Abstract
Mycobacterium leprae must adopt a metabolic strategy and undergo various metabolic alterations upon infection to survive inside the human body for years in a dormant state. A change in lipid homeostasis upon infection is highly pronounced in Mycobacterium leprae. Lipids play an essential role in the survival and pathogenesis of mycobacteria. Lipids are present in several forms and serve multiple roles from being a source of nutrition, providing rigidity, evading the host immune response to serving as virulence factors, etc. The synthesis and degradation of lipids is a highly regulated process and is the key to future drug designing and diagnosis for mycobacteria. In the current review, an account of the distinct roles served by lipids, the mechanism of their synthesis and degradation has been elucidated.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Hijacking the host: survival of pathogenic mycobacteria inside macrophages. Trends Microbiol. 10(3), 142–146 (2002).
- 2 . Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol. Lett. 123(1–2), 11–18 (1994).
- 3 . Mycobacterial persistence: adaptation to a changing environment. Trends Microbiol. 9(12), 597–605 (2001).
- 4 Is adipose tissue a place for Mycobacterium tuberculosis persistence? PLoS ONE 1(1), e43 (2006).
- 5 . Mycobacterium tuberculosis virulence: lipids inside and out. Nat. Med. 13(3), 284–285 (2007).
- 6 . Lipid metabolism and Type VII secretion systems dominate the genome scale virulence profile of Mycobacterium tuberculosis in human dendritic cells. BMC Genomics 16(1), 1 (2015).
- 7 Lipid composition and transcriptional response of Mycobacterium tuberculosis grown under iron-limitation in continuous culture: identification of a novel wax ester. Microbiology 153(5), 1435–1444 (2007).
- 8 . Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol. Rev. 36(3), 514–532 (2012).
- 9 Ancient mycobacterial lipids: key reference biomarkers in charting the evolution of tuberculosis. Tuberculosis 95, S133–S139 (2015).
- 10 . An in vitro model of Mycobacterium leprae induced granuloma formation. BMC Infect. Dis. 13(1), 1 (2013).
- 11 . The mouse foot-pad technique for cultivation of Mycobacterium leprae. Lepr. Rev. 77(1), 5 (2006).
- 12 . The effect of oxygenated mycolic acid composition on cell wall function and macrophage growth in Mycobacterium tuberculosis. Mol. Microbiol. 29(6), 1449–1458 (1998).
- 13 . Biosynthesis and virulent behavior of lipids produced by Mycobacterium tuberculosis: LAM and cord factor: an overview. Biotechnol. Res. Int. 2011, 274693 (2011).
- 14 Lipid biomarkers provide evolutionary signposts for the oldest known cases of tuberculosis. Tuberculosis 95, S127–S132 (2015).
- 15 . The T-cell response to lipid antigens of Mycobacterium tuberculosis. Front. Immunol. 5, 219 (2014).
- 16 . Lipids from Mycobacterium leprae cell wall are endowed with an anti-inflammatory property and inhibit macrophage function in vivo. Immunology 89(4), 613–618 (1996).
- 17 . Lipids from Mycobacterium leprae cell wall suppress T-cell activation in vivo and in vitro. Immunology 92(4), 429–436 (1997).
- 18 Lepromatous leprosy patients produce antibodies that recognise non-bilayer lipid arrangements containing mycolic acids. Mem. Inst. Oswaldo Cruz 107, 95–103 (2012).
- 19 . Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis. Tuberculosis 83(1), 91–97 (2003).
- 20 Detailed structural and quantitative analysis reveals the spatial organization of the cell walls of in vivo grown Mycobacterium leprae and in vitro grown Mycobacterium tuberculosis. J. Biol. Chem. 286(26), 23168–23177 (2011).
- 21 Massive gene decay in the leprosy bacillus. Nature 409(6823), 1007–1011 (2001). •• Gives excellent knowledge about reductive evolution in Mycobacterium leprae. A good account of the number of genes in various categories is given in comparison to M. tuberculosis.
- 22 Identification of trehalose dimycolate (cord factor) in Mycobacterium leprae. FEBS Lett. 581(18), 3345–3350 (2007).
- 23 . Lipoarabinomannan and related glycoconjugates: structure, biogenesis and role in Mycobacterium tuberculosis physiology and host-pathogen interaction. FEMS Microbiol. Rev. 35(6), 1126–1157 (2011).
