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Discovery of dormancy associated antigens of Mycobacterium tuberculosis : novel targets for the development of post-exposure or therapeutic tuberculosis vaccines

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(1)Discovery of dormancy associated antigens of Mycobacterium tuberculosis : novel targets for the development of post-exposure or therapeutic tuberculosis vaccines Lin, M.Y.. Citation Lin, M. Y. (2009, December 15). Discovery of dormancy associated antigens of Mycobacterium tuberculosis : novel targets for the development of postexposure or therapeutic tuberculosis vaccines. Retrieved from https://hdl.handle.net/1887/14507 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/14507. Note: To cite this publication please use the final published version (if applicable)..

(2)  Chapter1 Introductionand Outlineofthethesis          . ƒ”–Ž›’—„Ž‹•Š‡†‹ǣ  Dz ‘•–Ǧ’ƒ–Š‘‰‡‹–‡”ƒ –‹‘•‹Žƒ–‡–Mycobacteriumtuberculosis‹ˆ‡ –‹‘ǣ‹†‡–‹ˆ‹ ƒ–‹‘‘ˆ ‡™–ƒ”‰‡–•ˆ‘”–—„‡” —Ž‘•‹•‹–‡”˜‡–‹‘dz†‘ ”‡–ƒ„

(3) —‡‹•‘”†”—‰ƒ”‰‡–•ǤʹͲͲͺ ƒ”ǢͺȋͳȌǣͳͷǦʹͻǤ  ƒ†  Dz‘––‘™ƒ‡ƒ•Ž‡‡’‹‰‰‹ƒ–ǣ‡™‹•‹‰Š–•‹–‘Š‘•–Ǧ’ƒ–Š‘‰‡‹–‡”ƒ –‹‘•‹†‡–‹ˆ›‡™–ƒ”‰‡–• ˆ‘”˜ƒ ‹ƒ–‹‘ƒ‰ƒ‹•–Žƒ–‡–Mycobacteriumtuberculosis‹ˆ‡ –‹‘dz‹‘ŽŠ‡ǤʹͲͲͺƒ›Ǣ ͵ͺͻȋͷȌǣͶͻ͹ǦͷͳͳǤ.  .

(4)   . ͳʹ.

