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Cord factor

Cord factor, also known as trehalose 6,6'-dimycolate (TDM), is a glycolipid constituent of the cell walls of pathogenic mycobacteria, including Mycobacterium tuberculosis.^[1] It comprises a trehalose disaccharide esterified at the 6 and 6' positions with two long-chain, branched mycolic acids, typically exceeding 70 carbon atoms in length.^[2] This structure enables the formation of serpentine, cord-like bacterial aggregates, a hallmark morphological feature first observed in virulent strains and responsible for the compound's name.^[1] As a key virulence factor, cord factor promotes mycobacterial survival within host macrophages by inhibiting phagosome-lysosome fusion and delaying phagosome maturation.^[3] It elicits granuloma formation, the characteristic host response to tuberculosis, through activation of the Syk-Card9 signaling pathway following recognition by the C-type lectin receptor Mincle on innate immune cells.^[1] Additionally, cord factor stimulates production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) while contributing to the impermeability of the mycobacterial envelope, which underlies resistance to antibiotics and host defenses.^[2] Historically isolated in the 1950s from M. tuberculosis extracts, cord factor has been implicated in various pathological processes, including primary and secondary tuberculosis progression, lipid pneumonia, and cavitary lesion maintenance that facilitates bacterial transmission.^[3] Strains deficient in cord factor, whether through extraction or genetic mutation, exhibit reduced virulence and fail to induce typical granulomatous inflammation in animal models.^[1] Its dual role as both immunostimulatory and immunosuppressive underscores its importance in the complex interplay between mycobacteria and the host immune system.^[4]

Discovery and Nomenclature

Historical Background

The characteristic serpentine cord formation in virulent strains of Mycobacterium tuberculosis was first systematically described in 1947 by Gardner Middlebrook and colleagues, who observed these microscopic arrangements of bacterial cells during studies on the morphological differences between virulent and avirulent tubercle bacilli. Through microscopic examination of liquid cultures, they noted that highly virulent strains consistently formed elongated, rope-like cords composed of parallel chains of bacilli, while avirulent variants grew in dispersed or clumped patterns without such structures. This observation led Middlebrook to propose that cord formation was an essential marker of virulence, correlating directly with the pathogen's ability to cause disease in animal models. Building on this, Hubert Bloch isolated a lipid component responsible for inducing cord formation in 1950, extracting it from the cell walls of virulent M. tuberculosis strains using organic solvents. When this lipid extract, termed "cord factor," was added to cultures of non-cord-forming (avirulent) mycobacteria, it prompted the rapid assembly of serpentine cords, confirming its role in mediating this morphological phenotype. Bloch's experiments demonstrated that the factor was absent or minimal in avirulent strains, highlighting its specificity to pathogenic mycobacteria and its potential as a virulence determinant. Early investigations into cord factor's pathogenic implications involved injecting the lipid extract into laboratory animals, revealing its capacity to elicit granulomatous responses akin to those in tuberculosis infection. In mice and rabbits, subcutaneous or intravenous administration of cord factor produced localized chronic inflammation, weight loss, and the development of granuloma-like lesions in the lungs, liver, and other organs, mimicking aspects of mycobacterial disease progression. These findings linked cord factor to the induction of persistent inflammatory foci, underscoring its contribution to the host-pathogen interaction in early tuberculosis pathogenesis. Subsequent chemical analysis in 1956 identified cord factor as trehalose dimycolate, a glycolipid composed of trehalose esterified with mycolic acids.^[5]

Naming and Synonyms

Cord factor was originally named by Hubert Bloch in 1950 for a lipid fraction extracted from virulent strains of Mycobacterium tuberculosis that promoted the formation of serpentine, cord-like bacterial aggregates observable under microscopy, a morphology linked to enhanced pathogenicity. This designation reflected the distinctive "cording" phenomenon, where bacilli align in parallel chains, distinguishing virulent tubercle bacilli from avirulent variants.^[6] In 1956, detailed chemical characterization by Noll, Bloch, Asselineau, and Lederer revealed the structure of this lipid as trehalose 6,6'-dimycolate (TDM), a glycolipid composed of trehalose esterified with two mycolic acid chains, thereby establishing TDM as its primary chemical synonym. This elucidation confirmed the substance's role in mycobacterial cell wall composition and solidified the nomenclature in subsequent biochemical studies. Alternative designations such as trehalose dimycolate or simply dimycolate are commonly employed in scientific literature to emphasize its glycolipid nature, while "mycobacterial cord factor" is used to denote its occurrence in non-tuberculous species, including Mycobacterium leprae and other environmental mycobacteria.^[7] These synonyms highlight the compound's broader distribution across the genus Mycobacterium beyond tuberculosis pathogens.^[8]