- 24 . The continuing challenges of leprosy. Clin. Microbiol. Rev. 19(2), 338–381 (2006).
- 25 . Evidence for species-specific lipid antigens in Mycobacterium leprae. Int. J. Lepr. Other Mycobact. Dis. 48(4), 382–387 (1980).
- 26 . Mycobacterial lipoarabinomannan and related lipoglycans: from biogenesis to modulation of the immune response. Mol. Microbiol. 53(2), 391–403 (2004).
- 27 . The methyl-branched fortifications of Mycobacterium tuberculosis. Chem. Biol. 9(5), 545–553 (2002).
- 28 . The resumption of consumption: a review on tuberculosis. Mem. Inst. Oswaldo Cruz 101(7), 697–714 (2006).
- 29 . Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides. Proc. Natl Acad. Sci. 111(13), 4958–4963 (2014).
- 30 Immunological significance of Mycobacterium leprae cell walls. Proc. Natl Acad. Sci. 85(6), 1917–1921 (1988).
- 31 . The capsule of Mycobacterium tuberculosis and its implications for pathogenicity. Tuber. Lung. Dis. 79, 153–169 (1999).
- 32 . Isolation of a characteristic phthiocerol dimycocerosate from Mycobacterium leprae. Microbiology 129(3), 859–863 (1983).
- 33 . The envelope layers of mycobacteria with reference to their pathogenicity. Adv. Microb. Physiol. 39, 131–203 (1998).
- 34 . A novel phenolic glycolipid from Mycobacterium leprae possibly involved in immunogenicity and pathogenicity. J. Bacteriol. 147(3), 728–735 (1981).
- 35 . Recent observations concerning structure and function relationships in themycobacterial cell envelope: elaboration of a model in terms of mycobacterialpathogenicity, virulence and drug-resistance. Res. Microbiol. 142(4), 464–476 (1999).
- 36 Serodiagnosis of tuberculosis: comparison of immunoglobulin a (IgA) response to sulfolipid I with IgG and IgM responses to 2,3-diacyltrehalose, 2,3,6-triacyltrehalose, and cord factor antigens. J. Clin. Microbiol. 40(10), 3782–3788 (2002).
- 37 . The genome of Mycobacterium leprae: a minimal mycobacterial gene set. Genome Biol. 2(8), 1 (2001).
- 38 Characterization of sulfolipids of Mycobacterium tuberculosis H37Rv by multiple-stage linear ion-trap high-resolution mass spectrometry with electrospray ionization reveals that the family of sulfolipid II predominates. Biochemistry 50(42), 9135–9147 (2011).
- 39 . Structural definition of the non-reducing termini of mannose-capped LAMfrom Mycobacterium tuberculosis through selective enzymatic degradationand fast atom bombardment-mass spectrometry. Glycobiol. 3, 497–506 (1993).
- 40 . Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan withprofound physiological effects. Glycobiol. 8, 113–120 (1998).
- 41 . Identification of trehalose dimycolate (cord factor) in Mycobacterium leprae. FEBS Lett. 581(18), 3345–3350 (2007).
- 42 . Biosynthesis of mycobacterial lipids by polyketide synthases and beyond. Crit. Rev. Biochem. Mol. Biol. 49(3), 179–211 (2014).
- 43 . The role of Mycobacterium leprae phenolic glycolipid I (PGL-I) in serodiagnosis and in the pathogenesis of leprosy. Lepr. Rev. 82(4), 344 (2011).
- 44 Phenolic-glycolipid-1 and lipoarabinomannan preferentially modulate TCR- and CD28-triggered proximal biochemical events, leading to T-cell unresponsiveness in mycobacterial diseases. Lipids Health Dis. 11(1), 1 (2012).
- 45 Role of the cell wall phenolic glycolipid-1 in the peripheral nerve predilection of Mycobacterium leprae. Cell 103(3), 511–524 (2000). • M. leprae has a unique preference for Schwann cells. This publication explains why and at the same time highlights the importance of phenolic glycolipid-1 in M. leprae.
- 46 . Mycobacterium leprae inhibits dendritic cell activation and maturation. J. Immunol. 178(1), 338–344 (2007).
- 47 Mycobacterium leprae phenolglycolipid-1 expressed by engineered M. bovis BCG modulates early interaction with human phagocytes. PLoS Pathog. 6(10), e1001159 (2010).
