Infectivity, pathogenicity and sulpholipid fraction of some Indian and British strains of tubercle bacilli

Gangadharam, P. R. J.; Cohn, Maurice L.; Middlebrook, Gardner

doi:10.1016/s0041-3879(63)80087-2

Cited by 57 publications

(51 citation statements)

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“…These molecules are essential for many of the characteristics that distinguish mycobacterial pathogenesis, such as the inhibition of phagosomal maturation, drug resistance, and alteration of the host immune response (2)(3)(4)(5)(6). A family of cell surface sulfated lipids (dubbed sulfatides) were identified in M. tb extracts and correlated to strain virulence (7)(8)(9). The most abundant sulfatide, termed Sulfolipid-1 (SL-1), consists of a trehalose core, four fatty acyl groups, and a sulfate ester (Fig.…”

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confidence: 99%

PapA1 and PapA2 are acyltransferases essential for the biosynthesis of theMycobacterium tuberculosisvirulence factor Sulfolipid-1

Kumar

Schelle²,

Jain³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

111

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pathogenesis ͉ biochemistry ͉ glycolipid ͉ sulfation T he thick Mycobacterium tuberculosis (M. tb) cell wall consists of numerous glycolipids that are distinctive to the mycobacterial genus, including phosphatidylinositol mannosides, trehalose mycolates, and lipoarabinomannans (1). These molecules are essential for many of the characteristics that distinguish mycobacterial pathogenesis, such as the inhibition of phagosomal maturation, drug resistance, and alteration of the host immune response (2-6). A family of cell surface sulfated lipids (dubbed sulfatides) were identified in M. tb extracts and correlated to strain virulence (7-9). The most abundant sulfatide, termed Sulfolipid-1 (SL-1), consists of a trehalose core, four fatty acyl groups, and a sulfate ester (Fig. 1A) (10-13). Despite the discovery of SL-1 nearly 50 years ago, the biological function of the molecule is not known. Conflicting reports suggest a role for SL-1 in superoxide (O 2 Ϫ ) release from human neutrophils or monocytes, alteration of trehalose dimycolate toxicity, and inhibition of trehalose dimycolate-induced macrophage recruitment (14-19). The relevance of these studies to the physiological role of SL-1 in M. tb infection is debatable.Although the role of SL-1 remains elusive, advances in genetics and metabolite analysis have sped the discovery of genes, proteins, and intermediates associated with SL-1 biosynthesis (20). Currently, three proteins are known to be involved in SL-1 assembly: Stf0, Pks2, and MmpL8. The sulfotransferase Stf0 sulfates trehalose at the 2-position, forming trehalose-2-sulfate (T2S), thereby initiating SL-1 biosynthesis (21). Meanwhile, the polyketide synthase Pks2 synthesizes the phthioceranoyl and hydroxyphthioceranoyl lipids that occupy the 6-, 6Ј-, and 3Ј-positions of SL-1 (Fig. 1 A) (22). The proteins responsible for transfer of the Pks2 products and the palmitoyl group to the T2S core, and the order in which these lipids are added, have not yet been defined.Insight into the order of lipid addition came from characterization of the putative lipid transporter MmpL8 (23,24). A mutant strain, ⌬mmpL8, lacks SL-1 but accumulates the diacylated intermediate SL 1278 (named for its observed mass) inside the cell (Fig. 1B). This intermediate possesses two of the four SL-1-associated lipids: a hydroxyphthioceranoyl group at the 3Ј-position and a palmitoyl group at the 2Ј-position (24). SL 1278 was recently found to be an immunostimulant in human tuberculosis patients (25). The glycolipid is presented on the surface of M. tb-infected antigen-presenting cells by CD1b, a member of the MHC class I-like CD1 family. Intriguingly, the ⌬mmpL8 mutant, which lacks SL-1 but accumulates SL 1278 , shows attenuated virulence in mice (23,24). By contrast, a ⌬pks2 mutant, which lacks both SL-1 and SL 1278 , is indistinguishable from WT M. tb in mice and guinea pigs (23,26). These observations suggest that SL 1278 , and possibly other SL-1 intermediates, modulate M. tb pathogenesis.In our effort to define the functions of M. tb sulf...