Chemical Structure and Properties

Molecular Composition

Cord factor, chemically known as trehalose 6,6'-dimycolate (TDM), is a glycolipid characterized by a central trehalose moiety—a non-reducing disaccharide composed of two D-glucose units connected via an α,α-1,1-glycosidic bond—esterified at the 6 and 6' hydroxyl positions with two molecules of mycolic acid.^[9] This esterification links the hydrophilic trehalose head to the hydrophobic mycolic acid tails, defining its amphipathic nature as a key component of the mycobacterial cell envelope.^[10] Mycolic acids, the lipid components of cord factor, are exceptionally long-chain α-branched β-hydroxy fatty acids, typically spanning 70 to 90 carbon atoms in total length, with a shorter α-alkyl branch (C22–C26) and a longer meromycolic chain (C40–C60).^[11] These acids feature a conserved β-hydroxy group essential for ester bond formation and exhibit species-specific variations in the meromycolic chain, including functional groups such as cis- or trans-cyclopropane rings, double bonds in α-mycolates, methoxy groups in methoxy-mycolates, and keto groups in keto-mycolates, which contribute to structural diversity across Mycobacterium species.^[11] For instance, in Mycobacterium tuberculosis, the predominant pathogen, α-, methoxy-, and keto-mycolates predominate, influencing the overall composition of cord factor.^[11] Due to this heterogeneity in mycolic acid chains and functional groups, the molecular formula of cord factor is variable but can be approximated as C_{186}H_{366}O_{17} for a representative structure, underscoring its classification as a high-molecular-weight glycolipid with significant lipid content.^[9]

Physical and Chemical Characteristics

Cord factor, also known as trehalose 6,6'-dimycolate (TDM), exhibits pronounced hydrophobicity primarily due to its long-chain mycolic acid moieties, which render it poorly soluble in water but highly soluble in organic solvents such as chloroform and methanol mixtures.^[12] This amphiphilic character arises from the polar trehalose headgroup contrasted against the nonpolar mycolic acid tails, enabling TDM to self-assemble in different environments.^[13] In aqueous media, TDM forms micelles with the hydrophilic trehalose oriented outward and hydrophobic mycolic acids sequestered internally, while on hydrophobic surfaces like air-water or oil-water interfaces, it organizes into rigid, crystalline monolayers that are more stable than those formed by other biological amphiphiles.^[3] These monolayer formations contribute significantly to the impermeability of the mycobacterial cell wall by creating a robust barrier against aqueous penetration.^[13] Under physiological conditions, TDM demonstrates high stability, including resistance to hydrolysis, as it requires harsh alkaline conditions to break down into two mycolic acid molecules and one trehalose unit.^[13] Furthermore, TDM plays a key role in constructing the asymmetrical outer membrane bilayer of mycobacteria, where it intercalates with lipoarabinomannan to form a structured, impermeable layer that enhances overall membrane integrity.^[3] Variations in mycolic acid chain lengths and unsaturations further modulate these biophysical properties.^[12]