- 48 . Phenolic glycolipid-1 of Mycobacterium leprae binds complement component C3 in serum and mediates phagocytosis by human monocytes. J. Exp. Med. 174(5), 1031–1038 (1991).
- 49 Identification of the surface-exposed lipids on the cell envelopes of Mycobacterium tuberculosis and other mycobacterial species. J. Bacteriol. 178(2), 456–461 (1996).
- 50 . Leprosy: a review of laboratory and therapeutic aspects – part 2. An. Bras. Dermatol. 89(3), 389–401 (2014). •• Gives a good account of various diagnostic candidates of leprosy.
- 51 . An adapted ELISA method for differentiating pathogenic from nonpathogenic aPL by a beta 2 glycoprotein I dependency anticardiolipin assay. Thromb. Res. 114(5), 573–577 (2004).
- 52 . Lipids in host-pathogen interactions: pathogens exploit the complexity of the host cell lipidome. Prog. Lipid Res. 49(1), 1–26 (2010).
- 53 . Electron microscopic observations on the morphology of Mycobacterium leprae. Exp. Cell Res. 18(3), 521–527 (1959).
- 54 . Deciphering the contribution of lipid droplets in leprosy: multifunctional organelles with roles in Mycobacterium leprae pathogenesis. Mem. Inst. Oswaldo Cruz 107, 156–166 (2012). •• First of its kind which gives a very good account of the contribution of lipid droplets (LDs) in the survival and virulence of M. leprae.
- 55 . Lipid droplets and Mycobacterium leprae infection. J. Pathog. 2012, 361374 (2012).
- 56 Lipid droplet formation in leprosy: Toll-like receptor-regulated organelles involved in eicosanoid formation and Mycobacterium leprae pathogenesis. J. Leukoc. Biol. 87(3), 371–384 (2010). • Mechanisms governing the formation of LDs are given in detail as their role as immunomodulatory platforms.
- 57 . Leukocyte lipid bodies-biogenesis and functions in inflammation. Biochim. Biophys. Acta 1791(6), 540–551 (2009).
- 58 A novel in vitro multiple-stress dormancy model for Mycobacterium tuberculosis generates a lipid-loaded, drug-tolerant, dormant pathogen. PLoS ONE 4(6), e6077 (2009).
- 59 . Cell biology of Mycobacterium tuberculosis phagosome. Annu. Rev. Cell Dev. Biol. 20, 367–394 (2004).
- 60 . Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv. FEBS J. 277(11), 2416–2427 (2010).
- 61 Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393(6685), 537–544 (1998).
- 62 . Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid droplets and acquires a dormancy-like phenotype in lipid-loaded macrophages. PLoS Pathog. 7(6), e1002093 (2011). •• Mechanism of LD formation in M. tuberculosis is explained and origin of lipids which constitute it. Source of nutrition for M. tuberculosis during dormancy is well documented.
- 63 Lipid droplet-associated proteins are involved in the biosynthesis and hydrolysis of triacylglycerol in Mycobacterium bovis bacillus Calmette-Guerin. J. Biol. Chem. 285(28), 21662–21670 (2010).
- 64 . Essentiality of DevR/DosR interaction with SigA for the dormancy survival program in Mycobacterium tuberculosis. J. Bacteriol. 196(4), 790–799 (2014).
- 65 DosS is required for the complete virulence of Mycobacterium tuberculosis in mice with classical granulomatous lesions. Am. J. Respir. Cell Mol. Biol. 52(6), 708–716 (2015).
- 66 Cutting edge: vitamin D regulates lipid metabolism in Mycobacterium tuberculosis infection. J. Immunol. 193(1), 30–34 (2014).
- 67 . Mycobacterial phenolic glycolipid inhibits phagosome maturation and subverts the pro-inflammatory cytokine response. Traffic 9(11), 1936–1947 (2008).
- 68 Mycobacterium leprae intracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment. Cell. Microbiol. 16(6), 797–815 (2014). •• Establishes cholesterol as one of the most important lipid for M. leprae as well as a future drug candidate.
- 69 Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy. J. Clin. Invest. 118(8), 2917–2928 (2008).
- 70 . Mycobacterium leprae – the outer lipoidal surface. J. Biosci. 6(5), 685–689 (1984).
