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-mycolates in strain ‘habana’ TMC 5135, considered as immunogenic in tuberculosis and leprosy
1 Laboratorio Nacional de Referencia e Investigaciones en Tuberculosis y Micobacterias, Centro Colaborador OPS/OMS, Instituto de Medicina Tropical Pedro Kourí (IPK), La Habana, Cuba
2 Departamento de Genética y Microbiología, Facultad de Medicina y Odontología, Universidad de Murcia, Spain
Correspondence
Pedro L. Valero-Guillén
plvalero{at}um.es
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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-, '- and keto-mycolates. -Mycolates were composed of a complex mixture of 82 to 89 carbon atoms (C82–C89), with the predominant molecular species containing two di-substituted cyclopropane rings. Among keto-mycolates (C84–C89), those containing one trans di-substituted cyclopropane ring were the most abundant. The '-mycolates were monounsaturated (C64, C66). According to MS and 1H-NMR data, the strains studied differed in fine structural details of -mycolates and keto-mycolates. Notably, strain ‘habana’ TMC 5135 (belonging to the ‘habana’ group, and considered as highly immunogenic in tuberculosis and leprosy) presented a particular composition of -mycolates, with a major component (C87) containing one cis plus one trans di-substituted cyclopropane ring, unlike the type strain of M. simiae and other strains of the ‘habana’ group (IPK-220 and IPK-337R), in which the major component (C84) contained two cis di-substituted cyclopropane rings. In spite of this finding, the ‘habana’ strains were closely related to each other and mainly differed from the type strain of M. simiae in some details of the fine structure of keto-mycolates. The present work indicated that within an identical general pattern of mycolic acids, there is a complex composition in M. simiae and structural variation among different strains, as reported for pathogenic species of the genus. Noteworthy was the particular composition of -mycolates in strain ‘habana’ TMC 5135.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). Included in this species is a group of strains, originally isolated in Cuba from people suffering pulmonary infections, that was named ‘Mycobacterium habana’ (Valdivia, 1973). Strains of ‘Mycobacterium habana' are phenotypically identical to serotype 1 of Mycobacterium simiae, and show the same serological specificity (Meissner & Schröder, 1975). Although the synonymy between M. simiae and ‘M. habana’ has been clearly demonstrated (Weiszfeiler & Karczag, 1976), the epithet ‘habana’ is maintained for the original collection of strains, in particular because a series of investigations has suggested a vaccine potential for strain ‘M. habana’ TMC 5135 in tuberculosis and leprosy (reviewed by Mederos et al., 2006).
Mycolic acids are long-chain -alkyl-branched, β-hydroxylated fatty acids present in the cell envelope of mycobacteria and related micro-organisms. They are mainly linked to the arabinogalactan of the cell wall, although they also appear among the extractable lipids of the cell envelope of mycobacteria, for example esterified to trehalose, forming cord factor (dimycolates of trehalose) (Brennan & Nikaido, 1995; Daffé & Draper, 1998). In the genus Mycobacterium, the mycolic acids can be roughly separated into two groups: those containing additional oxygenated functions (methoxy-, keto-, epoxy-, carboxymycolates) in the so-called ‘mero’ chain, and those that do not (- and '-mycolates). Pathogenic mycobacteria contain complex mixtures of -mycolates with, in general, two cis di-substituted cyclopropane rings, and oxygenated mycolic acids, with one di-substituted cyclopropane ring (Minnikin, 1982; Watanabe et al., 2001). Molecular evidence suggests that cis di-substituted cyclopropane -mycolates and trans di-substituted oxygenated mycolic acids are implicated in some aspects of the pathogenesis of experimental tuberculosis (Riley, 2006). On the other hand, mycolic acids are currently employed as chemotaxonomic markers, and their analysis has been applied in the identification of the most important pathogens of the genus Mycobacterium (Barry et al., 1998; Butler & Guthertz, 2001).