Biosynthesis and Distribution

Biosynthetic Pathway

The biosynthesis of cord factor, also known as trehalose 6,6'-dimycolate (TDM), in mycobacteria commences with the production of trehalose, a disaccharide essential for the glycolipid's structure. Trehalose is primarily synthesized via the OtsA-OtsB pathway, where OtsA (trehalose-6-phosphate synthase) condenses UDP-glucose and glucose-6-phosphate to form trehalose-6-phosphate, which is then dephosphorylated by OtsB (trehalose-6-phosphate phosphatase). Mycobacteria also utilize the TreY/TreZ pathway, where the enzyme TreY (maltooligosyltrehalose synthase) catalyzes the conversion of the nonreducing terminal α-1,4-linked glucose residues in glycogen-like α-glucans into an α-1,1-linked trehalose moiety attached to a maltooligosyl chain, and TreZ (maltooligosyltrehalose trehalohydrolase) subsequently hydrolyzes the chain to release free trehalose. A third pathway involves TreS (trehalose synthase) converting maltose to trehalose. The OtsA-OtsB pathway predominates in mycobacteria, including Mycobacterium tuberculosis, while TreY/TreZ is active under conditions where glycogen serves as a glucose reservoir, providing the trehalose backbone for TDM assembly.^[14] Parallel to trehalose synthesis, mycolic acids—the long-chain fatty acids characteristic of mycobacterial cell walls—are produced through a dedicated polyketide synthase (PKS) machinery. The process involves iterative elongation of meromycolic acid chains by the multifunctional PKS13 enzyme complex, with activation of the meromycolic acid substrate occurring via FadD32, an acyl-AMP ligase that forms a high-energy acyl-adenylate (acyl-AMP) intermediate to facilitate chain condensation with an α-alkyl branch derived from shorter fatty acids. This activation step is critical, as FadD32 ensures the efficient incorporation of mycolic acids into glycolipids like TDM, and its disruption halts mycolic acid biosynthesis entirely.^[15] The assembly of TDM occurs through esterification of two mycolic acid molecules to the 6- and 6'-hydroxyl positions of trehalose, catalyzed primarily by the antigen 85 (Ag85) complex of mycolyltransferases (Ag85A, Ag85B, and Ag85C). The reaction proceeds in two stages: first, Ag85 transfers a mycolic acid from an activated donor (such as cell wall-bound mycolates) to the 6-position of trehalose, yielding trehalose monomycolate (TMM); second, another mycolic acid is transferred from TMM to the 6'-position of a second TMM molecule, forming the symmetric TDM.^[16] The Ag85 enzymes, belonging to the α/β hydrolase family, utilize a catalytic serine residue to mediate these transacylation reactions in the periplasmic space.^[17] Prior to or concurrent with transfer, mycolic acids undergo modifications such as cyclopropanation by enzymes like MmaA4 (cyclopropanase), which introduces trans-cyclopropane rings to fine-tune TDM's immunostimulatory properties; mutants lacking MmaA4 (ΔmmaA4) produce TDM with altered mycolic acid composition, resulting in reduced levels of oxygenated distal modifications and diminished virulence without substantially depleting overall TDM abundance.^[18] Genetic regulation of TDM biosynthesis is linked to environmental stresses, particularly in virulent strains like Mycobacterium tuberculosis, with adaptations in cell envelope remodeling under hypoxic conditions supporting persistence and cord formation. This ensures adaptive changes in the mycobacterial cell wall, with ΔmmaA4 mutants exhibiting perturbed TDM profiles that impair survival in low-oxygen environments.^[19]

Occurrence in Mycobacteria

Cord factor, also known as trehalose 6,6'-dimycolate (TDM), is a major component of the mycobacterial cell envelope, present in the outer monolayer across all species of the genus Mycobacterium. In the pathogenic species Mycobacterium tuberculosis, TDM is particularly abundant, representing the most prominent extractable lipid and comprising approximately 2% of the total bacterial dry weight.^[20] This glycolipid is essential for the virulent phenotype in laboratory strains such as H37Rv, where it facilitates the organized aggregation of bacilli into serpentine cords visible under microscopy, a trait linked to enhanced survival and persistence in host environments.^[6] TDM is conserved in non-tuberculous mycobacteria (NTM), including opportunistic pathogens like Mycobacterium avium and Mycobacterium kansasii, but exhibits species-specific variations in its mycolate moieties—the long-chain fatty acids esterified to the trehalose core. These mycolate profiles differ in chain length, branching, and functional groups such as cyclopropanes or hydroxyls, which modulate the glycolipid's ability to promote cord formation and influence overall envelope permeability.^[21] For instance, in M. avium, TDM contributes to biofilm-like structures and immune evasion, while in M. kansasii, the more oxygenated mycolates correlate with moderate cording and pulmonary pathogenicity, though less pronounced than in M. tuberculosis.^[22] In contrast, avirulent, saprophytic species such as Mycobacterium smegmatis produce TDM at notably lower levels compared to virulent counterparts under similar conditions. The shorter, less complex mycolic acids in M. smegmatis TDM prevent effective intermolecular interactions required for cord assembly, aligning with its non-pathogenic lifestyle and lack of tissue invasion potential.^[23] This reduced presence and structural deviation underscore TDM's role in species-specific adaptations within the mycobacterial phylogeny.^[20]

