Detailed structural and functional studies over the last decade have led to current recognition of the mycobacterial lipoarabinomannan (LAM) as a phosphatidylinositol anchored lipoglycan with diverse biological activities. Fatty acylation has been demonstrated to be essential for LAM to maintain its functional integrity although the focus has largely been on the arabinan motifs and the terminal capping function. It has recently been shown that the mannose caps may be involved not only in attenuating host immune response, but also in mediating the binding of mycobacteria to and subsequent entry into macrophages. This may further be linked to an intracellular trafficking pathway through which LAM is thought to be presented by CD1 to subsets of T-cells. The implication of LAM as major histocompatibility complex (MHC)-independent T-cell epitope and the ensuing immune response is an area of intensive studies. Another recent focus of research is the biosynthesis of arabinan which has been shown to be inhibitable by the anti-tuberculosis drug, ethambutol. The phenomenon of truncated LAM as synthesized by ethambutol resistant strains provides an invaluable handle for dissecting the array of arabinosyltransferases involved, as well as generating much needed structural variants for further structural and functional studies. It is hoped that with more systematic investigations based on clinical isolates and human cell lines, the true significance of LAM in the immunopathogenesis of tuberculosis and leprosy can eventually be explained.
Key words: CD1/ethambutol/lipoarabinomannan/lipomannan/mycobacteria/phosphatidylinositol mannosides/tuberculosis
Mycobacteria have evolved many specific adaptations that enable them to infect and survive within specific host cells. Such host-pathogen interactions are mediated by specialized molecules, in particular, those associated with the unique cell envelope. The essence of the mycobacterial cell wall is the mycolyl arabinogalactan-peptidoglycan complex (mAGP) and the associated lipoarabinomannan (LAM) (Brennan and Nikaido, 1995; Figure 1 ). mAGP constitutes the underlying core of the wall proper, whereas LAM has been shown to exert profound physiological effects. We review here our current understanding of the structure, biosynthesis, and function of this extraordinary lipoglycan which is likely to be a key virulence factor and drug target in the treatment of mycobacterial diseases including tuberculosis and leprosy.
The existence of an arabinose- and mannose-containing, serologically active polysaccharide in mycobacterial cell wall was first recognized in the 1930s (Chargaff and Schaefer, 1935; Menzel and Heidelberger, 1939; Seibert and Watson, 1941). Some 20 years later, Tsumita et al. (1960) and then Ohashi (1970), among others, demonstrated that there are two classes of arabinomannan (AM) in M.tuberculosis, namely acylated and nonacylated. Only the [rdquor]macromolecular lipopolysaccharide" type which contains palmitic and tuberculostearic acids was active in the hemagglutination assay.
Despite this observation, the early perception of AM was mainly that of a neutral polysaccharide, propounded by a series of structural studies by Azuma, Misaki, and coworkers (Azuma et al., 1968; Misaki et al., 1977), who also characterized the related arabinogalactan (AG) of mAGP. Working on a polysaccharide fraction isolated by vigorous alkaline extraction, they concluded that AM consists of an [alpha](1 -> 6)-linked D-Manp backbone to which were attached short side chains of [alpha](1 -> 2)linked D-Manp residues and [alpha](1 -> 5)-linked D-Araf residues. In addition, a serologically inactive mannan whose structure may resemble that of the mannan core of AM was also isolated.
In independent work, Weber and Gray (1979) isolated and partially characterized an acidic AM from M.smegmatis which was shown to comprise approximately 56 arabinosyl residues, 11 mannosyl residues, 2 phosphates, 6 monoesterified succinates, and 4 ether linked lactate groups. After saponification, this polysaccharide could be separated into phosphorylated and nonphosphorylated forms, but there was no mention of fatty acylation. The polysaccharide had the ability to precipitate antisera from rabbits immunized with cell walls of M.smegmatis, and it was concluded that both AM and AG shared the common immunodominant epitope, i.e., chains of contiguous [alpha]-(1 -> 5)-linked arabinofuranosyl residues.
Our present day understanding of the cell wall associated AM and mannan as true lipoglycans, termed LAM and lipomannan (LM), respectively, stems from the seminal work by Hunter, Chatterjee, Brennan, and coworkers (Hunter et al., 1986; Hunter and Brennan, 1990; Chatterjee et al., 1992a). Critically important in these works was the development and successful application of organic solvent extraction procedures followed by phenol-water biphasic wash, to yield LAM/LM in their native acylated states devoid of most of the proteins and neutral polysaccharides. Currently in the author's laboratory, the extracted LAM and LM are routinely separated as individual entities using size exclusion column chromatography with a matrix of Sephacryl S-200 in the presence of a buffer containing deoxycholic acid, 0.5 M EDTA, 1 M NaCl in 10 mM Tris at pH 8.0 (Chatterjee et al., 1992a). This allows most of the structural analysis, as well as biological studies, to be carried out on relatively pure LAM and LM preparation from various strains of mycobacteria.
Additionally, LAM/LM have been shown to bind to the hydrophobic matrix of octyl Sepharose through their fatty acyl chains at low concentrations of propanol (5-15%, v/v) and salt ( >= 0.05 M) (Leopold and Fischer, 1993). This property has been exploited to further separate LAM/LM from nonacylated forms or contaminating polysaccharides (Khoo et al., 1996). Alternatively, Leopold and Fischer (1993) demonstrated that LAM and LM can be resolved on such hydrophobic interaction columns. With an increasing propanol gradient, their elution profile was apparently dominated by the large size difference of the glycan moieties and then, secondly, by the number of fatty acids.
Phosphatidylinositol mannoside anchor
To date, our cumulative structural data are consistent with the mannan core in both LAM and LM being based on an [alpha]1 -> 6 linked backbone, substituted to varying degrees at position 2 with single [alpha]-Man residues, and directly attached to position 6 of the myo-inositol of a phosphatidylinositol (PI) anchor (see Figure 2 , for schematic model).
