Diversity of across Evolutionary Scales

Tuberculosis (TB) is a grave threat to global public health and is the second leading cause of death due to infectious disease. The causative agent, Mycobacterium tuberculosis (M.tb), has emerged in increasingly drug resistant forms that hamper our efforts to control TB. We need a better understanding of M.tb adaptation to guide development of more effective TB treatment and control strategies. The goal of this study was to gain insight into M.tb evolution within individual patients with TB. We found that TB patients harbor a diverse population of M.tb. We further found evidence to suggest that the bacterial population evolves measurably in response to selection pressures imposed by the environment within hosts. Changes were particularly notable in M.tb genes involved in the regulation, synthesis, and transportation of lipids and glycolipids of the bacterial cell envelope. These findings have important implications for drug and vaccine development, and provide insight into TB host pathogen interactions.

Vyšlo v časopise: Diversity of across Evolutionary Scales. PLoS Pathog 11(11): e32767. doi:10.1371/journal.ppat.1005257
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005257


Tuberculosis (TB) is a grave threat to global public health and is the second leading cause of death due to infectious disease. The causative agent, Mycobacterium tuberculosis (M.tb), has emerged in increasingly drug resistant forms that hamper our efforts to control TB. We need a better understanding of M.tb adaptation to guide development of more effective TB treatment and control strategies. The goal of this study was to gain insight into M.tb evolution within individual patients with TB. We found that TB patients harbor a diverse population of M.tb. We further found evidence to suggest that the bacterial population evolves measurably in response to selection pressures imposed by the environment within hosts. Changes were particularly notable in M.tb genes involved in the regulation, synthesis, and transportation of lipids and glycolipids of the bacterial cell envelope. These findings have important implications for drug and vaccine development, and provide insight into TB host pathogen interactions.


1. WHO | Global tuberculosis report 2014. In: WHO [Internet]. [cited 6 Jan 2015]. http://www.who.int/tb/publications/global_report/en/

2. Klopper M, Warren RM, Hayes C, Gey van Pittius NC, Streicher EM, Müller B, et al. Emergence and Spread of Extensively and Totally Drug-Resistant Tuberculosis, South Africa. Emerg Infect Dis. 2013;19: 449–455. doi: 10.3201/EID1903.120246 23622714

3. Achtman M. Insights from genomic comparisons of genetically monomorphic bacterial pathogens. Philos Trans R Soc B Biol Sci. 2012;367: 860–867.

4. Pepperell CS, Casto AM, Kitchen A, Granka JM, Cornejo OE, Holmes EC, et al. The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations. PLoS Pathog. 2013;9: e1003543. doi: 10.1371/journal.ppat.1003543 23966858

5. Pepperell C, Hoeppner VH, Lipatov M, Wobeser W, Schoolnik GK, Feldman MW. Bacterial Genetic Signatures of Human Social Phenomena among M. tuberculosis from an Aboriginal Canadian Population. Mol Biol Evol. 2010;27: 427–440. doi: 10.1093/molbev/msp261 19861642

6. Pepperell CS, Granka JM, Alexander DC, Behr MA, Chui L, Gordon J, et al. Dispersal of Mycobacterium tuberculosis via the Canadian fur trade. Proc Natl Acad Sci. 2011;108: 6526–6531. doi: 10.1073/pnas.1016708108 21464295

7. Namouchi A, Didelot X, Schöck U, Gicquel B, Rocha EPC. After the bottleneck: Genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection. Genome Res. 2012;22: 721–734. doi: 10.1101/gr.129544.111 22377718

8. Tanaka MM. Evidence for positive selection on Mycobacterium tuberculosis within patients. BMC Evol Biol. 2004;4: 31. 15355550

9. Golubchik T, Batty EM, Miller RR, Farr H, Young BC, Larner-Svensson H, et al. Within-Host Evolution of Staphylococcus aureus during Asymptomatic Carriage. PLoS ONE. 2013;8: e61319. doi: 10.1371/journal.pone.0061319 23658690

10. McAdam PR, Holmes A, Templeton KE, Fitzgerald JR. Adaptive Evolution of Staphylococcus aureus during Chronic Endobronchial Infection of a Cystic Fibrosis Patient. PLoS ONE. 2011;6.