Pathogenic Roles

Virulence Mechanisms

Cord factor, also known as trehalose dimycolate (TDM), plays a critical role in the intracellular survival of Mycobacterium tuberculosis by interfering with phagosome maturation in host macrophages. Specifically, TDM inhibits the fusion of phagosomes containing the bacteria with lysosomes, preventing acidification and degradation of the pathogen within the phagolysosome. This mechanism allows M. tuberculosis to persist intracellularly, evading lysosomal killing and promoting bacterial replication inside the host cell. Studies have demonstrated that TDM disrupts normal trafficking events, including interactions with SNARE proteins, which are essential for phagosome-lysosome fusion.^[24]^[25] In animal models of tuberculosis, TDM contributes significantly to bacterial virulence and survival. Mutants deficient in TDM production or modification exhibit markedly reduced pathogenicity. For instance, the M. tuberculosis ΔmmaA4 strain, which lacks proper oxygenation of mycolic acids incorporated into TDM, shows attenuated growth in mouse lungs. This attenuation leads to prolonged host survival, with infected mice living up to 450 days versus 225 days for wild-type infections, highlighting TDM's essential role in establishing persistent infection.^[26] TDM also modulates host cell death pathways to favor bacterial persistence. By upregulating anti-apoptotic proteins such as Bcl-2 in macrophages, TDM inhibits pro-inflammatory apoptosis, which would otherwise promote antigen presentation and immune activation. This shift allows infected cells to survive longer, reducing immune clearance and enabling M. tuberculosis to replicate without triggering robust adaptive responses. Such modulation supports the pathogen's strategy to maintain a non-inflammatory environment conducive to chronic infection.^[27]

Cord Formation and Toxicity

Cord factor, or trehalose 6,6'-dimycolate (TDM), induces the characteristic serpentine cord structures in virulent mycobacteria through hydrophobic interactions between the long-chain mycolic acid moieties esterified to the trehalose core. These interactions dominate the molecular surface, with mycolic acids comprising approximately 70% of the exposed area, promoting linear aggregation of bacterial cells into stable, rope-like formations that enhance persistence in host environments.^[28] This cording phenotype is prominently observed in virulent strains such as Mycobacterium tuberculosis H37Rv under nutrient-rich conditions, such as saline media, where TDM facilitates cell alignment and biofilm-like organization. In contrast, avirulent or saprophytic strains exhibit reduced cording due to alterations in TDM composition, underscoring its role as a virulence determinant.^[20] In its monolayer configuration, cord factor exerts potent cytotoxicity on host macrophages by disrupting mitochondrial function, leading to impaired electron transport and subsequent cell death.^[13] This toxicity integrates TDM into cellular membranes, inducing swelling and loss of mitochondrial integrity, which compromises energy production and triggers necrotic pathways.^[29] The monolayer presentation is critical, as it exposes the hydrophobic mycolic tails to interact directly with host lipid bilayers, amplifying damage compared to micellar forms that are relatively inert. The dependency on mycolic acid chain length further modulates both cord stability and toxicity, with longer chains (>C60) in virulent mycobacteria enhancing these effects relative to shorter variants in saprophytes.^[30] Virulent strains feature mycolic acids of 60–90 carbons, often oxygenated, which promote tighter hydrophobic packing in TDM, stabilizing cord architectures and increasing membrane-disruptive potential against macrophages.^[30] Saprophytic species, with chains typically limited to 60–62 carbons, produce less stable cords and exhibit diminished toxicity, highlighting how chain elongation correlates with enhanced pathogenicity.^[30]

