Mycobacterial Fatty Acid Esters of Sugars and Sulfosugars

Goren, Mayer B.

doi:10.1007/978-1-4899-2516-9_5

Cited by 29 publications

(50 citation statements)

References 171 publications

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“…The fact that, within the Mycobacterium genus, SL, PAT, and DAT are relatively restricted to the virulent strains of the M. tuberculosis complex (15,16,23) strongly suggests that this family of lipids serves important functions in the pathogenicity of tubercle bacilli, an assumption further supported by multiple in vitro and in vivo studies (for a review, see Refs. 13, 22, 23, 30 and references cited therein, and 31-34).…”

Section: Discussionmentioning

confidence: 95%

The Virulence-associated Two-component PhoP-PhoR System Controls the Biosynthesis of Polyketide-derived Lipids in Mycobacterium tuberculosis

Gonzalo-Asensio

Maia

Ferrer

et al. 2006

Journal of Biological Chemistry

197

175

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Two-component regulatory signal transduction systems are important elements of the adaptative response of prokaryotes to a variety of environmental stimuli. Disruption of PhoP-PhoR in Mycobacterium tuberculosisdramatically attenuates virulence, implying that this system directly and/or indirectly coordinates the expression of important virulence factors whose identity remains to be established. Interestingly, in knockingout the PhoP-PhoR two-component system in M. tuberculosis Mt103, dramatic changes in the colonial morphology, cording properties, and reactivity of the mutant strain to the basic dye neutral red, all intrinsic properties of tubercle bacilli known to correlate with virulence, were noted. Because deficiencies in the ability of the mutant to form serpentine cords and stain with the dye are likely the results of alterations of its cell envelope composition, we undertook to analyze the lipid content of phoP and phoP-phoR mutants constructed in two different strains of M. tuberculosis. Our results indicate that PhoP coordinately and positively regulates the synthesis of methyl-branched fatty acid-containing acyltrehaloses known to be restricted to pathogenic species of the M. tuberculosis complex, namely diacyltrehaloses, polyacyltrehaloses, and sulfolipids. Evidence is also provided that PhoP but not PhoR is required for the production of these lipids. This work represents an important step toward the functional characterization of PhoP-PhoR and the understanding of complex lipid synthesis in M. tuberculosis.Mycobacterium tuberculosis, the causative agent of tuberculosis in humans, is one of the leading causes of mortality due to a single infectious agent (1). In the tubercle bacillus as in other prokaryotes, two-component signal transduction systems are important elements of the adaptative response to a variety of stimuli (2). So far, of the 11 paired two-component systems, 5 unpaired response regulators and 2 unpaired protein sensors that M. tuberculosis possesses, the two-component system PhoP-PhoR is the one whose disruption was shown to affect the most dramatically the ability of M. tuberculosis to replicate in cellular and animal models (3). Interestingly, PhoP shows high similarity to the PhoP response regulator of Salmonella enterica serovar typhimurium, which senses Mg 2ϩ starvation and controls the expression of at least 40 genes, among which some encoding important virulence determinants (4). Further supporting the concept that PhoP is important for virulence and transmissibility of tubercle bacilli, a multidrug-resistant strain of Mycobacterium bovis (strain B) responsible for large tuberculosis outbreaks in Spain was found to carry an IS6110 insertion in the promoter region of phoP causing a strong up-regulation of the expression of this gene (5). To date, the stimuli sensed by the sensor histidine kinase PhoR and the genes controlled by the DNA-binding response regulator PhoP are not known. The identification of the environmental signals regulating PhoP-PhoR and the characterization of t...

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Section: Discussionmentioning

confidence: 95%

The Virulence-associated Two-component PhoP-PhoR System Controls the Biosynthesis of Polyketide-derived Lipids in Mycobacterium tuberculosis

Gonzalo-Asensio

Maia

Ferrer

et al. 2006

Journal of Biological Chemistry

197

175

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“…In the fi rst case, Ac 4 SGL would be elaborated from Ac 2 SGL in the cytosol, and Ac 4 SGL would be transported one PA ( 6 ). In this way, they demonstrated that the major species (SL-I) was acylated on the 3-, 6-, and 6 ′ -positions by one PA and two HPA; SL-I ′ was acylated by two PA and one HPA; and SL-II was acylated by three HPA.…”

Section: Discussionmentioning

confidence: 99%

Deciphering sulfoglycolipids of Mycobacterium tuberculosis

Layre

Paepe

Larrouy-Maumus

et al. 2011

Journal of Lipid Research

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“…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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confidence: 87%

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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Mycobacterial Fatty Acid Esters of Sugars and Sulfosugars

Cited by 29 publications

References 171 publications

The Virulence-associated Two-component PhoP-PhoR System Controls the Biosynthesis of Polyketide-derived Lipids in Mycobacterium tuberculosis

The Virulence-associated Two-component PhoP-PhoR System Controls the Biosynthesis of Polyketide-derived Lipids in Mycobacterium tuberculosis

Deciphering sulfoglycolipids of Mycobacterium tuberculosis

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

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