From PIM2 to mannan core
The biosynthesis of PIMs of M.tuberculosis was pursued as early as 1967 (Brennan and Ballou, 1967). The fundamental pathway that emerged from this early work was:PI -> PIM1 -> PIM2 -> PIM3 -> PIM4 -> PIM5 -> PIM6, withGDP-mannose as the mannosyl group donor (the subscript on M denotes the number of mannose residues). It was believed that PIM6 is not on the direct pathway to the formation of LAM but is an end product. On the other hand, PIM2 (or possibly PIM3 and PIM4) could be extended to a linear [alpha]1-6 mannan with a chain length of approximately 16 residues, by sequential transfer of [alpha]-mannose residues from GDP-mannose to PI via particulate microsomal enzymes (Besra et al., 1997). However, heptaprenyl-P-Man (C35-P-Man) and the decaprenyl-P-Man (C50-P-Man) have since been discovered (Yokoyama and Ballou, 1989), and these are now believed to be also the mannosyl donors in the initial polymerization of the mannan core of LAM (Besra and Brennan, unpublished observations).
Within this context, little is known about the status of LM, whether it represents another end product from a common biosynthetic pathway, or whether it is an intermediate and a substrate for arabinosylation. Nor is it known whether addition of a single mannose stub along the linear [alpha]1-6 mannan backbone bears any significance to the regulation of biosynthesis from PIMs to LM and LAM. The mannan cores from LAM of both M.tuberculosis Erdman (Chatterjee et al., 1993) and M.bovis BCG (Venisse et al., 1995) were inferred to be highly branched and estimated to be around 20 mannose residues in total, with considerable heterogeneity with respect to the exact length and degree of branching. The LM of Erdman appeared to be much longer than that of the corresponding LAM mannan core, as estimated from one MALDI-MS analysis (Khoo and Chatterjee, unpublished observations). In contrast, both LAM mannan core and LM from M.smegmatis were shown to be averaging about 26 residues (Khoo et al., 1996) and only about half of the [alpha]6-mannan backbone residues are further substituted at position 2. Despite detailed NMR and chemical analysis, the exact position and the number of the attachment site(s) for the arabinan chains have never been defined. This is further compounded by the putative presence of additional phosphorylation on the mannan core (Venisse et al., 1995; Khoo and Chatterjee, unpublished observations).
Arabinan motifs and capping functions
While the PI mannan core may be entirely embedded within the cell wall, the arabinan of LAM has been demonstrated to be exposed on the surface and directly implicated in the immunopathogenesis of leprosy and tuberculosis (Brennan et al., 1990). The seminal work, on what has been called arabinofuranosyl-terminated LAM (AraLAM) from a rapidly growing strain of Mycobacterium (Chatterjee et al., 1991), revealed two distinct types of nonreducing termini, which would give rise to the linear Ara4 and branched Ara6 motifs (Khoo et al., 1995b) when digested with a novel endoarabinanase obtained from a soil Cellulomonas species by selective culturing on mycobacterial arabinogalactan (McNeil et al., 1994) (Figure 3 ).
LAM as a heterogeneous lipoglycan
It is now well appreciated that LAM from any single source is heterogeneous in size, branching pattern, acylation, and phosphorylation, on both the arabinan and mannan portions. Thus, any structural feature that can be physicochemically defined is a weighted average of the composite molecular species. The extreme heterogeneity is evident from the broad diffuse band observed on SDS-PAGE analysis of LAM and LM (Hunter et al., 1986), as well as from several recent MALDI-MS studies which afforded an indication of the mean distribution of true molecular weight. It was shown that native LAM from M.bovis BCG and M.tuberculosis gave a broad peak centered at 17.3 kDa, and 16.7 kDa after deacylation, with a reported size distribution of 4 kDa heterogeneity (Venisse et al., 1993). Likewise, the molecular weight of LAM from M.smegmatis was estimated to be around 15 kDa from the MALDI mass spectrum of the permethylated samples (Khoo et al., 1996). Depending on the species/strains, the total arabinose averages around 70 - 80 residues, with different degrees of branching and relative amounts of the Ara4 and Ara6 terminal motifs. In fact, the latter feature, as estimated from high pH anion exchange chromatography (HPAEC) analysis of the endoarabinanase digestion products, becomes an important criterion in distinguishing the arabinan of LAM and AG (Khoo et al., 1996).
Despite apparent structural similarity, the biosyntheses of the arabinans of AG and LAM are differentially inhibited by the anti-tuberculosis drug ethambutol (Emb). It has been demonstrated that the incorporation of [14C]glucose into the cell wall arabinan of M.smegmatis was immediately inhibited upon addition of Emb to young cultures but that into LAM was not apparent until after 1 h of exposure (Takayama and Kilburn, 1989; Deng et al., 1995; Mikusová et al., 1995). Furthermore, when grown in the presence of Emb, an Emb-resistant mutant derived from M.smegmatis by consecutive passage in media containing increasing concentrations of Emb, apparently made [rdquor]normal" cell wall AG but while the LAM was truncated (Mikusová et al., 1995). Truncation in the structurewas subsequently demonstrated as primarily a consequence of selective and partial inhibition of the synthesis of the linear Ara4 terminal motif, which constitutes a substantial portion of the arabinan termini in LAM but not in AG (Besra et al., 1995; Khoo et al., 1996).