11. Kennemann L, Didelot X, Aebischer T, Kuhn S, Drescher B, Droege M, et al. Helicobacter pylori genome evolution during human infection. Proc Natl Acad Sci. 2011;108: 5033–5038. doi: 10.1073/pnas.1018444108 21383187

12. Ford CB, Lin PL, Chase MR, Shah RR, Iartchouk O, Galagan J, et al. Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet. 2011;43: 482–486. doi: 10.1038/ng.811 21516081

13. Lieberman TD, Michel J-B, Aingaran M, Potter-Bynoe G, Roux D, MRD Jr, et al. Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes. Nat Genet. 2011;43: 1275–1280. doi: 10.1038/ng.997 22081229

14. Feliziani S, Marvig RL, Luján AM, Moyano AJ, Di Rienzo JA, Krogh Johansen H, et al. Coexistence and Within-Host Evolution of Diversified Lineages of Hypermutable Pseudomonas aeruginosa in Long-term Cystic Fibrosis Infections. PLoS Genet. 2014;10: e1004651. doi: 10.1371/journal.pgen.1004651 25330091

15. Fothergill JL, Neill DR, Loman N, Winstanley C, Kadioglu A. Pseudomonas aeruginosa adaptation in the nasopharyngeal reservoir leads to migration and persistence in the lungs. Nat Commun. 2014;5.

16. Linz B, Windsor HM, McGraw JJ, Hansen LM, Gajewski JP, Tomsho LP, et al. A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques. Nat Commun. 2014;5.

17. Markussen T, Marvig RL, Gómez-Lozano M, Aanæs K, Burleigh AE, Høiby N, et al. Environmental Heterogeneity Drives Within-Host Diversification and Evolution of Pseudomonas aeruginosa. mBio. 2014;5: e01592–14. doi: 10.1128/mBio.01592-14 25227464

18. Marvig RL, Sommer LM, Molin S, Johansen HK. Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis. Nat Genet. 2014;

19. Clark ST, Diaz Caballero J, Cheang M, Coburn B, Wang PW, Donaldson SL, et al. Phenotypic diversity within a Pseudomonas aeruginosa population infecting an adult with cystic fibrosis. Sci Rep. 2015;5: 10932. doi: 10.1038/srep10932 26047320

20. Sahl JW, Sistrunk JR, Fraser CM, Hine E, Baby N, Begum Y, et al. Examination of the Enterotoxigenic Escherichia coli Population Structure during Human Infection. mBio. 2015;6: e00501–15. doi: 10.1128/mBio.00501-15 26060273

21. Stoesser N, Sheppard AE, Moore CE, Golubchik T, Parry CM, Nget P, et al. Extensive Within-Host Diversity in Fecally Carried Extended-Spectrum-Beta-Lactamase-Producing Escherichia coli Isolates: Implications for Transmission Analyses. J Clin Microbiol. 2015;53: 2122–2131. doi: 10.1128/JCM.00378-15 25903575

22. Lieberman TD, Flett KB, Yelin I, Martin TR, McAdam AJ, Priebe GP, et al. Genetic variation of a bacterial pathogen within individuals with cystic fibrosis provides a record of selective pressures. Nat Genet. 2014;46: 82–87. doi: 10.1038/ng.2848 24316980

23. Sun G, Luo T, Yang C, Dong X, Li J, Zhu Y, et al. Dynamic population changes in Mycobacterium tuberculosis during acquisition and fixation of drug resistance in patients. J Infect Dis. 2012;206: 1724–1733. doi: 10.1093/infdis/jis601 22984115

24. Saunders NJ, Trivedi UH, Thomson ML, Doig C, Laurenson IF, Blaxter ML. Deep resequencing of serial sputum isolates of Mycobacterium tuberculosis during therapeutic failure due to poor compliance reveals stepwise mutation of key resistance genes on an otherwise stable genetic background. J Infect. 2011;62: 212–217. doi: 10.1016/j.jinf.2011.01.003 21237201