- 71 . Cytochemical reactions of human leprosy bacilli and mycobacteria: ultrastructural implications. J. Bacteriol. 113(3), 1389–1399 (1973).
- 72 . The cutaneous infiltrates of leprosy. A transmission electron microscopy study. J. Exp. Med. 158(4), 1145–1159 (1983).
- 73 . Lipids in leprosy. 1. Histochemistry of lipids in murine leprosy. Int. J. Lepr. 38(4), 379–388 (1970).
- 74 Clofazimine modulates the expression of lipid metabolism proteins in Mycobacterium leprae-infected macrophages. PLoS Negl. Trop. Dis. 6(12), e1936 (2012).
- 75 Essential role of hormone-sensitive lipase (HSL) in the maintenance of lipid storage in Mycobacterium leprae-infected macrophages. Microb. Pathog. 52(5), 285–291 (2012). • Highlights the host dependency of M. leprae for lipolytic enzymes.
- 76 . Localization of CORO1A in the macrophages containing Mycobacterium leprae. Acta Histochem. Cytochem. 39(4), 107–112 (2006).
- 77 Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. EMBO Mol. Med. 2(7), 258–274 (2010).
- 78 . Mycobacterium tuberculosis-driven targeted recalibration of macrophage lipid homeostasis promotes the foamy phenotype. Cell Host Microbe. 12(5), 669–681 (2012).
- 79 . Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. J. Immunol. 146(1), 108–113 (1991).
- 80 . Expression of cyclooxygenase type 2 in lepromatous and tuberculoid leprosy lesions. Br. J. Dermatol. 148(4), 795–798 (2003).
- 81 . Inhibition of fatty acid synthase prevents preadipocyte differentiation. Biochem. Biophys. Res. Commun. 328(4), 1073–1082 (2005).
- 82 Dengue virus capsid protein usurps lipid droplets for viral particle formation. PLoS Pathog. 5(10), e1000632 (2009).
- 83 . Neutrophils recruited to the site of Mycobacterium bovis BCG infection undergo apoptosis and modulate lipid body biogenesis and prostaglandin E2 production by macrophages. Cell. Microbiol. 10(12), 2589–2604 (2008).
- 84 . Interleukin-1beta and tumour necrosis factor-alpha impede neutral lipid turnover in macrophage-derived foam cells. BMC Immunol. 9(1), 1 (2008).
- 85 The essential role of cholesterol metabolism in the intracellular survival of Mycobacterium leprae is not coupled to central carbon metabolism and energy production. J. Bacteriol. 197(23), 3698–3707 (2015).
- 86 Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids. PLoS Pathog. 5(2), e1000289 (2009).
- 87 . Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress. J. Biol. Chem. 288(10), 6788–6800 (2013).
- 88 . Mycobactin-mediated iron acquisition within macrophages. Nat. Chem. Biol. 1(3), 149–153 (2005).
- 89 . Mycobacterium leprae: genes, pseudogenes and genetic diversity. Future Microbiol. 6(1), 57–71 (2011).
- 90 . Oxidation of carbon sources through the tricarboxylic acid cycle in Mycobacterium leprae grown in armadillo liver. Microbiology 130(2), 381–389 (1984).
- 91 Overexpression of Rv3097c in Mycobacterium bovis BCG abolished the efficacy of BCG vaccine to protect against Mycobacterium tuberculosis infection in mice. Vaccine 29(29), 4754–4760 (2011).
- 92 Identification and characterisation of small-molecule inhibitors of Rv3097c-encoded lipase (LipY) of Mycobacterium tuberculosis that selectively inhibit growth of bacilli in hypoxia. Int. J. Antimicrob. Agents 42(1), 27–35 (2013).
- 93 . Rv2485c, a putative lipase of M. tuberculosis: expression, purification and biochemical characterization. Int. J. Trop. Dis. Health 4(1), 1–17 (2014).
- 94 Characterization of an acid inducible lipase Rv3203 from Mycobacterium tuberculosis H37Rv. Mol. Biol. Rep. 41(1), 285–296 (2014).
- 95 . Molecular characterization of oxidative stress-inducible LipD of Mycobacterium tuberculosis H37Rv. Curr. Microbiol. 68(3), 387–396 (2014).