The structure of polar glycopeptidolipids of ‘M. habana’ TMC 5135 has been reported (Khoo et al., 1996), as well as the general composition of lipids of several strains within the ‘habana’ group (Mederos et al., 1998), and this has taxonomic potential. However, the analysis of the fine structure of the mycolic acids of M. simiae is still pending. In the present work, we focused on this subject, including the type strain of the species and three ‘habana’ strains. The results obtained indicated that ‘M. habana’ TMC 5135, an immunogenic strain in tuberculosis and leprosy (Mederos et al., 2006), presents a particular composition of -mycolates within the general pattern of -, '- and keto-mycolates found in M. simiae (Minnikin et al., 1984).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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), checked for purity, collected, washed with saline, killed at 120 °C for 20 min, and dried in a vacuum over P2O5.
Extraction and purification of mycolic acids.
Dried cells (0.5–1.0 g) were extracted overnight at room temperature with ethanol/diethyl ether (1 : 1, v/v), filtered, and re-extracted with chloroform/methanol (1 : 1, v/v) under the same conditions (Khoo et al., 1996). Extractable lipids were employed for polar glycopeptidolipid analysis (data not shown). Delipidated cells were subjected to acid methanolysis in a mixture of dried methanol/toluene/H2SO4 (30 : 15 : 1, v/v), overnight at 75 °C (Minnikin et al., 1980). The extract was evaporated to dryness under nitrogen, and the liberated mycolic acid methyl esters (MAMEs) were purified by silica gel 60 (Merck) (particle size 0.063–0.200 µm) column chromatography employing diethyl ether in hexane (0, 2, 5, 7, 10, 15 and 20 %) as solvent. Fractions (3–5 ml) were collected, evaporated to dryness and analysed by analytical TLC (aluminium-backed silica-gel plates, Merck) using dichloromethane as solvent. Purified fractions with the same structural type of MAMEs were combined and analysed by 1H-NMR and MS (see below). When necessary, these compounds were repurified using preparative TLC (silica-gel plates, Merck), as previously described (Mederos et al., 1998). We did not find a significant influence of acid methanolysis on cyclopropane rings or double bonds, because no artefacts were revealed by 1H-NMR or MS. On the other hand, the recommendations of Watanabe et al. (2001) in the purification of mycolates were followed, to avoid mistakes with the proportion of cis/trans isomerism.
Structural analysis of MAMEs.
1H-NMR was carried out in a Brucker instrument, at 400 or 600 MHz at room temperature, with the samples dissolved in deuterochloroform (5–10 mg ml–1). Electron-impact MS (EI-MS) and fast-atom bombardment MS (FAB-MS) were performed in a VG AutoSpec instrument, as previously reported (Astola et al., 2002). For FAB-MS, m-nitrobenzyl alcohol was used as matrix and the samples were doped with NaCl. EI-MS provides information on the meroaldehyde chains, where cyclopropane rings and oxygenated functions are present (Minnikin, 1982), and on the methyl esters, which are diagnostic of the branched chains located at the position (Minnikin, 1982). FAB-MS reveals [M+Na]+ ions indicative of the molecular masses of the different molecular species of mycolates (Astola et al., 2002).
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RESULTS |
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; Minnikin et al., 1984), -, '- and keto-mycolates were present in the four strains studied. All mycolates could be identified without ambiguity by comparison of the 1H-NMR spectra obtained with those reported elsewhere (Watanabe et al., 1999, 2001). Illustrating these results, the 1H-NMR spectrum of -mycolates from strains ‘M. habana’ TMC 5135 (Fig. 1a) and ‘M. habana’ IPK-220 (Fig. 1b) are given. Signals for - and keto-mycolates centred at –0.33, 0.57 and 0.66 p.p.m. were attributed to a cis di-substituted cyclopropane ring, and those at 0.09–0.18 and 0.45 p.p.m. to a trans di-substituted cyclopropane ring. An additional proton resonating in the region centred at 0.66 p.p.m. was attributed to a CH–CH3 adjacent to a trans di-substituted cyclopropane ring. Chemical shifts of trans double bonds were located at 5.21 and 5.34 p.p.m. On the other hand, terminal CH3 and branched CH3 (adjacent to a trans di-substituted cyclopropane ring) resonances overlapped in the region 0.87–0.90 p.p.m. Branched methyl groups adjacent to a trans double bond and to the C=O (keto-mycolates) resonated as doublets at 0.94 and 1.05 p.p.m., respectively. Signals for the cis double bond in '-mycolates resonated at 5.36 p.p.m. The ratio terminal CH3/cis double bond for '-mycolates was always 
2.0, indicating that this lipid contained one double bond only.
