Mycobacterial Metabolic Syndrome: LprG and Rv1410 Regulate Triacylglyceride Levels, Growth Rate and Virulence in Mycobacterium tuberculosis

PLoS Pathogens

Volumn 12, Issue 1, 2016, Pages

  Martinot, Amanda J ^a   Farrow, Mary ^a   Bai, Lu ^b   Layre, Emilie ^c   Cheng, Tan Yun ^c   Tsai, Jennifer H ^d   Iqbal, Jahangir ^e   Annand, John W ^c   Sullivan, Zuri A ^a   Hussain, M Mahmood ^e   Sacchettini, James ^d   Moody, D Branch ^c   Seeliger, Jessica C ^b   Rubin, Eric J ^a  

^a HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^b STONY BROOK UNIVERSITY   (United States)

^c BRIGHAM AND WOMEN S HOSPITAL   (United States)

^d TEXAS A AND M UNIVERSITY   (United States)

^e Downstate Health Sciences University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

TRIACYLGLYCEROL; BACTERIAL PROTEIN; CARRIER PROTEIN; LIPOPROTEIN; P55 PROTEIN, MYCOBACTERIUM;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BACTERIAL GROWTH; BACTERIAL VIRULENCE; CONTROLLED STUDY; GENETIC MANIPULATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IMMUNE RESPONSE; INFECTION RISK; LIPID BILAYER; MASS SPECTROMETRY; METABOLIC SYNDROME X; MOUSE; MYCOBACTERIAL METABOLIC SYNDROME; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; PROTEIN EXPRESSION; PROTEIN HYDROLYSIS; WESTERN BLOTTING; ANIMAL; DISEASE MODEL; METABOLISM; MUTANT MOUSE STRAIN; PATHOGENICITY; TUBERCULOSIS; VIRULENCE;

ANIMALS; BACTERIAL PROTEINS; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DISEASE MODELS, ANIMAL; LIPOPROTEINS; MASS SPECTROMETRY; MEMBRANE TRANSPORT PROTEINS; MICE; MICE, MUTANT STRAINS; MYCOBACTERIUM TUBERCULOSIS; TUBERCULOSIS; VIRULENCE;

EID: 84956761544     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1005351     Document Type: Article

References (65)