25. Eldholm V, Norheim G, von der Lippe B, Kinander W, Dahle UR, Caugant DA, et al. Evolution of extensively drug-resistant Mycobacterium tuberculosis from a susceptible ancestor in a single patient. Genome Biol. 2014;15: 490. doi: 10.1186/s13059-014-0490-3 25418686

26. Merker M, Kohl TA, Roetzer A, Truebe L, Richter E, Rüsch-Gerdes S, et al. Whole Genome Sequencing Reveals Complex Evolution Patterns of Multidrug-Resistant Mycobacterium tuberculosis Beijing Strains in Patients. PLoS ONE. 2013;8: e82551. doi: 10.1371/journal.pone.0082551 24324807

27. Kofler R, Orozco-terWengel P, De Maio N, Pandey RV, Nolte V, Futschik A, et al. PoPoolation: a toolbox for population genetic analysis of next generation sequencing data from pooled individuals. PloS One. 2011;6: e15925. doi: 10.1371/journal.pone.0015925 21253599

28. Achaz G. Testing for Neutrality in Samples With Sequencing Errors. Genetics. 2008;179: 1409–1424. doi: 10.1534/genetics.107.082198 18562660

29. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet. 2013;advance online publication.

30. Sandgren A, Strong M, Muthukrishnan P, Weiner BK, Church GM, Murray MB. Tuberculosis Drug Resistance Mutation Database. PLoS Med. 2009;6: e1000002.

31. Ford CB, Shah RR, Maeda MK, Gagneux S, Murray MB, Cohen T, et al. Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat Genet. 2013;advance online publication.

32. Osorio NS, Rodrigues F, Gagneux S, Pedrosa J, Pinto-Carbo M, Castro AG, et al. Evidence for Diversifying Selection in a Set of Mycobacterium tuberculosis Genes in Response to Antibiotic- and Nonantibiotic-Related Pressure. Mol Biol Evol. 2013;30: 1326–36. doi: 10.1093/molbev/mst038 23449927

33. Tajima F. Statistical Method for Testing the Neutral Mutation Hypothesis by DNA Polymorphism. Genetics. 1989;123: 585–595. 2513255

34. Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L. Natural selection has driven population differentiation in modern humans. Nat Genet. 2008;40: 340–345. doi: 10.1038/ng.78 18246066

35. Myles S, Tang K, Somel M, Green RE, Kelso J, Stoneking M. Identification and Analysis of Genomic Regions with Large Between-Population Differentiation in Humans. Ann Hum Genet. 2008;72: 99–110. doi: 10.1111/j.1469-1809.2007.00390.x 18184145

36. The International HapMap Consortium. A haplotype map of the human genome. Nature. 2005;437: 1299–1320. 16255080

37. Kofler R, Pandey RV, Schlotterer C. PoPoolation2: identifying differentiation between populations using sequencing of pooled DNA samples (Pool-Seq). Bioinformatics. 2011;27: 3435–3436. doi: 10.1093/bioinformatics/btr589 22025480

38. Fabian DK, Kapun M, Nolte V, Kofler R, Schmidt PS, Schlötterer C, et al. Genome-wide patterns of latitudinal differentiation among populations of Drosophila melanogaster from North America. Mol Ecol. 2012;21: 4748–4769. doi: 10.1111/j.1365-294X.2012.05731.x 22913798

39. Lew JM, Kapopoulou A, Jones LM, Cole ST. TubercuList– 10 years after. Tuberculosis. 2011;91: 1–7. doi: 10.1016/j.tube.2010.09.008 20980199

40. Tatusov RL, Galperin MY, Natale DA, Koonin EV. The COG database: a tool for genome-scale analysis of protein functions and evolution. Nucleic Acids Res. 2000;28: 33–36. 10592175

41. Kryazhimskiy S, Plotkin JB. The population genetics of dN/dS. PLoS Genet. 2008;4: e1000304. doi: 10.1371/journal.pgen.1000304 19081788

42. Supply P, Warren RM, Bañuls A-L, Lesjean S, Van Der Spuy GD, Lewis L-A, et al. Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area. Mol Microbiol. 2003;47: 529–538. 12519202