Host Immune Interactions

Recognition by Host Receptors

Cord factor, also known as trehalose-6,6'-dimycolate (TDM), is primarily recognized by the host immune system through the C-type lectin receptor Mincle (encoded by CLEC4E), a pattern recognition receptor expressed on myeloid cells such as macrophages and dendritic cells. Mincle directly binds the trehalose-mycolate motif of TDM with high affinity, enabling specific detection of this mycobacterial glycolipid on the bacterial cell surface.^[31] This interaction is calcium-dependent and involves the carbohydrate recognition domain of Mincle, where the trehalose head group coordinates with a conserved Ca²⁺ ion via an EPN motif, while the mycolate lipid tails engage hydrophobic pockets in the receptor.^[32] Upon binding TDM, Mincle associates with the Fc receptor γ-chain (FcRγ) to recruit and activate the spleen tyrosine kinase (SYK), initiating downstream signaling through the CARD9 adaptor protein and leading to NF-κB and NFAT activation.^[33] This pathway is enhanced by cooperative interactions with other host receptors, including Toll-like receptor 2 (TLR2), which senses mycobacterial lipoproteins and amplifies Mincle-mediated responses in macrophages, and DC-SIGN (CD209), which can facilitate TDM presentation on dendritic cells to promote SYK-dependent signaling.^[34] Such synergies ensure robust innate immune activation without relying solely on Mincle, particularly in diverse cellular contexts. The molecular details of Mincle-TDM recognition have been elucidated by crystal structures of Mincle ectodomains complexed with TDM analogs or related ligands, reported in 2013 studies, which highlight key residues like Arg183 for lipid anchoring and explain the receptor's specificity for trehalose-based glycolipids.^[32] Evolutionarily, Mincle is conserved across mammals, but human polymorphisms in CLEC4E, such as single nucleotide variants rs10841845 and rs10841847, modulate receptor function and are associated with altered susceptibility to tuberculosis, with certain alleles conferring protection against pulmonary infection in population studies.^[35] These genetic variations underscore Mincle's role in host-pathogen adaptation. This initial recognition by Mincle primes pathways that culminate in cytokine release, contributing to antimycobacterial defenses.^[36]

Cytokine Responses and Pathological Effects

Cord factor, or trehalose 6,6'-dimycolate (TDM), triggers rapid upregulation of pro-inflammatory cytokines in host cells following exposure. In murine macrophages, TNF-α expression increases approximately 3-fold within 2 hours of TDM stimulation and remains elevated at 24 hours, contributing to the initiation of inflammatory cascades.^[37] Similarly, IL-6 and IL-12 production is induced in macrophages and dendritic cells, peaking within the first 24 hours and promoting the recruitment of immune cells essential for granuloma formation.^[38]^[39] These cytokines drive the organization of granulomatous structures in the lungs, mimicking early pathological responses in tuberculosis.^[40] In mouse models, TDM exposure leads to distinct pathological effects, including cachexia mediated by TNF-α, characterized by significant body weight loss and systemic wasting.^[41] Thymic atrophy occurs through apoptosis of thymocytes, reducing thymus size and impairing T-cell development.^[42] Neutrophilic inflammation is prominent in the lungs, with neutrophils enhancing granuloma formation and exacerbating tissue damage via Mincle-dependent signaling.^[43] Genome-wide analysis reveals 125 genes upregulated more than 1.5-fold (P < 0.05) at 2 hours post-exposure, expanding to 503 genes by 24 hours, reflecting a broadening inflammatory transcriptome.^[37] TDM contributes to chronic inflammation in tuberculosis by sustaining cytokine-driven responses that perpetuate granulomatous pathology.^[39] When injected intraperitoneally and intravenously in mice, purified TDM elicits lung inflammation, vascular occlusion, hemorrhage, and granuloma-like structures that closely resemble those in active Mycobacterium tuberculosis infection, including hypercoagulopathy and long-term tissue remodeling.^[44] This model demonstrates TDM's potency, as low doses (10 μg) suffice to induce sustained leukocyte infiltration and elevated levels of IL-10, IL-12p40, and granulocyte-macrophage colony-stimulating factor, underscoring its role in mimicking full infection outcomes.^[45]