1. WHO. Global Tuberculosis Report 2013. 2013;: 1–3.
2. Esmail H, Barry CE, IIIWilkinson RJ, Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies. Drug Discovery Today. 2012;17: 514–521. doi: 10.1016/j.drudis.2011.12.013 22198298
3. Griffin JE, Gawronski JD, DeJesus MA, Ioerger TR, Akerley BJ, Sassetti CM, Ramakrishnan L, High-Resolution Phenotypic Profiling Defines Genes Essential for Mycobacterial Growth and Cholesterol Catabolism. PLoS Pathog. 2011;7: e1002251. doi: 10.1371/journal.ppat.1002251 21980284
4. Galagan JE, Minch K, Peterson M, Lyubetskaya A, Azizi E, Sweet L, et al. The Mycobacterium tuberculosis regulatory network and hypoxia. Nature. NIH Public Access; 2013;499: 178–183. doi: 10.1038/nature12337 23823726
5. Sassetti CM, Rubin EJ, Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci USA. 2003;100: 12989–12994. 14569030
6. Zhang YJ, Ioerger TR, Huttenhower C, Long JE, Sassetti CM, Sacchettini JC, Behr MA, et al. Global Assessment of Genomic Regions Required for Growth in Mycobacterium tuberculosis. PLoS Pathog. 2012;8: e1002946. doi: 10.1371/journal.ppat.1002946 23028335
7. Drage MG, Tsai H-C, Pecora ND, Cheng T-Y, Arida AR, Shukla S, et al. Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2. Nat Struct Mol Biol. 2010;17: 1088–1095. doi: 10.1038/nsmb.1869 20694006
8. Shukla S, Richardson ET, Athman JJ, Shi L, Wearsch PA, McDonald D, Lewinsohn DM, et al. Mycobacterium tuberculosis Lipoprotein LprG Binds Lipoarabinomannan and Determines Its Cell Envelope Localization to Control Phagolysosomal Fusion. PLoS Pathog. 2014;10: e1004471. doi: 10.1371/journal.ppat.1004471 25356793
9. Gaur RL, Ren K, Blumenthal A, Bhamidi S, Gibbs S, Jackson M, Behr MA, et al. LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis. PLoS Pathog. 2014;10: e1004376. doi: 10.1371/journal.ppat.1004376 25232742
10. Silva PE, Bigi F, Santangelo MP, Romano MI, Martín C, Cataldi A, et al. Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2001;45: 800–804. 11181364
11. Ramón-García S, Martín C, Thompson CJ, Aínsa JA, Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth. Antimicrob Agents Chemother. 2009;53: 3675–3682. doi: 10.1128/AAC.00550-09 19564371
12. Farrow MF, Rubin EJ, Function of a mycobacterial major facilitator superfamily pump requires a membrane-associated lipoprotein. J Bacteriol. 2008;190: 1783–1791. 18156250
13. Sulzenbacher G, Canaan S, Bordat Y, Neyrolles O, Stadthagen G, Roig-Zamboni V, et al. LppX is a lipoprotein required for the translocation of phthiocerol dimycocerosates to the surface of Mycobacterium tuberculosis. EMBO J. 2006;25: 1436–1444. 16541102
14. Cox JS, Chen B, McNeil M, Jacobs WR, Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature. 1999;402: 79–83. 10573420
15. Hölscher C, Reiling N, Schaible UE, Hölscher A, Bathmann C, Korbel D, et al. Containment of aerogenic Mycobacterium tuberculosis infection in mice does not require MyD88 adaptor function for TLR2, -4 and -9. Eur J Immunol. 2008;38: 680–694. doi: 10.1002/eji.200736458 18266299
16. Fremond CM, Yeremeev V, Nicolle DM, Jacobs M, Quesniaux VF, Ryffel B, Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J Clin Invest. 2004;114: 1790–1799. 15599404
17. Sugawara I, Yamada H, Mizuno S, Takeda K, Akira S, Mycobacterial infection in MyD88-deficient mice. Microbiol Immunol. 2003;47: 841–847. 14638995
18. Bansal-Mutalik R, Nikaido H, Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides. Proc Natl Acad Sci USA. 2014;111: 4958–4963. doi: 10.1073/pnas.1403078111 24639491
19. Deb C, Daniel J, Sirakova TD, Abomoelak B, Dubey VS, Kolattukudy PE, A novel lipase belonging to the hormone-sensitive lipase family induced under starvation to utilize stored triacylglycerol in Mycobacterium tuberculosis. J Biol Chem. 2006;281: 3866–3875. 16354661
20. Low KL, Rao PSS, Shui G, Bendt AK, Pethe K, Dick T, et al. Triacylglycerol utilization is required for regrowth of in vitro hypoxic nonreplicating Mycobacterium bovis bacillus Calmette-Guerin. J Bacteriol. 2009;191: 5037–5043. doi: 10.1128/JB.00530-09 19525349
21. Layre E, Sweet L, Hong S, Madigan CA, Desjardins D, Young DC, et al. A Comparative Lipidomics Platform for Chemotaxonomic Analysis of Mycobacterium tuberculosis. Chem Biol. Elsevier Ltd; 2011;18: 1537–1549. doi: 10.1016/j.chembiol.2011.10.013 22195556
22. Madigan CA, Martinot AJ, Wei J-R, Madduri A, Cheng T-Y, Young DC, et al. Lipidomic analysis links mycobactin synthase K to iron uptake and virulence in M. tuberculosis. PLoS Pathog. 2015;11: e1004792. doi: 10.1371/journal.ppat.1004792 25815898