43. Zhang H, Li D, Zhao L, Fleming J, Lin N, Wang T, et al. Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance. Nat Genet. 2013;45: 1255–1260. doi: 10.1038/ng.2735 23995137

44. Farhat MR, Shapiro BJ, Kieser KJ, Sultana R, Jacobson KR, Victor TC, et al. Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis. Nat Genet. 2013;45: 1183–1189. doi: 10.1038/ng.2747 23995135

45. Griffin JE, Gawronski JD, DeJesus MA, Ioerger TR, Akerley BJ, Sassetti CM. 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

46. Merker M, Blin C, Mona S, Duforet-Frebourg N, Lecher S, Willery E, et al. Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage. Nat Genet. 2015;47: 242–249. doi: 10.1038/ng.3195 25599400

47. Gavalda S, Léger M, Rest B van der, Stella A, Bardou F, Montrozier H, et al. The Pks13/FadD32 Crosstalk for the Biosynthesis of Mycolic Acids in Mycobacterium tuberculosis. J Biol Chem. 2009;284: 19255–19264. doi: 10.1074/jbc.M109.006940 19436070

48. Kawate T, Iwase N, Shimizu M, Stanley SA, Wellington S, Kazyanskaya E, et al. Synthesis and structure–activity relationships of phenyl-substituted coumarins with anti-tubercular activity that target FadD32. Bioorg Med Chem Lett. 2013;23: 6052–6059. doi: 10.1016/j.bmcl.2013.09.035 24103299

49. Stanley SA, Kawate T, Iwase N, Shimizu M, Clatworthy AE, Kazyanskaya E, et al. Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. Proc Natl Acad Sci. 2013;110: 11565–11570. doi: 10.1073/pnas.1302114110 23798446

50. Chalut C, Botella L, Sousa-D’Auria C de, Houssin C, Guilhot C. The nonredundant roles of two 4′-phosphopantetheinyl transferases in vital processes of Mycobacteria. Proc Natl Acad Sci. 2006;103: 8511–8516. 16709676

51. Quadri LEN, Sello J, Keating TA, Weinreb PH, Walsh CT. Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem Biol. 1998;5: 631–645. 9831524

52. Quadri LEN. Biosynthesis of mycobacterial lipids by polyketide synthases and beyond. Crit Rev Biochem Mol Biol. 2014;49: 179–211. doi: 10.3109/10409238.2014.896859 24625105

53. Jackson M, Stadthagen G, Gicquel B. Long-chain multiple methyl-branched fatty acid-containing lipids of Mycobacterium tuberculosis: Biosynthesis, transport, regulation and biological activities. Tuberculosis. 2007;87: 78–86. 17030019

54. Neyrolles O, Guilhot C. Recent advances in deciphering the contribution of Mycobacterium tuberculosis lipids to pathogenesis. Tuberculosis. 2011;91: 187–195. doi: 10.1016/j.tube.2011.01.002 21330212

55. Domenech P, Reed MB, Barry CE. Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect Immun. 2005;73: 3492–501. 15908378

56. MacGurn JA, Cox JS. A Genetic Screen for Mycobacterium tuberculosis Mutants Defective for Phagosome Maturation Arrest Identifies Components of the ESX-1 Secretion System. Infect Immun. 2007;75: 2668–2678. 17353284

57. Pérez J, Garcia R, Bach H, de Waard JH, Jacobs WR Jr., Av-Gay Y, et al. Mycobacterium tuberculosis transporter MmpL7 is a potential substrate for kinase PknD. Biochem Biophys Res Commun. 2006;348: 6–12. 16879801

58. Primm TP, Andersen SJ, Mizrahi V, Avarbock D, Rubin H, Barry CE. The Stringent Response of Mycobacterium tuberculosis Is Required for Long-Term Survival. J Bacteriol. 2000;182: 4889–4898. 10940033

59. Dahl JL, Kraus CN, Boshoff HIM, Doan B, Foley K, Avarbock D, et al. The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proc Natl Acad Sci. 2003;100: 10026–10031. 12897239