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- and keto-mycolates are depicted in Table 1. It was deduced that all strains studied contained at least one cis di-substituted cyclopropane ring in -mycolates, and that molecular species with two cis di-substituted cyclopropane rings, with one cis plus one trans di-substituted cyclopropane ring, and with one cis di-substituted cyclopropane ring plus one trans double bond were present in the complex mixture of this compound (see below, Table 2). Similarly, major keto-mycolates with one trans di-substituted cyclopropane ring were predicted, although homologous series with one cis di-substituted cyclopropane ring or with one trans double bond completed the mixture of this kind of mycolate (see below, Table 3). Examining the data from Table 1, it was evident that strains of the ‘habana’ group exhibited more internal relationship among themselves than with M. simiae ATCC 25275T, although ‘M. habana’ TMC 5135 tended to have more trans cyclopropanation in -mycolates. On the other hand, M. simiae ATCC 25275T contained more cis cyclopropanation in -mycolates, and notably in keto-mycolates, than the ‘habana’ strains (Table 1).
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- and keto-mycolates are given in Tables 2
and 3, respectively. In general, all the strains studied produced the same meroaldehydes from the mycolates detected, although their relative abundances varied among the strains (Tables 2 and 3). Thus, in strains ATCC 25275T, IPK-220 and IPK-337R, m/z 824.6 (C58) predominated, whereas in strain TMC 5135, m/z 866.6 (C61) reached higher levels (Table 2). The major meroaldehyde from keto-mycolates was always m/z 882.6 (C61) (Table 3). Both - and keto-mycolates mainly produced C26 : 0 methyl ester (m/z 410.2), and a small amount of C24 : 0 methyl ester (m/z 382.2). The major meroaldehyde from '-mycolates was detected at m/z 574.5, whereas methyl esters appeared at m/z 410.2 and m/z 382.2 (the proportions of m/z 410.2 to m/z 382.2 varied from 4 : 1 to 2 : 1 depending on the strains).
The chain lengths of - (Table 2) and keto- (Table 3) mycolates were predicted from EI-MS spectra, and confirmed by FAB-MS. FAB-MS spectra of -mycolates are shown in Fig. 2. Notably, -mycolates from strain TMC 5135 varied from C84 to C89 (as free acids), with a major C87 component (Table 2), unlike ATCC 25275T, IPK-220 and IPK-337R, in which C84 appears as the major component (Table 2). Keto-mycolates ranged from C84 to C89, with a major component, in all cases, of C87 (Table 3). '-Mycolates were mono-unsaturated derivatives of C66 and C64. Examining 1H-NMR and MS data (Tables 1–3), and taking into account earlier work (Watanabe et al., 2001, 2002), it was deduced that -mycolates belong to the so-called 1 (no double bonds present) and 2 (with trans double bonds) series (Table 2), and keto-mycolates to the keto1 (no double bonds) and keto2 (with trans double bonds) series (Table 3). Based on earlier complete analyses of mycolic acids from different mycobacteria (Minnikin 1982; Watanabe et al., 2001, 2002), the even series of -mycolates should be composed by two cis di-substituted cyclopropane rings (1) or one cis di-substituted cyclopropane ring plus one trans double bond (2), whereas uneven chain length series of -mycolates should mainly contain one cis di-substituted plus one trans di-substituted cyclopropane ring (1). On the other hand, the keto1 series with uneven chain length should mainly include one trans di-substituted cyclopropane ring in the structure (Minnikin, 1982; Watanabe et al., 2001), whereas the keto2 series with an even chain length should contain one trans double bond. In the specific case of strain ATCC 25275T, keto3 mycolates (with one cis double bond) may also be predicted.