Biomedical Applications

Research Tools

Cord factor, also known as trehalose 6,6'-dimycolate (TDM), serves as a key experimental reagent in laboratory research on mycobacterial interactions with host cells, particularly through its incorporation into model systems that replicate aspects of the bacterial cell wall. Researchers coat hydrophobic latex or polystyrene beads with purified TDM extracted from mycobacteria such as Mycobacterium smegmatis or M. tuberculosis to simulate the glycolipid-rich outer envelope, enabling controlled studies of adhesion, uptake, and phagosome dynamics in macrophages. For instance, TDM-coated beads delay phagosome maturation by retaining early endosomal markers like the transferrin receptor while slowing acquisition of lysosomal markers such as LAMP1, mirroring the intracellular survival strategies of live mycobacteria.^[46]^[47] These bead models have been instrumental in dissecting receptor-mediated phagocytosis, revealing that TDM promotes Fcγ receptor engagement and Mincle-dependent uptake without altering surface marker expression on macrophages like MHCII or CD80.^[25] TDM can also be formulated into liposomes, forming stable lipid vesicles that incorporate the glycolipid alongside other mycobacterial lipids or phospholipids to more closely model the fluid mosaic structure of the mycomembrane. These TDM liposomes facilitate adhesion and uptake assays by providing a three-dimensional, curved surface that promotes interactions with host pattern recognition receptors, allowing quantitative assessment of internalization rates in cell lines such as RAW264.7 macrophages. Unlike rigid beads, liposomal models better capture the dynamic fluidity of mycobacterial envelopes, aiding investigations into how TDM influences membrane rigidity and endocytic trafficking during host-pathogen encounters.^[12]^[48] Synthetic analogs of TDM, featuring precisely defined mycolate chain lengths (e.g., C22-C26 saturated or branched variants), have been developed to probe ligand-receptor interactions in binding assays, offering greater control over structural variables than natural extracts. These analogs, such as trehalose dibehenate (TDB) or acylated trehalose esters with uniform acyl chains, bind avidly to the C-type lectin receptor Mincle on macrophages, with dissociation constants in the micromolar range, as determined by surface plasmon resonance and reporter cell assays. Such tools have elucidated the minimal structural requirements for Mincle activation, showing that shorter mycolate chains reduce binding affinity while maintaining glycolipid presentation.^[49]^[50]^[51] In proteomics applications, TDM-coated surfaces or clickable photocrosslinking probes enable the isolation and identification of host interacting proteins, with established protocols dating back to the early 2000s for bead-based pull-downs and evolving into advanced chemical proteomics by the 2010s. For example, TDM immobilized on beads or magnetic surfaces captures Mincle and associated adaptor proteins like FcRγ from macrophage lysates, followed by mass spectrometry to map interaction networks; more recently, photoactivatable TDM mimics have identified SNARE proteins (e.g., VAMP3, syntaxin-6) as direct binders that regulate phagosome fusion. These methods, often using label-free quantification, have revealed over 800 differentially regulated host proteins in TDM-exposed cells, prioritizing those involved in endosomal trafficking and inflammation.^[52]^[24] TDM tools also briefly reference granuloma-like structures in vitro, linking protein isolations to downstream pathological effects.^[53]