23. Madigan CA, Cheng T-Y, Layre E, Young DC, McConnell MJ, Debono CA, et al. Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis. Proc Natl Acad Sci USA. 2012;109: 1257–1262. doi: 10.1073/pnas.1109958109 22232695
24. Bianco MV, Blanco FC, Imperiale B, Forrellad MA, Rocha RV, Klepp LI, et al. Role of P27 -P55 operon from Mycobacterium tuberculosis in the resistance to toxic compounds. BMC infectious diseases. 2011;11: 195. doi: 10.1186/1471-2334-11-195 21762531
25. Daffé M, Draper P, The envelope layers of mycobacteria with reference to their pathogenicity. Adv Microb Physiol. 1998;39: 131–203. 9328647
26. Ortalo-Magné A, Lemassu A, Laneelle MA, Bardou F, Silve G, Gounon P, et al. Identification of the surface-exposed lipids on the cell envelopes of Mycobacterium tuberculosis and other mycobacterial species. J Bacteriol. 1996;178: 456–461. 8550466
27. Athar H, A simple, rapid, and sensitive fluorescence assay for microsomal triglyceride transfer protein. J Lipid Res. 2004;45: 764–772. 14754905
28. Gehring AJ, Dobos KM, Belisle JT, Harding CV, Boom WH, Mycobacterium tuberculosis LprG (Rv1411c): a novel TLR-2 ligand that inhibits human macrophage class II MHC antigen processing. J Immunol. 2004;173: 2660–2668. 15294983
29. Bigi F, Gioffré A, Klepp L, Santangelo M de LP, Alito A, Caimi K, et al. The knockout of the lprG-Rv1410 operon produces strong attenuation of Mycobacterium tuberculosis. Microbes Infect. 2004;6: 182–187. 14998516
30. Hernandez-Pando R, Schön T, Orozco EH, Serafin J, Estrada-García I, Expression of inducible nitric oxide synthase and nitrotyrosine during the evolution of experimental pulmonary tuberculosis. Exp Toxicol Pathol. 2001;53: 257–265. 11665849
31. MacMicking JD, North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan CF, Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci U S A. 1997;94: 5243–5248. 9144222
32. Scanga CA, Mohan VP, Tanaka K, Alland D, Flynn JL, Chan J, The inducible nitric oxide synthase locus confers protection against aerogenic challenge of both clinical and laboratory strains of Mycobacterium tuberculosis in mice. Infect Immun. 2001;69: 7711–7717. 11705952
33. Yang C-S, Shin D-M, Kim K-H, Lee Z-W, Lee C-H, Park SG, et al. NADPH Oxidase 2 Interaction with TLR2 Is Required for Efficient Innate Immune Responses to Mycobacteria via Cathelicidin Expression. The Journal of Immunology. 2009;182: 3696–3705. doi: 10.4049/jimmunol.0802217 19265148
34. Jackson SH, Gallin JI, Holland SM, The p47phox mouse knock-out model of chronic granulomatous disease. J Exp Med. 1995;182: 751–758. 7650482
35. Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, Orme IM, Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med. 1993;178: 2243–2247. 8245795
36. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR, An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993;178: 2249–2254. 7504064
37. Smith NLD, Denning DW, Clinical implications of interferon- γ genetic and epigenetic variants. Immunology. 2014;143: 499–511. doi: 10.1111/imm.12362 25052001
38. Richardson ET, Shukla S, Sweet DR, Wearsch PA, Tsichlis PN, Boom WH, et al. TLR2-dependent ERK signaling in Mycobacterium tuberculosis-infected macrophages drives anti-inflammatory responses and inhibits Th1 polarization of responding T cells. Infect Immun. 2015.
39. Pandey AK, Sassetti CM, Mycobacterial persistence requires the utilization of host cholesterol. Proc Natl Acad Sci USA. 2008;105: 4376–4380. doi: 10.1073/pnas.0711159105 18334639
40. Eoh H, Rhee KY, Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids. Proc Natl Acad Sci USA. 2014;111: 4976–4981. doi: 10.1073/pnas.1400390111 24639517
41. Yang X, Nesbitt NM, Dubnau E, Smith I, Sampson NS, Cholesterol Metabolism Increases the Metabolic Pool of Propionate in Mycobacterium tuberculosis. Biochemistry. 2009;48: 3819–3821. doi: 10.1021/bi9005418 19364125
42. Daniel J, Deb C, Dubey VS, Sirakova TD, Abomoelak B, Morbidoni HR, et al. Induction of a Novel Class of Diacylglycerol Acyltransferases and Triacylglycerol Accumulation in Mycobacterium tuberculosis as It Goes into a Dormancy-Like State in Culture. J Bacteriol. 2004;186: 5017–5030. 15262939
43. Singh G, Singh G, Jadeja D, Kaur J, Lipid hydrolizing enzymes in virulence: Mycobacterium tuberculosis as a model system. Crit Rev Microbiol. 2010;36: 259–269. doi: 10.3109/1040841X.2010.482923 20500016
44. Deb C, Lee C- M, Dubey VS, Daniel J, Abomoelak B, Sirakova TD, Ahmed N, et al. A Novel In Vitro Multiple-Stress Dormancy Model for Mycobacterium tuberculosis Generates a Lipid-Loaded, Drug-Tolerant, Dormant Pathogen. PLoS ONE. 2009;4: e6077. doi: 10.1371/journal.pone.0006077 19562030