Similar truncation of LAM was observed when M.smegmatis was transfected with plasmids containing the emb region from M.avium which encodes for Emb resistance. Sequence analysis indicated that there are three genes in this region, embR, embA, and embB, and that the translationally coupled embA and embB genes are necessary and sufficient to confer an Emb-resistant phenotype when expressed in M.smegmatis on a multicopy vector (Belanger et al., 1996). Thus, Emb resistant strains were derived by electroporation with the plasmids pAEB 148 (containing embR, embA, and embB) and pAEB 109 (containing only embA and embB). A cell-free system developed by Lee et al. (1995) was previously shown to be effective in using the lipid carrier, decaprenylphosphoarabinose (DPA), as a donor of arabinose in the polymerization of arabinan. The incorporation of radiolabeled Ara into a polymer of arabinan was inhibited to a maximum level of 70% when increasing amounts of Emb were added to the reaction mixture containing membrane fractions of M.smegmatis. A comparative study showed that similar extracts from the Emb resistant recombinant strains carrying pAEB148 and pAEB109 were only inhibited to about 30-35% and 55-60%, respectively (Belanger et al., 1996). These results indicated that embA and embB gene are associated with high level of Emb-resistant arabinosyltransferase activity and that embR is required for maximum resistance.
Based on the known structure of arabinan, it may be speculated that the polymerization of arabinan is essentially an [alpha]1 -> 5 elongation of the arabinan chains punctuated by [alpha]3-branching. The linear terminal Ara4 motif is a consequence of nonbranched termination with [beta]2-Ara, whereas the terminal Ara6 motif is the branched counterpart. Thus, Emb may be inhibiting all or most of the arabinosyltransferases involved in the biosynthesis of arabinan, a phenomenon not unexpected, given that all individual arabinosyltransferases are likely to recognize and utilize the same donor such as DPA, and hence containing structurally homologous active sites. The differential effect of Emb in eliciting synthesis of truncated LAMs but normal AG in the resistant strains is a consequence of the differential requirement of these two arabinan-containing components in growth. Selection for growth in culture in the presence of Emb entails that the mutant or recombinant must now be able to make functional AG, whereas a defective LAM is tolerable, at least for in vitro growth. These would translate into a more stringent requirement for the [alpha]3-branching arabinosyltransferase (or the composite biosynthesis machinery specifically required for making Ara6); a target needs neutralization by overexpression or mutation in order to grow. In the presence of Emb, the competition between branching and elongation would then be distorted in favor of the branching Ara6 terminal motif, resulting in the phenomenon of truncated LAM.
The observation that a full size mature LAM is not a requisite for mycobacterial growth in culture does not discount the biological significance in its partial inhibition. It may be argued that in order for LAM to effectively induce and/or suppress the proper immune response in the host (see following sections), a fully functional LAM is required and that most of its function will be critical depending on the integrity of its terminal arabinan motifs, its exposure on the surface and perhaps active secretion. To date, it is still unclear how LAM is associated with the cell wall. By virtue of its extraction methods, LAM appears to be firmly, but not covalently, attached to the walls. Furthermore, monoclonal antibodies to LAM recognize whole mycobacterial cells in ELISA experiments, suggesting that at least part of the molecule is situated on the exterior of the cell, accessible to the environment (Gaylord et al., 1987).
Two possible situations have been hypothesized: (1) LAM is anchored in the plasma membrane by its [rdquor]lipid anchor," and protrudes through the thickness of the wall so that its terminal arabinose or mannose-capped arabinose units are accessible to the outside (McNeil and Brennan, 1991); (2) LAM is incorporated by its PI-anchor into the outer leaflet of a proposed outer-membrane analogue in mycobacteria, and along with other polar wall-associated lipids makes up this membrane (Rastogi, 1991). Both these hypotheses are consistent with external presentation of terminal arabinose or mannose caps. The relatively strong conditions needed to release LAM from mycobacteria seem to favor the first hypothesis, but there is no strong evidence to support either hypothesis. A third possibility is that LAM has no permanent situation in the envelope, but is essentially a secreted molecule which passes through the envelope, so that the envelope-associated population merely represents those molecules in transit between a probable site of synthesis in the plasma membrane and the exterior of the mycobacterial cell. Lemassu and Daffé (1994) further demonstrated the existence of non-PI containing arabinomannan in the so-called capsular polysaccharide associated with M.tuberculosis which consists of mannose-capped arabinan motifs essentially identical to ManLAM. This raised the possibility that recognition by antibody of the whole cell was directed against these extracellular arabinomannans which may also be partly responsible for the many biological activities attributed to LAM.
LAM exhibits a wide spectrum of immunomodulatory functions, but the biological implication of the in vitro immunological data is not always clear. Using AraLAM, ManLAM, and M.leprae LAM, the early data obtained include LAM-induced abrogation of T-cell activation (Kaplan et al., 1987); inhibition of various IFN-[gamma]-induced functions including macrophage microbicidal and tumoricidal activity (Sibley et al., 1988), scavenging of potentially cytotoxic oxygen free radicals (Chan et al., 1991); inhibition of protein kinase C activity (Chan et al., 1991); and evocation of a large array of cytokines associated with macrophages such as [alpha]-TNF (Moreno et al., 1988, 1989; Barnes et al., 1992a; Chatterjee et al., 1992c; Adams et al., 1993), granulocyte-macrophage-CSF, IL-1a, IL-1b, IL-6, and IL-10 (Barnes et al., 1992b).
In these studies, AraLAM was consistently shown to be much more potent in evoking [alpha]-TNF and other responses, relative to ManLAM. Similarly, although both LAMs elicited immediate early response genes (including c-fos, JE, KC) in murine bone marrow-derived macrophages (Roach et al., 1993), only AraLAM induced both [alpha]-TNF and a potentially lethal TNF-dependent NO response (Roach et al., 1995). Recently, AraLAM and not ManLAM was found to induce interleukin 12 (IL-12) expression in murine macrophages which may thus drive naive T-cells toward T-helper type 1 (Th1) cell development (Yoshida and Koide, 1997). The earlier hypothesis linking the mannose-capping function of LAM to attenuation in immunopotency and thus serving as virulence factor, was somewhat weakened by the subsequent realization that LAMs from M.tuberculosis, irrespective of virulence status, are all mannose-capped (Khoo et al., 1995b). Furthermore, the activity of AraLAM may be entirely due to its inositol phosphate capping, a feature not found on LAMs from pathogenic M.tuberculosis or M.leprae (Khoo et al., 1995b; Gilleron et al., 1997).