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confidence: 99%

PapA1 and PapA2 are acyltransferases essential for the biosynthesis of theMycobacterium tuberculosisvirulence factor Sulfolipid-1

Kumar

Schelle²,

Jain³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Examination of some 60 clinical isolates of M. tuberculosis from different geographical origins suggested a highly significant statistical correlation between the production of sulfolipids in culture and the rank order of virulence for the guinea pig (8,12,15,18). The most virulent strains were generally prolific producers of sulfolipids, whereas attenuated strains were notably deficient in sulfolipid production.…”

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“…The most virulent strains were generally prolific producers of sulfolipids, whereas attenuated strains were notably deficient in sulfolipid production. However, the observation that some attenuated strains were proficient in sulfolipid synthesis and that a few virulent strains were devoid of these molecules led the authors to the careful conclusion that the presence of sulfolipids may not be a sufficient requirement for the expression of virulence (8,12).…”

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Sulfolipid Deficiency Does Not Affect the Virulence ofMycobacterium tuberculosisH37Rv in Mice and Guinea Pigs

et al. 2003

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Lipids that are found only in the cell envelope of pathogenic mycobacteria, such as those containing multiple methyl-branched fatty acids, have long been thought to play a role in pathogenesis. Among these complex lipids, sulfolipids have been the most extensively studied over the last 50 years. The numerous biological effects exhibited by purified sulfolipids on phagocytic cells led to the idea that these molecules are probably important virulence factors facilitating the intracellular survival of Mycobacterium tuberculosis. However, definitive evidence to support this concept has been lacking. The recent construction of an isogenic sulfolipid-deficient mutant of M. tuberculosis H37Rv (Sirakova et al., J. Biol. Chem. 276:16833-16839, 2001) has for the first time provided the opportunity to directly assess the contribution of these complex lipids to pathogenesis. In the present study, we show that against all expectations, sulfolipid deficiency does not significantly affect the replication, persistence, and pathogenicity of M. tuberculosis H37Rv in mice and guinea pigs or in cultured macrophages.Tuberculosis remains a major health problem worldwide (26). Mycobacterium tuberculosis, the causative agent of this disease in humans, has the capacity to infect, replicate in, and persist inside host macrophages. The virulence factors enabling M. tuberculosis to escape the bactericidal mechanisms of these cells, notably by blocking phagosome-lysosome fusion, are essentially unknown (6). A study conducted some 55 years ago by Middlebrook and collaborators (21) recognized that the curious ability of the tubercle bacillus to grow in culture as serpentine cords was relatively restricted to virulent strains. Dubos and Middlebrook (7) also observed that the virulent cord-forming strains invariably absorbed the cationic dye neutral red, while most attenuated strains of M. tuberculosis and saprophytic mycobacteria did not.In a search for the component of virulent mycobacteria that induced uptake of the dye, Middlebrook and coworkers (20) isolated sulfolipids. This family of molecules is composed of sulfated trehalose esters acylated with three to four acyl groups consisting of one short saturated fatty acid (palmitic acid or stearic acid) and different combinations of long-chain multiple methyl-branched fatty acids (the phthioceranic and hydroxyphthioceranic acids) (for a review, see references 9 and 11). Consistent with their suspected role in virulence, sulfolipids are found only in the human pathogen M. tuberculosis (9). Interestingly, sulfolipids are present in the virulent laboratory strain M. tuberculosis H37Rv but absent from the avirulent strain M. tuberculosis H37Ra (20).

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“…However, the role of SL-1 in M.tb pathogenesis seems to be dependent of the model system studied. In this context, results obtained from in vitro and in vivo studies (the latter using different animal models and M.tb strains) dispute the role of SL-1 in M.tb pathogenesis (Brozna et al, 1991;Gangadharam et al, 1963;Goren et al, 1974Goren et al, , 1982Pabst et al, 1988;Rousseau et al, 2003;L. Zhang et al, 1988L.…”

Section: The Peripheral Lipid Layer In the M Tuberculosis Cell Wallmentioning

confidence: 99%

Broadening Our View About the Role of Mycobacterium tuberculosis Cell Envelope Components During Infection: A Battle for Survival

Torrelles¹

2012

Understanding Tuberculosis - Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity

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Infectivity, pathogenicity and sulpholipid fraction of some Indian and British strains of tubercle bacilli

Cited by 57 publications

References 1 publication

PapA1 and PapA2 are acyltransferases essential for the biosynthesis of theMycobacterium tuberculosisvirulence factor Sulfolipid-1

PapA1 and PapA2 are acyltransferases essential for the biosynthesis of theMycobacterium tuberculosisvirulence factor Sulfolipid-1

Sulfolipid Deficiency Does Not Affect the Virulence ofMycobacterium tuberculosisH37Rv in Mice and Guinea Pigs

Broadening Our View About the Role of Mycobacterium tuberculosis Cell Envelope Components During Infection: A Battle for Survival

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