(5) Introductionandoutlineofthethesis . Introduction Tuberculosis:preface  Mycobacteriumtuberculosis,–Š‡ ƒ—•ƒ–‹˜‡ƒ‰‡–‘ˆ–—„‡” —Ž‘•‹•ȋǡƒŽ•‘‘™ƒ•–Š‡ Dz™Š‹–‡ ’Žƒ‰—‡dzȌǡ ™ƒ• ‹†‡–‹ˆ‹‡† „› ‘„‡”– ‘ Š ‹ ͳͺͺʹǤ M. tuberculosis’ Š‹‰ŠŽ› ‘’Ž‡š ‹–‡”ƒ –‹‘• ™‹–Š –Š‡ Š—ƒ Š‘•– Šƒ˜‡ „‡‡ •–—†‹‡† ‹–‡•‡Ž› ‡˜‡” •‹ ‡Ǥ ‡•’‹–‡ –Š‡•‡ ‡ˆˆ‘”–• ƒ› ”‹–‹ ƒŽ ‰ƒ’• ‹ ‘—” ‘™Ž‡†‰‡ ”‡ƒ‹ǡ ’”‡ Ž—†‹‰ •— ‡••ˆ—Ž ‘–”‘Ž ‘ˆ –Š‡  ’ƒ†‡‹ Ǥ M. tuberculosis ‹• ‘‡ ‘ˆ –Š‡ ™‘”Ž†ǯ• ‘•– •— ‡••ˆ—Ž ƒ† •‘’Š‹•–‹ ƒ–‡† ’ƒ–Š‘‰‡•ǡ ƒ• ‹– ƒ—•‡• ’‡”•‹•–‡– ‹ˆ‡ –‹‘ ‹ ™Šƒ– ‹• ‡•–‹ƒ–‡† –‘ „‡ ‘˜‡” ʹ „‹ŽŽ‹‘ ’‡‘’Ž‡ǡ ›‡– Žƒ”‰‡Ž› ™‹–Š‘—– ƒ—•‹‰ Ž‹‹ ƒŽ •›’–‘• ȋƒ•›’–‘ƒ–‹ ‘”DzŽƒ–‡–dz‹ˆ‡ –‹‘dzȌȋͳǦ͵ȌǤ —ƒ „‡‹‰• ”‡’”‡•‡– –Š‡ ‘Ž› ‘™ ƒ–—”ƒŽ ”‡•‡”˜‘‹” ‘ˆ–Š‡ „ƒ ‹ŽŽ—•Ǥ ‘ŽŽ‘™‹‰ ’”‹ƒ”› ‹ˆ‡ –‹‘ǡ ‘Ž› ͷǦͳͲΨ ‘ˆ –Š‘•‡ ‹ˆ‡ –‡† ™‹ŽŽ ‡˜‡” †‡˜‡Ž‘’ ƒ –‹˜‡  †‹•‡ƒ•‡ǡ ‘•–Ž› ™‹–Š‹ –™‘ ›‡ƒ”• ƒ† ‘‘Ž› ’”‡•‡–‹‰ ƒ• ’—Ž‘ƒ”›  ‹ –Š‡ ƒ†—Ž–Ǥ ‹‰Š––‘ͳͲ‹ŽŽ‹‘‹†‹˜‹†—ƒŽ•‡™Ž›†‡˜‡Ž‘’ƒ –‹˜‡‡ƒ Š›‡ƒ”ǡƒ†ʹǦ͵‹ŽŽ‹‘†‹‡ ˆ”‘ –Š‡ †‹•‡ƒ•‡Ǥ Š‡ ”‡ƒ‹‹‰ ͻͲǦͻͷΨ ‘ˆ ‹ˆ‡ –‡† ƒ•‡• †‡˜‡Ž‘’• Žƒ–‡– M. tuberculosis ‹ˆ‡ –‹‘ǡ ™Š‹ Š ƒ „‡ ƒ‹–ƒ‹‡† ˆ‘” –Š‡ Ž‹ˆ‡–‹‡ ‘ˆ –Š‡ ’‡”•‘ —Ž‡•• –Š‡ ‹—‘Ž‘‰‹  „ƒŽƒ ‡ „‡–™‡‡ ’ƒ–Š‘‰‡ ƒ† Š‘•– ‹• ’‡”–—”„‡†Ǣ –Š‹• ƒ –”‹‰‰‡” ”‡ƒ –‹˜ƒ–‹‘ ‘ˆ M. tuberculosis ƒ† ”‡•—Ž– ‹ ’”‘‰”‡••‹‘ –‘ ƒ –‹˜‡ Ǥ Š‡ ‡‘”‘—• ”‡•‡”˜‘‹”‘ˆŽƒ–‡–Ž›‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•”‡’”‡•‡–•–Š‡ƒ‹•‘—” ‡‘ˆ‡™ ƒ•‡• ȋʹȌǡƒŽ–Š‘—‰Š‹–Šƒ•„‡ ‘‡ Ž‡ƒ”–Šƒ–‡™ ƒ•‡• ƒƒŽ•‘ƒ”‹•‡†—‡–‘‡š‘‰‡‘—• ”‡Ǧ‹ˆ‡ –‹‘ ™‹–Š M. tuberculosis ‹ ƒ”‡ƒ• ™‹–Š Š‹‰Š  ‡†‡‹ ‹–› ȋͶǡͷȌǤ Š‡ „‡•–Ǧ ‘™ ˆƒ –‘” †”‹˜‹‰ ’”‘‰”‡••‹‘ ‘ˆ Žƒ–‡– –‘™ƒ”†• ƒ –‹˜‡ ‹ˆ‡ –‹‘ ‹• Š—ƒ ‹—‘†‡ˆ‹ ‹‡ › ˜‹”—• ȋ

(6) Ȍ ‘Ǧ‹ˆ‡ –‹‘ǣ –Š‹• ‹ ”‡ƒ•‡• –Š‡ ’”‘’‘”–‹‘ ‘ˆ  †‹•‡ƒ•‡ ”‡ƒ –‹˜ƒ–‹‘ ˆ”‘ ͷǦͳͲΨ ‹ ƒ Ž‹ˆ‡–‹‡ –‘ ͷǦͳͲΨ ’‡” Ž‹ˆ‡Ǧ›‡ƒ” ȋ͸ȌǤ —‡ –‘ –Š‡ ‡š’ƒ†‹‰

