-enriched lipid domains will lead to phagocytosis of the neutrophils. ...
Emerging pharmacological strategies that target major virulence factors of antibiotic-resistant Mycobacterium tuberculosis (Mtb) are presented and discussed. This review is divided into three parts corresponding to structures and functions important for Mtb pathogenicity: the cell wall, the lipoarabinomannan, and the secretory proteins. Within the cell wall, we further focus on three biopolymeric sub-components: mycolic acids, arabinogalactan, and peptidoglycan. We present a comprehensive overview of drugs and drug candidates that target cell walls, envelopes, and secretory systems. An understanding at a molecular level of Mtb pathogenesis is provided, and potential future directions in therapeutic strategies are suggested to access new drugs to combat the growing global threat of antibiotic-resistant Mtb infection.
... embC (Rv3793) encode arabinosyltransferase for polymerizing arabinose into arabinan to form LAM [44]. LAM is an immunomodulator that causes phagosome maturation arrest, blocks oxidative response, modulates host cell signaling, influences cytokine production, alters T cell-mediated immunity, and affects Antibiotics 2023, 12, 852 3 of 16 antibody production [45,46]. Furthermore, LAM is modulated during infection, and a defect in LAM decreases disease progression [36,47]. ...
... Moreover, mycobacterial adaptation and non-replicating state are associated with antibiotic tolerance, as presented in stress models and TB patients [8][9][10][12][13][14]. encode arabinosyltransferase for polymerizing arabinose into arabinan to form LAM [44]. LAM is an immunomodulator that causes phagosome maturation arrest, blocks oxidative response, modulates host cell signaling, influences cytokine production, alters T cell-mediated immunity, and affects antibody production [45,46]. Furthermore, LAM is modulated during infection, and a defect in LAM decreases disease progression [36,47]. ...
Isoniazid (INH) is an antibiotic that is widely used to treat tuberculosis (TB). Adaptation to environmental stress is a survival strategy for Mycobacterium tuberculosis and is associated with antibiotic resistance development. Here, mycobacterial adaptation following INH treatment was studied using a multi-stress system (MS), which mimics host-derived stress. Mtb H37Rv (drug-susceptible), mono-isoniazid resistant (INH-R), mono-rifampicin resistant (RIF-R), and multidrug-resistant (MDR) strains were cultivated in the MS with or without INH. The expression of stress-response genes (hspX, tgs1, icl1, and sigE) and lipoarabinomannan (LAM)-related genes (pimB, mptA, mptC, dprE1, dprE2, and embC), which play important roles in the host–pathogen interaction, were measured using real-time PCR. The different adaptations of the drug-resistant (DR) and drug-susceptible (DS) strains were presented in this work. icl1 and dprE1 were up-regulated in the DR strains in the MS, implying their roles as markers of virulence and potential drug targets. In the presence of INH, hspX, tgs1, and sigE were up-regulated in the INH-R and RIF-R strains, while icl1 and LAM-related genes were up-regulated in the H37Rv strain. This study demonstrates the complexity of mycobacterial adaptation through stress response regulation and LAM expression in response to INH under the MS, which could potentially be applied for TB treatment and monitoring in the future.
... Host resistance to M. tuberculosis requires a combination of innate and adaptive responses, which are essential for protection against infection (Mayer-Barber and Barber, 2015;Zhou et al., 2019). The protective response of T cells in M. tuberculosis infection is usually derived from helper 1 T cells (Th1/CD4 + T lymphocytes) producing cytokines such as IFN-γ or TNF-α, which contribute to the recruitment of monocytes and granulocytes, stimulating the antimicrobial activity of macrophages (Walzl et al., 2011). ...
TNF-α is a Th1 cytokine profile active in the control of Mycobacterium tuberculosis infection, IL-10 is associated with persistence of bacterial infection. The aim of the study was to investigate the association of TNFA -308G/A and IL10 -819C/T polymorphisms and TNFA and IL10 gene expression levels with pulmonary and extrapulmonary tuberculosis (n = 200) and control (n = 200). The individuals were submitted to genotyping and quantification of gene expression performed by real-time quantitative polymerase chain reaction (qPCR). No association was observed between the frequencies of polymorphisms evaluated and pulmonary tuberculosis. The frequency of polymorphic genotypes for TNFA -308G/A were associated with the extrapulmonary tuberculosis (p = 0.0445). The levels of TNFA expression were lower in the pulmonary tuberculosis group than in the control (p = 0.0009). There was a positive correlation between the levels of TNFA and IL10 in patients with pulmonary tuberculosis (r = 0.560; p = 0.0103). Reduced levels of TNFA expression may promote the formation of an anti-inflammatory microenvironment, favoring the persistence of the bacillus in the host, contributing to the establishment of pulmonary tuberculosis.