Nevertheless, in a recent study using human fetal microglial cells, both ManLAM and AraLAM were shown to have TNF-[alpha] stimulating properties, suggesting that the source of macrophages may be an important determinant of the response to different LAMs (Peterson et al., 1995). Thus, only studies involving ManLAM on human cell lines may be considered to bear real semblance to infection in vivo and pathogenesis. The granulomatous immune response in tuberculosis is characterized by delayed hypersensitivity and is mediated by various cytokines released by the stimulated mononuclear phagocytes, including TNF-[alpha] and IL-1b. ManLAM, free of LPS contamination, has been shown to stimulate mononuclear phagocytes to release TNF-[alpha], IL-1b, and IL-6 (Zhang et al., 1993, 1994). It was thought that IL-6 may play a role in clinical manifestations and pathological events of tuberculosis infection as it was identified in the granulomas in animal models of BCG infection. In a subsequent study, it was demonstrated that there is a striking upregulation by ManLAM of IL-8 mRNA expression in alveolar macrophages from patients with pulmonary TB (Zhang et al., 1995). IL-8 synthesis and release is an early response of macrophages after phagocytosis of M.tuberculosis which serves to attract both acute and chronic inflammatory infiltrates associated with necrotizing granulomas in lung tissue and thus participates in the process of containment of the pathogen. In addition, ManLAM from the virulent strains of M. tuberculosis (Erdman and H37Rv), but not AraLAM, could stimulate phagocytosis by interacting with the human macrophage mannose receptor (Schlesinger, 1993; Schlesinger et al., 1994, 1996). Thus, mannose-caps on ManLAM of M.tuberculosis strains may mediate efficient binding and entry, and regulate the initial events of phagocytosis as well as survival within the host macrophages.
Despite many of the well documented activities of LAMs on cells of lymphomonocytic origin, mechanisms by which LAMs mediate these effects are poorly understood. Although most of the immunobiological activities are thought to be directly elicited by the terminal carbohydrate head group, such as the mannose capping on ManLAM or phosphoinositol capping on the AraLAM, it has been shown that the lipid moiety is nonetheless essential to maintain its functional integrity (Barnes et al., 1992a).
In a recent elegant report (Llangumaran et al., 1995), it was demonstrated that LAM could integrate directly into the host cell membrane through its PI anchor, an event that could be competitively inhibited by PIM6. In the same study, it was also shown that LAMs were preferentially incorporated into plasma membrane domains enriched in endogenous GPI-linked proteins and interfere with the lateral mobility of the GPI-linked Thy-1 surface glycoproteins in the plane of the membrane. The acyl chains on LAM were found to be critical for LAMs to interact with the target cell membrane. Thus, LAM was claimed to be inserted directly into the plasma membrane bilayer of target cells through the acyl chains of its PI anchors without apparent involvement of the surface receptors. This interaction is quite distinct from the interaction of the ManLAM with macrophage mannose receptor involved in the phagocytosis of LAM-coated microspheres (Schlesinger et al., 1994). Not only can the mannose receptor mediate the initial uptake and internalization, but it may also deliver LAM to late endosomes for eventual presentation to T-cells by CD1b molecules (Prigozy et al., 1997).
T-cell recognition of LAM and other mycobacterial hydrophobic nonpeptide antigens have been the major findings leading to the currently accepted phenomenon of major histocompatability complex (MHC)-independent pathways for antigen presentation (Melián et al., 1996; Jullien et al., 1997). In studies directly related to LAM (Sieling et al., 1995), two [alpha][beta]+, CD4-, CD8- (double negative, DN) T-cell lines derived, respectively, from a leprosy skin lesion and the peripheral blood of normal donors were found to be responsive to LAM/LM/PIMs in the presence of CD1b-expressing antigen presenting cells. Presentation of these lipoglycan antigens required internalization and endosomal acidification, but was independent of both class I and class II MHC molecules. Significantly, the presence of an acylated PI unit and the mannan core with [alpha]1 -> 2 Manp residues was required and that only LAM, but not enterobacterial lipopolysaccharides from E.coli, lipophosphoglycans from Leishmania donovani, or lipoteichoic acids from Streptococcus pyogenes, was reactive against the derived DN T-cells. Furthermore, the T-cells derived from leprosy skin lesion only responded to LAM from M.leprae, whereas those from normal donors recognized LAMs from both M.tuberculosis Erdman and M.leprae. This suggests that although the lipid units are required, probably for binding to the hydrophobic [alpha]1 and [alpha]2 domains of CD1 which correspond spatially to the peptide-binding groove in MHC molecules (Porcelli, 1995), fine specificity in binding may reside in the glycan epitopes. More recently, three other DN T-cell lines from normal donors were found to recognize protease resistant mycobacterial lipoglycan antigens in the context of CD1c (Beckman et al., 1996). Interestingly, one T-cell line was also found to respond specifically to M.leprae LAM and not the structurally similar M.tuberculosis LAM.