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), and a major fragment attributed to the meroaldehyde was found at m/z 613.3. It was considered that a further major fragment located at m/z 321.1 was compatible with the structure proposed for 1-mycolates in Fig. 3(a). In a similar way, the major meroaldehyde for M. simiae ATCC 25275T, ‘habana’ IPK-220 and ‘habana’ IPK-337R was at m/z 824.4 (C58) (Table 2). In the case of M. simiae ATCC 25275T, the major fragments for the C58 meroaldehyde were tentatively assigned to m/z 571.2 and m/z 307.1, thus justifying the structure proposed in Fig. 3(b). However, strains ‘habana’ IPK-220 and ‘habana’ IPK-337R gave similar abundances for m/z 613.3 and m/z 571.2 (even m/z 613.3 tended to be higher), probably indicating that the abundances of C58 and C61 meroaldehydes were actually equivalent. The major meroaldehyde from keto1-mycolates (C87) contained C61 in all strains studied (Table 3), and it was thought to fragment at m/z 601.3, and subsequently at m/z 293.2, as found in the EI-MS (not shown): a tentative structure is proposed in Fig. 3(c).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Minnikin et al., 1984). The major -mycolates combined two di-substituted cyclopropane rings, and the major oxygenated mycolates (keto-mycolates) contained one trans di-substituted cyclopropane ring. Thus, they belonged to the 1- and keto1-mycolate types, respectively, as defined by Watanabe et al. (2001, 2002). As depicted in Tables 2 and 3, 2- and keto2-mycolates could also be detected in all strains examined. The -mycolates appeared unexpectedly long in comparison with those found in pathogenic mycobacteria (Minnikin, 1982; Watanabe et al., 2001, 2002), but it is uncertain if additional di-substituted cyclopropane rings or double bonds are also present in the mero chains of - and keto-mycolates, as found for different strains of the Mycobacterium tuberculosis complex, Mycobacterium kansasii and Mycobacterium avium (Watanabe et al., 2001, 2002). The same general mycolic acid composition as that of M. simiae has also been found in M. avium (Watanabe et al., 2001, 2002), although pathogenic mycobacteria mostly contain 1-mycolates with two cis di-substituted cyclopropane rings (Minnikin, 1982; Watanabe et al., 2001, 2002); however, this is also similar to the mycolic acid composition of the saprophytic species M. gordonae (Astola et al., 2002).
‘M. habana’ TMC 5135 tended to have longer -mycolates, and the major ones combined one cis plus one trans di-substituted cyclopropane ring in their structure. This kind of -mycolate has been detected elsewhere in M. kansasii and the M. avium complex (Watanabe et al., 2002). Data from Table 2 strongly suggested that this kind of mycolate prevails in strain TMC 5135, in contrast to other strains, in which -mycolates with two cis di-substituted cyclopropane rings could be predicted to be the most abundant. This was not reflected in the HPLC pattern previously reported for these strains (Mederos et al., 1998), probably because trans or cis isomerism does not influence the results of HPLC. Also noteworthy was the fact that the major - and keto-mycolates presented similar chain length in ‘M. habana’ TMC 5135, unlike the other strains studied. This suggests that this strain has some particular variations in the general routes of biosynthesis of -mycolates (see Takayama et al., 2005), because major -mycolates are slightly shorter than keto-mycolates (Minnikin, 1982; Watanabe et al., 2001, 2002).