... CD8 T cells could identify mycobacterium-infected macrophages, and these macrophages are attacked by enzymes secreted by CD8 T cells, which directly protect against M. tb (40). After immunization with BCG, B cell activation in serum increases, and IgG against M. tb increases significantly (42,43). These antibodies can also form bacterial-antibody complexes that can induce increased M. tb processing and antigen presentation by antigen-presenting cells (APCs) to CD4T cells, leading to increased CD8 T cell activation and cytotoxic responses to M. tb (43,44). ...
... After immunization with BCG, B cell activation in serum increases, and IgG against M. tb increases significantly (42,43). These antibodies can also form bacterial-antibody complexes that can induce increased M. tb processing and antigen presentation by antigen-presenting cells (APCs) to CD4T cells, leading to increased CD8 T cell activation and cytotoxic responses to M. tb (43,44). ...
Bacille Calmette-Guérin (BCG) is the only approved vaccine for tuberculosis (TB) prevention worldwide. BCG has an excellent protective effect on miliary tuberculosis and tuberculous meningitis in children or infants. Interestingly, a growing number of studies have shown that BCG vaccination can induce nonspecific and specific immunity to fight against other respiratory disease pathogens, including SARS-CoV-2. The continuous emergence of variants of SARS-CoV-2 makes the protective efficiency of COVID-19-specific vaccines an unprecedented challenge. Therefore, it has been hypothesized that BCG-induced trained immunity might protect against COVID-19 infection. This study comprehensively described BCG-induced nonspecific and specific immunity and the mechanism of trained immunity. In addition, this study also reviewed the research on BCG revaccination to prevent TB, the impact of BCG on other non-tuberculous diseases, and the clinical trials of BCG to prevent COVID-19 infection. These data will provide new evidence to confirm the hypotheses mentioned above.
... ManLAM'nin T hücrelerinin aktivasyonunu/çoğalmasını doğrudan engellediği ve T hücreler tarafından salınan spesifik sitokinleri modüle ettikleri gösterilmiştir (13). ManLAM, genellikle makrofajlar ve DH'ler üzerinde eksprese edilen patern tanıma reseptörleri (PRR'ler) tarafından tanınır (16). Yapılan çalışmalarda ManLAM'nin başlangıçta makrofajlardan, TNF, IL-6 ve IL-12 gibi proenflamatuvar sitokinlerin (15), ayrıca DH'lerden anti-enflamatuvar özellikte olan IL-10 ve IL-2 sitokinlerinin de salınımını uyardığı bildirilmiştir (17). ...
... Yapılan çalışmalarda ManLAM'nin başlangıçta makrofajlardan, TNF, IL-6 ve IL-12 gibi proenflamatuvar sitokinlerin (15), ayrıca DH'lerden anti-enflamatuvar özellikte olan IL-10 ve IL-2 sitokinlerinin de salınımını uyardığı bildirilmiştir (17). Makrofajlar tarafından fagosite edilen basilin yüzeyinden ManLAM konak hücre içerisinde salınır ve enfekte makrofajların endomembranları arasına girerek fagozomal olgunlaşmayı inhibe eder (16). ...
... LAM is a lipoglycan that serves as a potent virulence factor that modulates the host immune response and plays an important role in the pathogenesis of Mtb infection [27,28]. Virulent Mtb and M. bovis species express mannose-capped LAM [29]. LAM-guided anti-TB treatment in HIV-TB patients seems associated with decreased mortality [30]. ...
For the rapid, reliable, and cost-effective methods of tuberculosis (TB) auxiliary diagnosis, antibody (Ab) detection to multiple antigens of Mycobacterium tuberculosis (Mtb) has great potential; however, this methodology requires optimization. We constructed 38KD-MPT32-MPT64, CFP10-Mtb81-EspC, and Ag85B-HBHA fusion proteins and evaluated the serum Ab response to these fusion proteins and to lipoarabinomannan (LAM) by ELISA in 50 TB patients and 17 non-TB subjects. IgG responses to the three fusion proteins and to LAM were significantly higher in TB patients, especially in Xpert Mtb-positive TB patients (TB-Xpert+), than in non-TB subjects. Only the anti-38KD-MPT32-MPT64 Ab showed higher levels in the Xpert Mtb-negative TB patients (TB-Xpert−) than in the non-TB, and only the anti-LAM Ab showed higher levels in the TB-Xpert+ group than in the TB-Xpert− group. Anti-Ag85B-HBHA Ab-positive samples could be accurately identified using 38KD-MPT32-MPT64. The combination of 38KD-MPT32-MPT64, CFP10-Mtb81-EspC, and LAM conferred definite complementarity for the serum IgG detection of TB, with relatively high sensitivity (74.0%) and specificity (88.2%). These data suggest that the combination of 38KD-MPT32-MPT64, CFP10-Mtb81-EspC, and LAM antigens provided a basis for IgG detection and for evaluation of the humoral immune response in patients with TB.