The implication of CD1-restricted T-cell recognition of LAM/LM is unclear at present. T-cells activated by LAM secrete proinflammatory cytokines and are cytolytic (Sieling et al., 1995). The presence of M.leprae LAM-specific DN T-cells in localized leprosy skin lesions indicates a role for this novel antigen presentation pathway in host defense. It has been suggested that broad recognition of nonpolymorphic antigen presenting molecules may be important in the acquisition of cell mediated immunity to persistent intracellular pathogens that synthesize a diverse range of unusual lipoglycans, including LAM. A model of LAM and CD1b trafficking through the endosomal compartments of antigen presenting cells was recently proposed. The colocalization of the mannose receptor, LAM, and CD1b in the MHC class II antigen loading compartment (MIIC) prompted the suggestion that the mannose receptor delivers LAM for loading onto CD1b in MIIC, followed by the trafficking of LAM-CD1b complex to cell surface (Prigozy et al., 1997). This pathway therefore links recognition of microbial antigens by a receptor of the innate immune system to the induction of adaptive T-cell responses, and is relevant to LAM shed by infecting mycobacteria in lung cavities. Alternatively, LAM may be released into mycobacteria laden phagosomes and reaches the endocytic pathway by intracellular trafficking through other lysosomal-like vesicles (Xu et al., 1994).
In addition to direct recognition, LAM may also specifically induce human peripheral blood T-cell chemotaxis. It was shown that the culture supernatants from human alveolar macrophages infected in vitro with virulent M.tuberculosis could induce T-cell migration (Berman et al., 1996). Much of the migratory activity present in the supernatants could be blocked using a monoclonal antibody against LAM, suggesting that LAM is one of the chemotactic factors released. Furthermore, both AraLAM and M.tuberculosis ManLAM, but not LAM from Mycobacterium bovis, BCG, could induce T-cell chemotaxis in vitro. Thus, as in the case of CD1-restricted T-cell recognition, fine structural differences among LAMs from different sources can be discriminating and important when considering their biological functions and potency in eliciting host immune responses. The seemingly heterogeneous nature may perhaps conceal a well evolved adaptation enabling the intracellular pathogen to fine tune a perfect balance against the host defense system for its survival and propagation.
We end this review with some thoughts concerning the structure-to-function frontier. We have introduced a historical perspective on how our laboratory, starting with fascinating problems in the field of structural definition, has gradually become involved in the issues of biosynthesis, immunology, and pathogenesis. One of the vital contributions which we bring to such progress is a sensitivity for precisely defined structures. Much has been learned about the chemistry and biology of LAM in the past few years, and yet much more remains to be defined, as is obvious from this review. It is felt that for a true appreciation, future work on delineating the roles of LAM in immunopathogenesis needs to be focused on in vivo studies involving human cell lines whenever possible. On the other hand, we now consciously direct our next phase of structural studies on LAMs obtained from clinical isolates with a variety of virulence and drug resistant profiles. It is hoped that we can eventually delineate the structural motifs which contribute as virulence factors and/or protective epitopes and thereby derive effective drugs and vaccines against tuberculosis.
The research reviewed in this article was possible only through the dedication, enthusiasm, and creativity of scores of coworkers, whose names are acknowledged on the publications cited from this laboratory. External funding was provided by NIH, NIAID AI-37139 to D.C.
AG, arabinogalactan; AM, arabinomannan; AraLAM, non-mannose capped LAM; DN T-cell, [alpha][beta]+, CD4-, CD8- double negative T-cells; Emb, ethambutol; ManLAM, mannose-capped LAM; LAM, liporabinomannan; LM, lipomannan; PI, phosphatidylinositol; PIMx, phosphatidylinositol mannosides with subscript [rdquor]x" denotes the number of mannose residues.
2To whom correspondence should be addressed
Glycobiology
Pages
©
MINI REVIEW
Introduction
Early perception of arabinomannan
LAM, the current structural model
Ethambutol resistance and truncated LAMs
Orientation of LAM in cell envelope
Biological functions of LAM
Migration and t-cell recognition of LAM
Concluding remarks
Acknowledgments
Abbreviations
References
Introduction
Early perception of arabinomannan
LAM, the current structural model
Ethambutol resistance and truncated LAMs
Orientation of LAM in cell envelope
Biological functions of LAM
Migration and t-cell recognition of LAM
Concluding remarks
Acknowledgments
Abbreviations
References
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J. B. Torrelles, A. K. Azad, and L. S. Schlesinger Fine Discrimination in the Recognition of Individual Species of Phosphatidyl-myo-Inositol Mannosides from Mycobacterium tuberculosis by C-Type Lectin Pattern Recognition Receptors J. Immunol., August 1, 2006; 177(3): 1805 - 1816. [Abstract] [Full Text] [PDF]
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P. Dinadayala, D. Kaur, S. Berg, A. G. Amin, V. D. Vissa, D. Chatterjee, P. J. Brennan, and D. C. Crick Genetic Basis for the Synthesis of the Immunomodulatory Mannose Caps of Lipoarabinomannan in Mycobacterium tuberculosis J. Biol. Chem., July 21, 2006; 281(29): 20027 - 20035. [Abstract] [Full Text] [PDF]