60. Gonzalo-Asensio J, Mostowy S, Harders-Westerveen J, Huygen K, Hernández-Pando R, Thole J, et al. PhoP: A Missing Piece in the Intricate Puzzle of Mycobacterium tuberculosis Virulence. Ahmed N, editor. PLoS ONE. 2008;3: e3496. doi: 10.1371/journal.pone.0003496 18946503

61. Guo M, Feng H, Zhang J, Wang W, Wang Y, Li Y, et al. Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system. Genome Res. 2009;19: 1301–1308. doi: 10.1101/gr.086595.108 19228590

62. Gonzalo-Asensio J, Malaga W, Pawlik A, Astarie-Dequeker C, Passemar C, Moreau F, et al. Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator. Proc Natl Acad Sci. 2014; 201406693.

63. Sherrid AM, Rustad TR, Cangelosi GA, Sherman DR. Characterization of a Clp Protease Gene Regulator and the Reaeration Response in Mycobacterium tuberculosis. PLoS ONE. 2010;5: e11622. doi: 10.1371/journal.pone.0011622 20661284

64. Peyron P, Vaubourgeix J, Poquet Y, Levillain F, Botanch C, Bardou F, et al. Foamy Macrophages from Tuberculous Patients’ Granulomas Constitute a Nutrient-Rich Reservoir for M. tuberculosis Persistence. PLoS Pathog. 2008;4: e1000204. doi: 10.1371/journal.ppat.1000204 19002241

65. Rao V, Gao F, Chen B, Jacobs WR, Glickman MS. Trans -cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis–induced inflammation and virulence. J Clin Invest. 2006;116: 1660–1667. 16741578

66. Camacho LR, Ensergueix D, Perez E, Gicquel B, Guilhot C. Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol Microbiol. 1999;34: 257–267. 10564470

67. 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

68. Kaufmann SHE, Rubin Eric. Handbook of tuberculosis: molecular biology and biochemistry. Weinheim: Wiley-VCH; 2008.

69. Day TA, Mittler JE, Nixon MR, Thompson C, Miner MD, Hickey MJ, et al. Mycobacterium tuberculosis strains lacking the surface lipid phthiocerol dimycocerosate are susceptible to killing by an early innate host response. Infect Immun. 2014; IAI.01340–13.

70. Lemassu A, Lanéelle M-A, Daffé M. Revised structure of a trehalose-containing immunoreactive glycolipid of Mycobacterium tuberculosis. FEMS Microbiol Lett. 1991;78: 171–176.

71. Minnikin DE, Dobson G, Sesardic D, Ridell M. Mycolipenates and Mycolipanolates of Trehalose from Mycobacterium tuberculosis. J Gen Microbiol. 1985;131: 1369–1374. 3930656

72. Rousseau C, Neyrolles O, Bordat Y, Giroux S, Sirakova TD, Prevost M-C, et al. Deficiency in mycolipenate- and mycosanoate-derived acyltrehaloses enhances early interactions of Mycobacterium tuberculosis with host cells. Cell Microbiol. 2003;5: 405–415. 12780778

73. Saavedra R, Segura E, Leyva R, Esparza LA, López-Marín LM. Mycobacterial Di-O-Acyl-Trehalose Inhibits Mitogen- and Antigen-Induced Proliferation of Murine T Cells In Vitro. Clin Diagn Lab Immunol. 2001;8: 1081–1088. 11687444

74. Lee K-S, Dubey VS, Kolattukudy PE, Song C-H, Shin A-R, Jung S-B, et al. Diacyltrehalose of Mycobacterium tuberculosis inhibits lipopolysaccharide- and mycobacteria-induced proinflammatory cytokine production in human monocytic cells. FEMS Microbiol Lett. 2007;267: 121–128. 17156119

75. Goren MB, D’Arcy Hart P, Young MR, Armstrong JA. Prevention of phagosome-lysosome fusion in cultured macrophages by sulfatides of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 1976;73: 2510–2514. 821057