Therapeutic and Diagnostic Uses

Cord factor, also known as trehalose 6,6'-dimycolate (TDM), has shown promise as an adjuvant in vaccine formulations due to its ability to enhance Th1 immune responses. In tuberculosis (TB) vaccines, synthetic analogues like trehalose 6,6'-dibehenate (TDB) incorporated into cationic liposomes (e.g., CAF01) stimulate robust Th1 and Th17 T cell responses when combined with subunit antigens such as H1, providing protection against Mycobacterium tuberculosis challenge comparable to BCG in mouse models.^[54] This adjuvanticity is mediated through Mincle receptor activation and FcRγ–Syk–Card9 signaling, promoting antigen-specific IFN-γ production and lung-resident memory T cells.^[55] In BCG-based formulations, TDB boosts Th1/Th17 responses, improving overall vaccine efficacy against TB.^[56] For cancer applications, mycolic acid components of TDM induce Th1-biased responses with IL-12 and IFN-γ production in tumor vaccination models, suppressing tumor growth and enhancing cytotoxic T lymphocyte activity in preventive and therapeutic settings using ovalbumin antigens in mice.^[57] Clinical evaluation of TDM analogues in adjuvants like CAF01 has advanced to phase I trials for TB subunit vaccines post-2015, demonstrating strong Th1 responses with minimal adverse effects in humans.^[55] As a diagnostic marker, TDM and its mycolic acid constituents can be detected in sputum using liquid chromatography-mass spectrometry (LC-MS), offering a sensitive approach to identify M. tuberculosis infection. This method achieves 94% sensitivity and 93% specificity for mycolic acids in adult TB sputum samples, enabling distinction of virulent strains based on lipid profiles such as alpha-, methoxy-, and keto-mycolic acid variants that differ across mycobacterial species.^[58] Untargeted mass spectrometry further reveals TDM-related biomarkers in clinical samples, supporting rapid TB diagnosis even in low-burden pediatric cases where sputum is limited.^[59] Compared to acid-fast bacilli (AFB) staining, which has only 23% positivity in children and moderate sensitivity in adults, mass spectrometry-based TDM detection provides superior accuracy without relying on bacterial morphology or viable counts.^[58] Therapeutic targeting of TDM focuses on disrupting its interactions to mitigate granuloma pathology in TB. Small molecule hybrids like isoniazid-nicotinic acid derivatives (e.g., INH-D2) inhibit TDM-induced inflammation by blocking Syk/PI3K pathways, reducing TNF-α, IL-6, macrophage infiltration, and hypoxia in mouse lung granuloma models, thereby alleviating pulmonary damage.^[60] Prenylated flavonoids from Sophora flavescens, such as sophoraflavanone G, act as Mincle-Syk-Erk inhibitors to suppress TDM-stimulated cytokine and chemokine production (e.g., TNF-α, IL-6, CCL2), decreasing neutrophil and macrophage recruitment and nearly eliminating granulomas at 200 mg/kg doses in mice.^[61] These approaches exploit TDM's role in excessive inflammation while preserving anti-mycobacterial immunity. For anti-cancer uses, TDM's induction of IL-12 and IFN-γ in tumors supports immune activation, as seen in models where mycolic acid adjuvants limit tumor progression through enhanced Th1 responses.^[57]