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L. Shi, S. Berg, A. Lee, J. S. Spencer, J. Zhang, V. Vissa, M. R. McNeil, K.-H. Khoo, and D. Chatterjee The Carboxy Terminus of EmbC from Mycobacterium smegmatis Mediates Chain Length Extension of the Arabinan in Lipoarabinomannan J. Biol. Chem., July 14, 2006; 281(28): 19512 - 19526. [Abstract] [Full Text] [PDF]
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S. Kovacevic, D. Anderson, Y. S. Morita, J. Patterson, R. Haites, B. N. I. McMillan, R. Coppel, M. J. McConville, and H. Billman-Jacobe Identification of a Novel Protein with a Role in Lipoarabinomannan Biosynthesis in Mycobacteria J. Biol. Chem., April 7, 2006; 281(14): 9011 - 9017. [Abstract] [Full Text] [PDF]
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K. Sharma, M. Gupta, M. Pathak, N. Gupta, A. Koul, S. Sarangi, R. Baweja, and Y. Singh Transcriptional Control of the Mycobacterial embCAB Operon by PknH through a Regulatory Protein, EmbR, In Vivo. J. Bacteriol., April 1, 2006; 188(8): 2936 - 2944. [Abstract] [Full Text] [PDF]
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 Y. Yamazaki, L. Danelishvili, M. Wu, M. MacNab, and L. E. Bermudez Mycobacterium avium Genes Associated with the Ability To Form a Biofilm Appl. Envir. Microbiol., January 1, 2006; 72(1): 819 - 825. [Abstract] [Full Text] [PDF]
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 P. B. Kang, A. K. Azad, J. B. Torrelles, T. M. Kaufman, A. Beharka, E. Tibesar, L. E. DesJardin, and L. S. Schlesinger The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis J. Exp. Med., October 3, 2005; 202(7): 987 - 999. [Abstract] [Full Text] [PDF]
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 M. H. Hazbon, M. Bobadilla del Valle, M. I. Guerrero, M. Varma-Basil, I. Filliol, M. Cavatore, R. Colangeli, H. Safi, H. Billman-Jacobe, C. Lavender, et al. Role of embB Codon 306 Mutations in Mycobacterium tuberculosis Revisited: a Novel Association with Broad Drug Resistance and IS6110 Clustering Rather than Ethambutol Resistance Antimicrob. Agents Chemother., September 1, 2005; 49(9): 3794 - 3802. [Abstract] [Full Text] [PDF]
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K. J. C. Gibson, M. Gilleron, P. Constant, B. Sichi, G. Puzo, G. S. Besra, and J. Nigou A Lipomannan Variant with Strong TLR-2-dependent Pro-inflammatory Activity in Saccharothrix aerocolonigenes J. Biol. Chem., August 5, 2005; 280(31): 28347 - 28356. [Abstract] [Full Text] [PDF]
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Y. S. Morita, R. Velasquez, E. Taig, R. F. Waller, J. H. Patterson, D. Tull, S. J. Williams, H. Billman-Jacobe, and M. J. McConville Compartmentalization of Lipid Biosynthesis in Mycobacteria J. Biol. Chem., June 3, 2005; 280(22): 21645 - 21652. [Abstract] [Full Text] [PDF]
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S. Berg, J. Starbuck, J. B. Torrelles, V. D. Vissa, D. C. Crick, D. Chatterjee, and P. J. Brennan Roles of Conserved Proline and Glycosyltransferase Motifs of EmbC in Biosynthesis of Lipoarabinomannan J. Biol. Chem., February 18, 2005; 280(7): 5651 - 5663. [Abstract] [Full Text] [PDF]
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M. Gilleron, N. J. Garton, J. Nigou, T. Brando, G. Puzo, and I. C. Sutcliffe Characterization of a Truncated Lipoarabinomannan from the Actinomycete Turicella otitidis J. Bacteriol., February 1, 2005; 187(3): 854 - 861. [Abstract] [Full Text] [PDF]
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 R. E.B. Lee, W. Li, D. Chatterjee, and R. E. Lee Rapid structural characterization of the arabinogalactan and lipoarabinomannan in live mycobacterial cells using 2D and 3D HR-MAS NMR: structural changes in the arabinan due to ethambutol treatment and gene mutation are observed Glycobiology, February 1, 2005; 15(2): 139 - 151. [Abstract] [Full Text] [PDF]
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R. W. Stokes, R. Norris-Jones, D. E. Brooks, T. J. Beveridge, D. Doxsee, and L. M. Thorson The Glycan-Rich Outer Layer of the Cell Wall of Mycobacterium tuberculosis Acts as an Antiphagocytic Capsule Limiting the Association of the Bacterium with Macrophages Infect. Immun., October 1, 2004; 72(10): 5676 - 5686. [Abstract] [Full Text] [PDF]
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J. B. Torrelles, K.-H. Khoo, P. A. Sieling, R. L. Modlin, N. Zhang, A. M. Marques, A. Treumann, C. D. Rithner, P. J. Brennan, and D. Chatterjee Truncated Structural Variants of Lipoarabinomannan in Mycobacterium leprae and an Ethambutol-resistant Strain of Mycobacterium tuberculosis J. Biol. Chem., September 24, 2004; 279(39): 41227 - 41239. [Abstract] [Full Text] [PDF]
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K. J. C. Gibson, M. Gilleron, P. Constant, T. Brando, G. Puzo, G. S. Besra, and J. Nigou Tsukamurella paurometabola Lipoglycan, a New Lipoarabinomannan Variant with Pro-inflammatory Activity J. Biol. Chem., May 28, 2004; 279(22): 22973 - 22982. [Abstract] [Full Text] [PDF]
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D. C. Alexander, J. R. W. Jones, T. Tan, J. M. Chen, and J. Liu PimF, a Mannosyltransferase of Mycobacteria, Is Involved in the Biosynthesis of Phosphatidylinositol Mannosides and Lipoarabinomannan J. Biol. Chem., April 30, 2004; 279(18): 18824 - 18833. [Abstract] [Full Text] [PDF]
