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  1. Thank you for viewing this presentation. • We would like to remind you that this material is the property of the author.It is provided to you by the ERS for your personal use only, as submitted by the author. • 2010 by the author

  2. TNF TLR2TLR4 M. tuberculosis Mf Man, migration, and M. tuberculosis evolution Stefan Niemann Molecular Mycobacteriology Research Center Borstel, Borstel, Germany "Learning from strains in the field" I have no, real or perceived, conflicts of interest that relate to this presentation.

  3. Evolution and adaptation "Everything existing in the universe is the fruit of chance and necessity.“ Democritus, 460-370 B.C.

  4. M. tuberculosis complex • Human pathogenic species • M. tuberculosis • M. africanum • M. canettii • Animal pathogenic species • M. bovis • M. caprae • M. pinnipedii • M. microti • Gram-positive, acid fast • Characteristic cell wall • Genetically monomorph • Differentiation based on phenotypical characteristics • Obligate intracellular pathogens

  5. M.tb. (Clade I) S LAM III Uganda II LAM II Uganda I Ghana 94129 2176/99 18 1521/99 99123 96 2319/99 46 97062 118 98026 99060 2253/99 2333/99 96085 99035 99043 2201/99 12 IPC47 2582/02 2307/99 2263/99 X1 and X3 34 98104 10515/01 104 2211/99 97116 35 00-046 IPC32 2169/99 2191/99 53 5357/02 99120 82 66 120 99016 96119 2173/99 41 98 10 95 2111/99 2379/99 99024 37 10486/01 00-031 2597/02 1438/02 98034 1647/99 41 4 98024 42 2224/99 2570/02 98006 2329/99 97 1571/99 2197/99 2331/99 LAM I 98100 13 99102 71 98077 87 00-101 10469/01 10470/01 40 00-040 98107 97108 10493/01 23 00-083 40 Haarlem I 98004 3262/02 158 4217/02 101 3310/02 98065 7 28 4431/02 2336/02 Cameroun 4428/02 4993/02 0446/01 4130/02 80 10438/01 121 10481/01 29 13 1428/02 5390/02 8 58 50 5429/02 60 10445/01 00-071 5400/02 86 51 10439/01 3342/02 1417/02 9679/00 99008 9400/02 Haarlem II 32 109 4850/03 121 Mt14323 M6 1 IPC35 74 147 53 B2 33 21 77 7190/03 98008 87 43 99005 1797/03 93 67 00-055 63 EAI 97070 97066 00-068 123 98079 36 95054 947/01 X2 B4 65 98094 98036 21 559 7936/01 97010 96076 03BR0062 2637/02 220 6427/01 97088 72 203 9267/01 04BR0311 9915/01 217 7747/01 04BR0050 43 02BR0061 822 47 106 9398/01 M28 112 99019 04BR0142 03BR0070 04BR0235 69 19 131 111 04BR0032 1443/02 2569/02 04BR0270 10494/01 10458/02 02BR0024 03BR0311 54 03BR0145 8303/02 83 7507/01 03BR0204 10473/01 44 04BR0309 03BR0162 5432/02 10480/01 1805/02 West-Africa 1b 4802/03 30 CentralAsiaDehli 1410/02 90 1473/02 04BR0159 4804/03 14 3243/02 04BR0278 3364/02 1465/02 03BR0116 5398/02 7746/01 03BR0107 1449/02 5473/02 03BR0139 45 8260/01 4445/02 5434/02 20 69 03BR0244 10400/02 03BR0298 49 3482/03 81 3309/02 24 03BR0027 92 3256/02 West-Africa 1a 76 3277/02 2577/02 85 97025 7011/02 101 4498/02 34 03BR0041 3329/02 6 9062/01 Seal 83 02BR0046 62 8668/99 1696/00 03BR0109 10476/01 25 8986/99 5468/02 9550/00 4436/02 8163/02 03BR0290 417/01 10485/01 5346/02 8490/00 287/99 03BR0104 951/01 4499/02 11443/99 8753/00 7618/99 8522/00 10514/01 1479/00 1601/01 8236/02 6997/99 10462/01 751/01 Beijing 130 M. microti 10512/01 7540/01 5383/02 9564/00 9577/99 1694/00 2 bov929 bov01 71 10517/01 7072/01 73 M. caprae 126 117 4258/00 1290/03 8217/02 West-Africa 2 M. canettii(Outgroup) M.africanum M. bovis (Clade II) 0.1 Diverse population structure Phylogenetic tree: 24 Loci MIRU Mycobacterial Interspersed repetitive Units-VNTRs 352 strains Wirth et al. Plos Path 2008

  6. Evolution and global phylogeography Wirth et al. Plos Path 2008

  7. Pathobiological adaptation ?

  8. Pathobiological adaptation

  9. Pathobiological adaptation • Investigation of 5 different genotypes • 3 clinical isolates per genotype • Reference strains: H37Rv, CDC1551 • Representatives of major lineages: • Haarlem • EAI • Beijing • Uganda • West African 2 Homolka et al. PLoS Pathogens in press

  10. Pathobiological adaptation Homolka et al. PLoS Pathogens 2010

  11. Biological diversity • Growth profile of all strains in activated murine macrophages • MOI 3:1 • Determination of CFU on 7H10/OADC solid media Homolka et al. PLoS Pathogens 2010

  12. Pathobiological diversity Genotype specific expression profiles H37Rv Uganda Haarlem Beijing EAI West African 2 CDC1551 In vitro Resting MØ– 24hr Homolka et al. PLoS Pathogens 2010

  13. Pathobiological diversity Definition of a „Intracellular“ core transcriptome H37Rv West African 2 Uganda Haarlem EAI Beijing Homolka et al. PLoS Pathogens 2010

  14. M. M. canettii canettii can can 12 12 Indo Indo - - Oceanic Oceanic 239 239 105 105 TbD1 TbD1 207 207 181 181 East East - - Asian Asian 150 150 9 9 142 142 East East - - African African - - Indian Indian 750 750 Middle East Middle East 122 122 115 115 182 182 183 183 Americas Americas Europe Europe 193 193 Euro Euro - - American American 219 219 pks pks 15/1 15/1 H37Rv H37Rv - - like like Δ Δ 7bp 7bp West Africa West Africa 174 174 726 726 South Africa South Africa 761 761 Central Africa Central Africa 724 724 West West - - African African - - 1 1 711 711 West West - - African African - - 2 2 702 702 7, 8, 10 7, 8, 10 lineage lineage M. M. bovis bovis Host – Pathogen adaptation Prospective study in Ghana 2001 – 2005 1900 patients, 2000 controls Intemann et al. PLoS Pathog 2009

  15. M. tuberculosis antigens Comas et al. Nat Gen 2010

  16. M. tuberculosis antigens cAfter exclusion of the three outlier antigens esxH, pstS1 and Rv1986 Comas et al. Nat Gen 2010

  17. Summary Diverse population structure Reduced purifying selection results in high functional diversity Genetic diversity translates to biological diversity Clade specific transcription signatures Antigens are hyperconserved Future research should try to integrate diversity of the pathogen and the host

  18. Thanks to........... MIRU P. Supply Institute Pasteur Lille TB-Team Borstel Molecular Mycobacteriology T. Wirth Muséum National d'Histoire Naturelle Paris MLST P. Small, S. Gagneux Institute for Systems Biology, Seattle MRC, London All other cooperation partners Transcriptome D. Russel, K. Rhode Cornell University Funding:

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