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Direct recognition of the mycobacterial glycolipid, trehalose ...
Dec 14, 2009 · Among these, the cord factor is the first immunostimulatory component to be identified that might elicit pulmonary inflammation, a ...
[32]
Toll-Like Receptor 2 and Mincle Cooperatively Sense ...
Jun 20, 2017 · TDM from pathogenic mycobacteria is known as cord factor, based on its role in the clumping of mycobacteria during in vitro culture, and has ...<|control11|><|separator|>
[33]
Association between CLEC4E gene polymorphism of mincle and ...
Aug 20, 2019 · Genetic polymorphisms regulate resistance and susceptibility to tuberculosis. The C-type lectin receptor of family 4 member E (CLEC4E) ...
[34]
Recognition of the mycobacterial cord factor by Mincle
Jan 24, 2013 · Recently, TDM has been shown to activate the Syk-Card9 signaling pathway in macrophages through binding to the C-type lectin receptor Mincle.Missing: affinity KD
[35]
Mycobacterial Trehalose Dimycolate Reprograms Macrophage ...
Trehalose dimycolate induces the regulation of a unique set of macrophage genes. While immunostimulatory effects of TDM are well studied, a comprehensive ...Missing: DosR regulon
[36]
High Secretion of Interleukin-6 and Increased MINCLE Receptor ...
Mar 28, 2018 · Administration of TDM in mice leads to granuloma formation [13], accompanied by a cascade of pro-inflammatory cytokine production that includes ...
[37]
Granulomas and Inflammation: Host-Directed Therapies ... - Frontiers
The TDM-driven granulomatous response is initiated and maintained by pro-inflammatory cytokines (TNF-α and IL-6) and complement C5 and can be down modulated by ...
[38]
Cytokine message and protein expression during lung granuloma ...
Trehalose-6,6'-dimycolate (TDM), or cord factor, is a mycobacterial cell wall component that induces granuloma formation and proinflammatory cytokine ...
[39]
Tumor necrosis factor (cachectin) mediates induction of cachexia by ...
The mechanism by which cord factor (CF), a toxic glycolipid from mycobacteria, induces cachexia was studied in BALB/c mice. Body weight was markedly reduced ...
[40]
In vivo induction of apoptosis in the thymus by administration of ...
The present study demonstrated for the first time in vivo induction of apoptosis in the mouse thymus by mycobacterial cord factor (CF) (trehalose 6,6'- ...Missing: TDM | Show results with:TDM<|separator|>
[41]
Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced ...
Trehalose 6,6′-dimycolate (TDM), a cord factor of Mycobacterium tuberculosis (Mtb), is an important regulator of immune responses during Mtb infections.
[42]
Trehalose 6,6-Dimycolate from Mycobacterium tuberculosis Induces ...
Trehalose 6′6-dimycolate (TDM) activates innate inflammation and likely also stimulates chronic inflammation observed during disease progression. Noninfectious ...Missing: DosR regulon<|control11|><|separator|>
[43]
Oral recombinant human or mouse lactoferrin reduces ... - NIH
TDM is capable of inducing granulomatous pathology in mouse models that resembles those induced by MTB infection. Using the acute TDM model, this work ...
[44]
Delay of phagosome maturation by a mycobacterial lipid is reversed ...
Mar 21, 2008 · Here, we report that trehalose dimycolate coated onto beads increased the bead retention in early phagosomes, i.e. at a similar stage as viable ...Missing: isolation | Show results with:isolation
[45]
Trehalose 6,6′-dimycolate on the surface of Mycobacterium ...
Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis -induced inflammation and virulence. J Clin Invest ...
[46]
The liposome of trehalose dimycolate extracted from M. bovis BCG ...
Feb 11, 2021 · The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8 + T cells.
[47]
Defining the conformation of human mincle that interacts with ... - NIH
Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate. J Immunol. 2010;184 ...
[48]
Mechanism for Recognition of an Unusual Mycobacterial Glycolipid ...
... cord factor. It comprises a Glcα1–1Glcα headgroup and two complex ... Both X and Y are mycolic acid in trehalose dimycolate. B, enhancement of the ...Missing: physical organic<|control11|><|separator|>
[49]
Rational design of adjuvants targeting the C-type lectin Mincle | PNAS
Feb 21, 2017 · These data are in agreement with the higher relative magnitude of TLR2 vs. Mincle signaling in BMDMs and moMΦs compared with BMDCs, as ...
[50]
Proteomics of Mycobacterium Infection: Moving towards a Better ...
Jan 30, 2018 · RAW264.7 incubated with Mtb or trehalose-dimycolate-coated beads for 30 min, Label-free, 835, Mitochondria, cytoskeleton, plasma membrane, ER ...
[51]
[PDF] Trehalose dimycolate inhibits phagosome maturation and promotes ...
Dec 16, 2024 · TDM can also impair the host response and promote intracellular mycobacterial survival by inhibiting phagosome maturation and acidification in ...
[52]
Mycobacterial Trehalose Dimycolate Reprograms Macrophage ...
... mycobacterial trehalose dimycolate and Mycobacterium tuberculosis. ... Tumor necrosis factor (cachectin) mediates induction of cachexia by cord factor from ...
[53]
Adjuvanticity of a synthetic cord factor analogue for subunit ... - NIH
H1 antigen was used at 1 μg/ml and 10 μg/ml final concentrations for restimulation. Wells containing medium only or 1 μg/ml ConA were used as negative and ...
[54]
Frontiers | Advancing Adjuvants for Mycobacterium tuberculosis Therapeutics
Summary of each segment:
[55]
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.740117/full
[56]
https://doi.org/10.1371/journal.pone.0053531
[57]
Pediatric Tuberculosis: The Impact of “Omics” on Diagnostics ... - MDPI
... trehalose dimycolate (TDM), phosphatidyl-myo-inositol ... tuberculosis by use of untargeted mass spectrometry reveals novel biomarkers for diagnosis.3.2. Transcriptomics · 3.3. Proteomics · 3.4. Lipidomics<|separator|>
[58]
https://www.mdpi.com/1422-0067/21/19/6979
[59]
https://doi.org/10.1002/emmm.201100185
[60]
Sophora flavescens protects against mycobacterial Trehalose ...
Mar 2, 2018 · Among the MTB cell wall components, trehalose 6,6-dimycolate (TDM), constituting 90–95% of the outer membrane lipids, is the most abundant ...