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D. N. Dao, L. Kremer, Y. Guerardel, A. Molano, W. R. Jacobs Jr., S. A. Porcelli, and V. Briken Mycobacterium tuberculosis Lipomannan Induces Apoptosis and Interleukin-12 Production in Macrophages Infect. Immun., April 1, 2004; 72(4): 2067 - 2074. [Abstract] [Full Text] [PDF]
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V. J. Quesniaux, D. M. Nicolle, D. Torres, L. Kremer, Y. Guerardel, J. Nigou, G. Puzo, F. Erard, and B. Ryffel Toll-Like Receptor 2 (TLR2)-Dependent-Positive and TLR2-Independent-Negative Regulation of Proinflammatory Cytokines by Mycobacterial Lipomannans J. Immunol., April 1, 2004; 172(7): 4425 - 4434. [Abstract] [Full Text] [PDF]
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K. J. C. Gibson, L. Eggeling, W. N. Maughan, K. Krumbach, S. S. Gurcha, J. Nigou, G. Puzo, H. Sahm, and G. S. Besra Disruption of Cg-Ppm1, a Polyprenyl Monophosphomannose Synthase, and the Generation of Lipoglycan-less Mutants in Corynebacterium glutamicum J. Biol. Chem., October 17, 2003; 278(42): 40842 - 40850. [Abstract] [Full Text] [PDF]
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J. Kordulakova, M. Gilleron, G. Puzo, P. J. Brennan, B. Gicquel, K. Mikusova, and M. Jackson Identification of the Required Acyltransferase Step in the Biosynthesis of the Phosphatidylinositol Mannosides of Mycobacterium Species J. Biol. Chem., September 19, 2003; 278(38): 36285 - 36295. [Abstract] [Full Text] [PDF]
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Y. Guerardel, E. Maes, V. Briken, F. Chirat, Y. Leroy, C. Locht, G. Strecker, and L. Kremer Lipomannan and Lipoarabinomannan from a Clinical Isolate of Mycobacterium kansasii: NOVEL STRUCTURAL FEATURES AND APOPTOSIS-INDUCING PROPERTIES J. Biol. Chem., September 19, 2003; 278(38): 36637 - 36651. [Abstract] [Full Text] [PDF]
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C. Vignal, Y. Guerardel, L. Kremer, M. Masson, D. Legrand, J. Mazurier, and E. Elass Lipomannans, But Not Lipoarabinomannans, Purified from Mycobacterium chelonae and Mycobacterium kansasii Induce TNF-{alpha} and IL-8 Secretion by a CD14-Toll-Like Receptor 2-Dependent Mechanism J. Immunol., August 15, 2003; 171(4): 2014 - 2023. [Abstract] [Full Text] [PDF]
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 R. I. Tapping and P. S. Tobias Mycobacterial lipoarabinomannan mediates physical interactions between TLR1 and TLR2 to induce signaling Innate Immunity, August 1, 2003; 9(4): 264 - 268. [Abstract] [PDF]
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 K. J. C. Gibson, M. Gilleron, P. Constant, G. Puzo, J. Nigou, and G. S. Besra Structural and functional features of Rhodococcus ruber lipoarabinomannan Microbiology, June 1, 2003; 149(6): 1437 - 1445. [Abstract] [Full Text] [PDF]
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K. R. Morris, R. D. Lutz, H.-S. Choi, T. Kamitani, K. Chmura, and E. D. Chan Role of the NF-{kappa}B Signaling Pathway and {kappa}B cis-Regulatory Elements on the IRF-1 and iNOS Promoter Regions in Mycobacterial Lipoarabinomannan Induction of Nitric Oxide Infect. Immun., March 1, 2003; 71(3): 1442 - 1452. [Abstract] [Full Text] [PDF]
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N. Maeda, J. Nigou, J.-L. Herrmann, M. Jackson, A. Amara, P. H. Lagrange, G. Puzo, B. Gicquel, and O. Neyrolles The Cell Surface Receptor DC-SIGN Discriminates between Mycobacterium Species through Selective Recognition of the Mannose Caps on Lipoarabinomannan J. Biol. Chem., February 14, 2003; 278(8): 5513 - 5516. [Abstract] [Full Text] [PDF]
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T. B.H. Geijtenbeek, S. J. van Vliet, E. A. Koppel, M. Sanchez-Hernandez, C. M.J.E. Vandenbroucke-Grauls, B. Appelmelk, and Y. van Kooyk Mycobacteria Target DC-SIGN to Suppress Dendritic Cell Function J. Exp. Med., January 6, 2003; 197(1): 7 - 17. [Abstract] [Full Text] [PDF]
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H. Hale-Donze, T. Greenwell-Wild, D. Mizel, T. M. Doherty, D. Chatterjee, J. M. Orenstein, and S. M. Wahl Mycobacterium avium Complex Promotes Recruitment of Monocyte Hosts for HIV-1 and Bacteria J. Immunol., October 1, 2002; 169(7): 3854 - 3862. [Abstract] [Full Text] [PDF]
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J. Kordulakova, M. Gilleron, K. Mikusova, G. Puzo, P. J. Brennan, B. Gicquel, and M. Jackson Definition of the First Mannosylation Step in Phosphatidylinositol Mannoside Synthesis. PimA IS ESSENTIAL FOR GROWTH OF MYCOBACTERIA J. Biol. Chem., August 23, 2002; 277(35): 31335 - 31344. [Abstract] [Full Text] [PDF]
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N. J. Garton, M. Gilleron, T. Brando, H.-H. Dan, S. Giguere, G. Puzo, J. F. Prescott, and I. C. Sutcliffe A Novel Lipoarabinomannan from the Equine Pathogen Rhodococcus equi. STRUCTURE AND EFFECT ON MACROPHAGE CYTOKINE PRODUCTION J. Biol. Chem., August 23, 2002; 277(35): 31722 - 31733. [Abstract] [Full Text] [PDF]
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Y. Guerardel, E. Maes, E. Elass, Y. Leroy, P. Timmerman, G. S. Besra, C. Locht, G. Strecker, and L. Kremer Structural Study of Lipomannan and Lipoarabinomannan from Mycobacterium chelonae. PRESENCE OF UNUSUAL COMPONENTS WITH alpha 1,3-MANNOPYRANOSE SIDE CHAINS J. Biol. Chem., August 16, 2002; 277(34): 30635 - 30648. [Abstract] [Full Text] [PDF]