76. Brozna JP, Horan M, Rademacher JM, Pabst KM, Pabst MJ. Monocyte responses to sulfatide from Mycobacterium tuberculosis: inhibition of priming for enhanced release of superoxide, associated with increased secretion of interleukin-1 and tumor necrosis factor alpha, and altered protein phosphorylation. Infect Immun. 1991;59: 2542–2548. 1649796

77. Brodin P, Poquet Y, Levillain F, Peguillet I, Larrouy-Maumus G, Gilleron M, et al. High Content Phenotypic Cell-Based Visual Screen Identifies Mycobacterium tuberculosis Acyltrehalose-Containing Glycolipids Involved in Phagosome Remodeling. PLoS Pathog. 2010;6: e1001100. doi: 10.1371/journal.ppat.1001100 20844580

78. Moody DB, Ulrichs T, Mühlecker W, Young DC, Gurcha SS, Grant E, et al. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature. 2000;404: 884–888. 10786796

79. Matsunaga I, Bhatt A, Young DC, Cheng T-Y, Eyles SJ, Besra GS, et al. Mycobacterium tuberculosis pks12 Produces a Novel Polyketide Presented by CD1c to T Cells. J Exp Med. 2004;200: 1559–1569. 15611286

80. Sirakova TD, Dubey VS, Kim H-J, Cynamon MH, Kolattukudy PE. The Largest Open Reading Frame (pks12) in the Mycobacterium tuberculosis Genome Is Involved in Pathogenesis and Dimycocerosyl Phthiocerol Synthesis. Infect Immun. 2003;71: 3794–3801. 12819062

81. Ly D, Kasmar AG, Cheng T-Y, Jong A de, Huang S, Roy S, et al. CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens. J Exp Med. 2013;210: 729–741. doi: 10.1084/jem.20120624 23530121

82. Lynett J, Stokes RW. Selection of transposon mutants of Mycobacterium tuberculosis with increased macrophage infectivity identifies fadD23 to be involved in sulfolipid production and association with macrophages. Microbiology. 2007;153: 3133–3140. 17768256

83. Rosas-Magallanes V, Stadthagen-Gomez G, Rauzier J, Barreiro LB, Tailleux L, Boudou F, et al. Signature-Tagged Transposon Mutagenesis Identifies Novel Mycobacterium tuberculosis Genes Involved in the Parasitism of Human Macrophages. Infect Immun. 2007;75: 504–507. 17030567

84. Beaulieu AM, Rath P, Imhof M, Siddall ME, Roberts J, Schnappinger D, et al. Genome-Wide Screen for Mycobacterium tuberculosis Genes That Regulate Host Immunity. PLoS ONE. 2010;5.

85. Dutta NK, Mehra S, Didier PJ, Roy CJ, Doyle LA, Alvarez X, et al. Genetic Requirements for the Survival of Tubercle Bacilli in Primates. J Infect Dis. 2010;201: 1743–1752. doi: 10.1086/652497 20394526

86. Reed MB, Domenech P, Manca C, Su H, Barczak AK, Kreiswirth BN, et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature. 2004;431: 84–87. 15343336

87. Passemar C, Arbués A, Malaga W, Mercier I, Moreau F, Lepourry L, et al. Multiple deletions in the polyketide synthase gene repertoire of Mycobacterium tuberculosis reveal functional overlap of cell envelope lipids in host–pathogen interactions. Cell Microbiol. 2014;16: 195–213. doi: 10.1111/cmi.12214 24028583

88. Jain M, Petzold CJ, Schelle MW, Leavell MD, Mougous JD, Bertozzi CR, et al. Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling. Proc Natl Acad Sci. 2007;104: 5133–5138. 17360366

89. Kruh NA, Borgaro JG, Ruzsicska BP, Xu H, Tonge PJ. A Novel Interaction Linking the FAS-II and Phthiocerol Dimycocerosate (PDIM) Biosynthetic Pathways. J Biol Chem. 2008;283: 31719–31725. doi: 10.1074/jbc.M802169200 18703500

90. Domenech P, Reed MB. Rapid and spontaneous loss of phthiocerol dimycocerosate (PDIM) from Mycobacterium tuberculosis grown in vitro: implications for virulence studies. Microbiology. 2009;155: 3532–43. doi: 10.1099/mic.0.029199-0 19661177