Although, in general, similar molecular species were predicted for the different strains, the results obtained revealed that the ‘habana’ group were closely related to one another, differing from the type strain of M. simiae. We do not assign taxonomic implications to this finding, because DNA–DNA hybridization analyses have confirmed the synonymy between the two micro-organisms (Baess & Magnusson, 1982). On the other hand, variations in the fine structure of mycolates have been noted within strains of the same species of the genus Mycobacterium (Watanabe et al., 2001, 2002).
A particular and distinctive composition of -mycolates in ‘M. habana’ TMC 5135 could be defined. This strain is considered highly immunogenic in experimental tuberculosis in mice, and has received interest from several investigators as a possible vaccine candidate in tuberculosis and leprosy (reviewed by Mederos et al., 2006). Obviously, at present, it is not known if the fine structure of -mycolic acids has an influence on the immunogenic properties of this strain. Recent experimental data indicate that strains ‘M. habana’ TMC 5135 and ‘M. habana’ IPK-220, which differ in the fine structure of mycolates (this work), are not equally immunogenic or virulent in a BALB/c mouse model of progressive pulmonary tuberculosis (Valdés et al., 2007a, b). Thus, the load of ‘M. habana’ IPK-220 was higher than that of ‘M. habana’ TMC 5135, and the latter strain rapidly produced small granulomas (Valdés et al., 2007b). In connection with this finding, ‘M. habana’ TMC 5135 induces the production of interferon (INF)-
in vaccinated mice when different type of cells are stimulated with various antigens of M. tuberculosis, whereas ‘M. habana’ IPK-220 fails in the induction of this molecule (Valdés et al., 2007a). These results cannot be directly attributed to mycolic acid composition, because both strains also differ in the polar glycopeptidolipid TLC profile (Mederos et al., 1998). It was noteworthy, however, that mutants of M. tuberculosis lacking a proximal cis di-substituted cyclopropane ring in -mycolates (Rao et al., 2005) or a trans di-substituted cyclopropane ring in oxygenated mycolates (Rao et al., 2006) differ from wild strains in their pathogenic and immunogenic properties. Moreover, mutants of M. tuberculosis altered in their capacity to synthesize oxygenated mycolates present attenuated virulence in mice (Bhatt et al., 2007; Dubnau et al., 2000). The true significance of these data for human tuberculosis is still obscure (Riley, 2006), although they might indicate that the fine structure of mycolic acids has some influence in the pathogenesis of tuberculosis. The mechanisms involved are unknown, but it should be noted that mycolic acids (Beckman et al., 1994) and other lipids (de la Salle et al., 2005; Schaible & Kaufmann, 2000) are recognized by a subset of T cells in a CD1-restricted way. It has also been reported that infected macrophages release and traffic a variety of mycobacterial lipids, mostly glycolipids (Rhoades et al., 2003), and that the ‘in vivo’ induction of several cytokines [interleukin (IL)-1a, IL-1b, tumour necrosis factor (TNF)-] related to granuloma formation is mainly due to trehalose di-mycolates (Geisel et al., 2005). In this context, it would be interesting to know the exact structure of the trehalose di-mycolates of ‘M. habana’ TMC 5135 and compare their biological activity to that of other strains of M. simiae.
In conclusion, the present work reveals that within a similar mycolic acid pattern, the different strains examined of M. simiae present variations in the fine structure of these compounds, a finding that has also been noted in several pathogenic species of the genus (Watanabe et al., 2001, 2002). ‘M. habana’ TMC 5135 shows a particular combination of -mycolates that mostly combines one cis di-substituted plus one trans di-substituted cyclopropane ring. It remains open to further research if the fine structure of the mycolic acids of ‘M. habana’ TMC 5135 has an influence on the immunogenic properties of the strain.
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ACKNOWLEDGEMENTS |
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Edited by: G. S. Besra
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REFERENCES |
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Received 4 July 2007;
revised 8 August 2007;
accepted 16 August 2007.
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, cis di-substituted cyclopropane ring; trans