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 A. Billiau and P. Matthys Modes of action of Freund's adjuvants in experimental models of autoimmune diseases J. Leukoc. Biol., December 1, 2001; 70(6): 849 - 860. [Abstract] [Full Text] [PDF]
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J. R. Schwebach, A. Casadevall, R. Schneerson, Z. Dai, X. Wang, J. B. Robbins, and A. Glatman-Freedman Expression of a Mycobacterium tuberculosis Arabinomannan Antigen In Vitro and In Vivo Infect. Immun., September 1, 2001; 69(9): 5671 - 5678. [Abstract] [Full Text] [PDF]
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J. Nigou, C. Zelle-Rieser, M. Gilleron, M. Thurnher, and G. Puzo Mannosylated Lipoarabinomannans Inhibit IL-12 Production by Human Dendritic Cells: Evidence for a Negative Signal Delivered Through the Mannose Receptor J. Immunol., June 15, 2001; 166(12): 7477 - 7485. [Abstract] [Full Text] [PDF]
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Y. Ma, R. J. Stern, M. S. Scherman, V. D. Vissa, W. Yan, V. C. Jones, F. Zhang, S. G. Franzblau, W. H. Lewis, and M. R. McNeil Drug Targeting Mycobacterium tuberculosis Cell Wall Synthesis: Genetics of dTDP-Rhamnose Synthetic Enzymes and Development of a Microtiter Plate-Based Screen for Inhibitors of Conversion of dTDP-Glucose to dTDP-Rhamnose Antimicrob. Agents Chemother., May 1, 2001; 45(5): 1407 - 1416. [Abstract] [Full Text]
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E. D. Chan, K. R. Morris, J. T. Belisle, P. Hill, L. K. Remigio, P. J. Brennan, and D. W. H. Riches Induction of Inducible Nitric Oxide Synthase-NO{middle dot} by Lipoarabinomannan of Mycobacterium tuberculosis Is Mediated by MEK1-ERK, MKK7-JNK, and NF-{kappa}B Signaling Pathways Infect. Immun., April 1, 2001; 69(4): 2001 - 2010. [Abstract] [Full Text] [PDF]
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L. M. Thorson, D. Doxsee, M. G. Scott, P. Wheeler, and R. W. Stokes Effect of Mycobacterial Phospholipids on Interaction of Mycobacterium tuberculosis with Macrophages Infect. Immun., April 1, 2001; 69(4): 2172 - 2179. [Abstract] [Full Text] [PDF]
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D. B. Moody, M. R. Guy, E. Grant, T.-Y. Cheng, M. B. Brenner, G. S. Besra, and S. A. Porcelli Cd1b-Mediated T Cell Recognition of a Glycolipid Antigen Generated from Mycobacterial Lipid and Host Carbohydrate during Infection J. Exp. Med., October 2, 2000; 192(7): 965 - 976. [Abstract] [Full Text] [PDF]
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C. Astarie-Dequeker, J. Nigou, G. Puzo, and I. Maridonneau-Parini Lipoarabinomannans Activate the Protein Tyrosine Kinase Hck in Human Neutrophils Infect. Immun., August 1, 2000; 68(8): 4827 - 4830. [Abstract] [Full Text] [PDF]
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M. Gilleron, L. Bala, T. Brando, A. Vercellone, and G. Puzo Mycobacterium tuberculosis H37Rv Parietal and Cellular Lipoarabinomannans. CHARACTERIZATION OF THE ACYL- AND GLYCO-FORMS J. Biol. Chem., January 7, 2000; 275(1): 677 - 684. [Abstract] [Full Text] [PDF]
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K.-H. Khoo, E. Jarboe, A. Barker, J. Torrelles, C.-W. Kuo, and D. Chatterjee Altered Expression Profile of the Surface Glycopeptidolipids in Drug-resistant Clinical Isolates of Mycobacterium avium Complex J. Biol. Chem., April 2, 1999; 274(14): 9778 - 9785. [Abstract] [Full Text] [PDF]
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S. M. Wahl, T. Greenwell-Wild, G. Peng, H. Hale-Donze, T. M. Doherty, D. Mizel, and J. M. Orenstein Mycobacterium avium complex augments macrophage HIV-1 production and increases CCR5 expression PNAS, October 13, 1998; 95(21): 12574 - 12579. [Abstract] [Full Text] [PDF]
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D. Maiti, A. Bhattacharyya, and J. Basu Lipoarabinomannan from Mycobacterium tuberculosis Promotes Macrophage Survival by Phosphorylating Bad through a Phosphatidylinositol 3-Kinase/Akt Pathway J. Biol. Chem., January 5, 2001; 276(1): 329 - 333. [Abstract] [Full Text] [PDF]
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K.-H. Khoo, J.-B. Tang, and D. Chatterjee Variation in Mannose-capped Terminal Arabinan Motifs of Lipoarabinomannans from Clinical Isolates of Mycobacterium tuberculosis and Mycobacterium avium Complex J. Biol. Chem., February 2, 2001; 276(6): 3863 - 3871. [Abstract] [Full Text] [PDF]
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M. Jackson, D. C. Crick, and P. J. Brennan Phosphatidylinositol Is an Essential Phospholipid of Mycobacteria J. Biol. Chem., September 22, 2000; 275(39): 30092 - 30099. [Abstract] [Full Text] [PDF]
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V. E. Escuyer, M.-A. Lety, J. B. Torrelles, K.-H. Khoo, J.-B. Tang, C. D. Rithner, C. Frehel, M. R. McNeil, P. J. Brennan, and D. Chatterjee The Role of the embA and embB Gene Products in the Biosynthesis of the Terminal Hexaarabinofuranosyl Motif of Mycobacterium smegmatis Arabinogalactan J. Biol. Chem., December 21, 2001; 276(52): 48854 - 48862. [Abstract] [Full Text] [PDF]
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M. Gilleron, C. Ronet, M. Mempel, B. Monsarrat, G. Gachelin, and G. Puzo Acylation State of the Phosphatidylinositol Mannosides from Mycobacterium bovis Bacillus Calmette Guerin and Ability to Induce Granuloma and Recruit Natural Killer T Cells J. Biol. Chem., September 7, 2001; 276(37): 34896 - 34904. [Abstract] [Full Text] [PDF]
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