91. Betts JC, Lukey PT, Robb LC, McAdam RA, Duncan K. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol. 2002;43: 717–731. 11929527

92. Rodriguez JE, Ramirez AS, Salas LP, Helguera-Repetto C, Gonzalez-y-Merchand J, Soto CY, et al. Transcription of Genes Involved in Sulfolipid and Polyacyltrehalose Biosynthesis of Mycobacterium tuberculosis in Experimental Latent Tuberculosis Infection. PLoS ONE. 2013;8.

93. Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, Monahan IM, et al. Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages Insights into the Phagosomal Environment. J Exp Med. 2003;198: 693–704. 12953091

94. Talaat AM, Lyons R, Howard ST, Johnston SA. The temporal expression profile of Mycobacterium tuberculosis infection in mice. Proc Natl Acad Sci U A. 2004;101: 4602–7.

95. Singh A, Gupta R, Vishwakarma RA, Narayanan PR, Paramasivan CN, Ramanathan VD, et al. Requirement of the mymA Operon for Appropriate Cell Wall Ultrastructure and Persistence of Mycobacterium tuberculosis in the Spleens of Guinea Pigs. J Bacteriol. 2005;187: 4173–4186. 15937179

96. Minoche AE, Dohm JC, Himmelbauer H. Evaluation of genomic high-throughput sequencing data generated on Illumina HiSeq and Genome Analyzer systems. Genome Biol. 2011;12: R112. doi: 10.1186/gb-2011-12-11-r112 22067484

97. Hirsh AE, Tsolaki AG, DeRiemer K, Feldman MW, Small PM. Stable association between strains of Mycobacterium tuberculosis and their human host populations. Proc Natl Acad Sci U S A. 2004;101: 4871–4876. 15041743

98. Firdessa R, Berg S, Hailu E, Schelling E, Gumi B, Erenso G, et al. Mycobacterial Lineages Causing Pulmonary and Extrapulmonary Tuberculosis, Ethiopia. Emerg Infect Dis. 2013;19: 460–463. doi: 10.3201/eid1903.120256 23622814

99. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet.journal. 2011;17: pp. 10–12.

100. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393: 537–544. 9634230

101. Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. ArXiv13033997 Q-Bio. 2013; http://arxiv.org/abs/1303.3997

102. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43: 491–498. doi: 10.1038/ng.806 21478889

103. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25: 2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

104. Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics. 2009;25: 1754–1760. doi: 10.1093/bioinformatics/btp324 19451168

105. Reddy TBK, Riley R, Wymore F, Montgomery P, DeCaprio D, Engels R, et al. TB database: an integrated platform for tuberculosis research. Nucleic Acids Res. 2009;37: D499–D508. doi: 10.1093/nar/gkn652 18835847

106. R Development Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, Austria: R Foundation for Statistical Computing; http://www.R-project.org/

107. Sassetti CM, Boyd DH, Rubin EJ. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 2003;48: 77–84. 12657046

108. Sassetti CM, Rubin EJ. Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci. 2003;100: 12989–12994. 14569030

109. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics. 2014; btu153.

110. Li L, Stoeckert CJ, Roos DS. OrthoMCL: Identification of Ortholog Groups for Eukaryotic Genomes. Genome Res. 2003;13: 2178–2189. 12952885

111. Katoh K, Standley DM. MAFFT: iterative refinement and additional methods. Methods Mol Biol Clifton NJ. 2014;1079: 131–146.

112. Capella-Gutiérrez S, Silla-Martínez JM, Gabaldón T. trimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses. Bioinformatics. 2009; btp348.

113. Stamatakis A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics. 2014;30: 1312–1313. doi: 10.1093/bioinformatics/btu033 24451623

114. Huson DH, Scornavacca C. Dendroscope 3: An Interactive Tool for Rooted Phylogenetic Trees and Networks. Syst Biol. 2012; sys062.

Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens

2015 Číslo 11
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.


Nemáte účet?  Registrujte sa