- 96 . LipC(Rv0220) is an immunogenic cell surface esterase of Mycobacterium tuberculosis. Infect. Immun. 80, 243–253 (2012).
- 97 . The lipF promoter of Mycobacteriumtuberculosis is upregulated specifically by acidic pH but not by otherstress conditions. Microbiol. Res. 164, 228–232 (2009).
- 98 . Expression and characterization of the carboxylesterase Rv3487c from Mycobacterium tuberculosis. Prot. Exp. Purific. 42, 59–66 (2005).
- 99 . Identification of a virulence genecluster of Mycobacterium tuberculosis bysignature-tagged transposon mutagenesis. Mol. Microbiol. 34(2), 257–267 (1999).
- 100 . Expression andcharacterization of the protein Rv1399c from Mycobacterium tuberculosis. Biochem. 271, 3953–3961 (2004).
- 101 . Roles of SigB and SigF in the Mycobacterium tuberculosis sigma factornetwork. J. Bacteriol. 190(2), 699–707 (2008).
- 102 . Origin of asymmetryin adenylyl cyclases: structures of Mycobacterium tuberculosis Rv1900c. EMBO J. 24(4), 663–673 (2005).
- 103 . Comprehensive proteomic profiling of the membrane constituents of a Mycobacterium tuberculosis strain. Mol. Cell Proteomics 2(12), 1284–1296 (2003).
- 104 . Characterization of LipN (Rv2970c) of Mycobacterium tuberculosis H37Rv and its probable role inxenobiotic degradation. J. Cell Biochem. 117, 390–401 (2016).
- 105 . Deciphering the genes involved inpathogenesis of Mycobacterium tuberculosis. Tuberculosis 85(5–6), 325–335 (2005).
- 106 . The role of Rel(Mtb)-mediated adaptation to stationaryphase in long-term persistence of Mycobacterium tuberculosis inmice. Proc. Natl Acad. Sci. 100, 10026–10031 (2003).
- 107 . Does the lipR gene of tuberclebacilli have a role in tuberculosis transmission and pathogenesis?. Tuberculosis 89, 114–119 (2009).
- 108 . The Mycobacterium tuberculosis regulatory network and hypoxia. Nature 499, 178–183 (2013).
- 109 . Evaluation of a nutrient starvationmodel of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol. Microbiol. 43, 717–731 (2002).
- 110 Involvement of the fadD33 gene in the growth of Mycobacterium tuberculosis in the liver of BALB/c mice. Microbiology 148(12), 3873–3880 (2002).
- 111 . An acyl-CoA synthetase in Mycobacterium tuberculosis involved in triacylglycerol accumulation during dormancy. PLoS ONE 9(12), e114877 (2014).
- 112 . Analysis of Mycobacterium leprae gene expression using DNA microarray. Microb. Pathog. 49(4), 181–185 (2010).
- 113 Identification of a diacylglycerol acyltransferase gene involved in accumulation of triacylglycerol in Mycobacterium tuberculosis under stress. Microbiology 152(9), 2717–2725 (2006).
- 114 pks5-recombination-mediated surface remodelling in Mycobacterium tuberculosis emergence. Nat. Microbiol. 1, 15019 (2016). • Establishes pks as a marker of virulence for M. tuberculosis and marks the evolution of M. tuberculosis from less virulent mycobacteria like M. canetti.
- 115 . Mycobacterial polyketide-associated proteins are acyltransferases: proof of principle with Mycobacterium tuberculosis PapA5. Proc. Natl Acad. Sci. USA 101(13), 4608–4613 (2004).
- 116 . Chemical synthesis and serology of disaccharides and trisaccharides of phenolic glycolipid antigens from the leprosy bacillus and preparation of a disaccharide protein conjugate for serodiagnosis of leprosy. Infect. Immun. 43(1), 245–252 (1984).
- 117 . Serum metabolomics reveals higher levels of polyunsaturated fatty acids in lepromatous leprosy: potential markers for susceptibility and pathogenesis. PLoS Negl. Trop. Dis. 5(9), e1303 (2011).
- 118 . The proteomics of lipid droplets: structure, dynamics, and functions of the organelle conserved from bacteria to humans. J. Lipid Res. 53, 1245–1253 (2012).
- 119 Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis evidence that this lipid is involved in the cell wall permeability barrier. J. Biol. Chem. 276(23), 19845–19854 (2001).