45. Wheeler PR, Bulmer K, Ratledge C, Fatty acid oxidation and the beta-oxidation complex in Mycobacterium leprae and two axenically cultivable mycobacteria that are pathogens. J Gen Microbiol. 1991;137: 885–893. 1856682
46. Lee W, VanderVen BC, Fahey RJ, Russell DG, Intracellular Mycobacterium tuberculosis Exploits Host-derived Fatty Acids to Limit Metabolic Stress. Journal of Biological Chemistry. 2013;288: 6788–6800. doi: 10.1074/jbc.M112.445056 23306194
47. VanderVen BC, Fahey RJ, Lee W, Liu Y, Abramovitch RB, Memmott C, et al. Novel Inhibitors of Cholesterol Degradation in Mycobacterium tuberculosis Reveal How the Bacterium's Metabolism Is Constrained by the Intracellular Environment. PLoS Pathog. 2015;11: e1004679. doi: 10.1371/journal.ppat.1004679 25675247
48. Mondino S, Gago G, Gramajo H, Transcriptional regulation of fatty acid biosynthesis in mycobacteria. Mol Microbiol. 2013;89: 372–387. doi: 10.1111/mmi.12282 23721164
49. Shleeva M, Goncharenko A, Kudykina Y, Young D, Young M, Kaprelyants A, Cyclic amp-dependent resuscitation of dormant mycobacteria by exogenous free Fatty acids. PLoS ONE. 2013;8: e82914–e82914. doi: 10.1371/journal.pone.0082914 24376605
50. Nickel J, Irzik K, Van Ooyen J, Eggeling L, The TetR-type transcriptional regulator FasR of Corynebacterium glutamicum controls genes of lipid synthesis during growth on acetate. Mol Microbiol. 2010;78: 253–265. doi: 10.1111/j.1365-2958.2010.07337.x 20923423
51. Masiewicz P, Wolański M, Brzostek A, Dziadek J, Zakrzewska-Czerwińska J, Propionate represses the dnaA gene via the methylcitrate pathway-regulating transcription factor, PrpR, in Mycobacterium tuberculosis. Antonie Van Leeuwenhoek. 2014;105: 951–959. doi: 10.1007/s10482-014-0153-0 24705740
52. Daniel J, Sirakova T, Kolattukudy P, An acyl-CoA synthetase in Mycobacterium tuberculosis involved in triacylglycerol accumulation during dormancy. PLoS ONE. 2014;9: e114877. doi: 10.1371/journal.pone.0114877 25490545
53. Alvarez H, Steinbüchel A. Triacylglycerols in prokaryotic microorganisms. Applied Microbiology and Biotechnology. 2002;60: 367–376. 12466875
54. Alvarez HM, Triacylglycerol and wax ester-accumulating machinery in prokaryotes. Biochimie. 2015.
55. Garton NJ, Christensen H, Minnikin DE, Adegbola RA, Barer MR, Intracellular lipophilic inclusions of mycobacteria in vitro and in sputum. Microbiology (Reading, Engl). 2002;148: 2951–2958.
56. Black PN, DiRusso CC, Molecular and biochemical analyses of fatty acid transport, metabolism, and gene regulation in Escherichia coli. Biochim Biophys Acta. 1994;1210: 123–145. 8280762
57. Singh A, Crossman DK, Mai D, Guidry L, Voskuil MI, Renfrow MB, Bishai W, et al. Mycobacterium tuberculosis WhiB3 Maintains Redox Homeostasis by Regulating Virulence Lipid Anabolism to Modulate Macrophage Response. PLoS Pathog. 2009;5: e1000545. doi: 10.1371/journal.ppat.1000545 19680450
58. Ramón-García S, Stewart GR, Hui ZK, Mohn WW, Thompson CJ, The mycobacterial P55 efflux pump is required for optimal growth on cholesterol. Virulence. 2015;6: 444–448. doi: 10.1080/21505594.2015.1044195 26155739
59. Daniel J, Maamar H, Deb C, Sirakova TD, Kolattukudy PE, Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid droplets and acquires a dormancy-like phenotype in lipid-loaded macrophages. PLoS Pathog. 2011;7: e1002093. doi: 10.1371/journal.ppat.1002093 21731490
60. Fujita Y, Matsuoka H, Hirooka K, Regulation of fatty acid metabolism in bacteria. Mol Microbiol. 2007;66: 829–839. 17919287
61. Irzik K, Van Ooyen J, Gatgens J, Krumbach K, Bott M, Eggeling L, Acyl-CoA sensing by FasR to adjust fatty acid synthesis in Corynebacterium glutamicum. J Biotechnol. 2014;192PA: 96–101.
62. Yousuf S, Angara R, Vindal V, Ranjan A, Rv0494 is a starvation-inducible, auto-regulatory FadR-like regulator from Mycobacterium tuberculosis. Microbiology. 2015;161: 463–476. doi: 10.1099/mic.0.000017 25527627
63. Delmar JA, Chou T-H, Wright CC, Licon MH, Doh JK, Radhakrishnan A, et al. Structural Basis for the Regulation of the MmpL Transporters of Mycobacterium tuberculosis. Journal of Biological Chemistry. 2015.
64. de Carvalho LPS, Fischer SM, Marrero J, Nathan C, Ehrt S, Rhee KY, Metabolomics of Mycobacterium tuberculosis Reveals Compartmentalized Co-Catabolism of Carbon Substrates. Chem Biol. Elsevier Ltd; 2010;17: 1122–1131.
65. Garton NJ, Waddell SJ, Sherratt AL, Lee S-M, Smith RJ, Senner C, et al. Cytological and Transcript Analyses Reveal Fat and Lazy Persister-Like Bacilli in Tuberculous Sputum. PLoS Med. 2008;5: e75. doi: 10.1371/journal.pmed.0050075 18384229