(7) Ȁ

(8)  ’ƒ†‡‹  –Š‡ —„‡” ‘ˆ  ”‡ƒ –‹˜ƒ–‹‘ ”‡Žƒ–‡† ƒ•—ƒŽ–‹‡• ‹• ‰”‘™‹‰Ǥ –Š‡” Š‘•– ƒ† ‡˜‹”‘‡–ƒŽ ˆƒ –‘”• ‹˜‘Ž˜‡† ‹ ‘’”‘‹•‹‰ –Š‡ Š‘•–ǯ• ƒ„‹Ž‹–› –‘ ‘–”‘Ž M. tuberculosis ‹ˆ‡ –‹‘ ‹ Ž—†‡ ƒŽ—–”‹–‹‘ǡ ƒ‰‡‹‰ǡ •–”‡•• ȋ͹Ȍǡ –›’‡Ǧʹ†‹ƒ„‡–‡•ȋͺȌǡ–Š‡—•‡‘ˆ‹—‘•—’’”‡••‹˜‡ƒ‰‡–•ȋ•— Šƒ• ‘”–‹ ‘•–‡”‘‹†•ƒ† ƒ–‹Ǧ ‘‘ Ž‘ƒŽƒ–‹„‘†‹‡•Ȍƒ†Ž‹‡Ž›‰‡‡–‹ ƒŽŽ› ‘–”‘ŽŽ‡†Š‘•–ˆƒ –‘”•Ǥ–Š‡ ’ƒ–Š‘‰‡ǯ••‹†‡ǡ–Š‡„ƒ –‡”‹ƒŽˆƒ –‘”•‡••‡–‹ƒŽ–‘™ƒ‹‰—’–Š‹••Ž‡‡’‹‰Dz‰‹ƒ–dzƒ† –Š‡‹”’”‡ ‹•‡‹–‡”’Žƒ›™‹–ŠŠ‘•–‘Ž‡ —Ž‡•”‡ƒ‹–‘„‡‹†‡–‹ˆ‹‡†Ǥ  AntiTBstrategies:pastandpresent Š‡ ‘•– ‡ˆˆ‹ ‹‡– ƒ† ‘•–Ǧ‡ˆˆ‡ –‹˜‡ ‹–‡”˜‡–‹‘ •–”ƒ–‡‰› ƒ‰ƒ‹•– ƒ› ‹ˆ‡ –‹‘—• †‹•‡ƒ•‡ ‹• ˜ƒ ‹ƒ–‹‘Ǥ ‹ ‡ –Š‡ ͳͻʹͲǯ• Mycobacterium bovis „ƒ ‹ŽŽ‡ ƒŽ‡––‡Ǧ —±”‹ ȋ Ȍ •–”ƒ‹• Šƒ˜‡ „‡‡ ™‹†‡Ž› —•‡† ƒ• ’”‘’Š›Žƒ –‹   ˜ƒ ‹‡•Ǥ   ˜ƒ ‹‡• ƒ”‡ Ž‹˜‡ ƒ––‡—ƒ–‡† „ƒ –‡”‹ƒŽ •–”ƒ‹• –Šƒ– •Šƒ”‡ ƒ Š‹‰Š †‡‰”‡‡ ‘ˆ ‰‡‡–‹  ƒ† ‰‡‘‹  Š‘‘Ž‘‰› ȋεͻͷ ΨȌ ™‹–Š M. tuberculosis ȋͻȌǤ ‡•’‹–‡ ‹–• —•‡ ‹ ƒ••‹˜‡ ˜ƒ ‹ƒ–‹‘ ’”‘‰”ƒ‡•ǡ ǯ•„‡‡ˆ‹–•ƒ†‡ˆˆ‹ ƒ ›”‡ƒ‹•—„Œ‡ –•‘ˆ†‡„ƒ–‡Ǥ Šƒ•’”‘˜‡–‘ „‡ Š‹‰ŠŽ› ‡ˆˆ‹ ƒ ‹‘—• ƒ‰ƒ‹•– •‡˜‡”‡  ‹ Š‹Ž†”‡ǡ ‹ Ž—†‹‰  ‡‹‰‹–‹• ƒ† ‹Ž‹ƒ”› Ǥ

(9)  ƒ††‹–‹‘ǡ   ’”‘–‡ –• ƒ†—Ž–• ƒ‰ƒ‹•– Ž‡’”‘•›ǡ ™Š‹ Š ‹• ƒ—•‡† „› –Š‡ ”‡Žƒ–‡† •’‡ ‹‡• Mycobacterium leprae ȋͳͲǦͳʹȌǤ ˆ‘”–—ƒ–‡Ž›ǡ –Š‹• †‘‡• ‘– –”ƒ•Žƒ–‡ –‘•—ˆˆ‹ ‹‡–’”‘–‡ –‹‘‘ˆƒ†—Ž–•ƒ‰ƒ‹•––Š‡ƒ‹ƒ† ‘–ƒ‰‹‘—•ˆ‘”‘ˆǡ™Š‹ Š‹•. ͳ͵.

(10) Chapter1. ’—Ž‘ƒ”›  ‹ –Š‡ ƒ†—Ž–Ǥ ‡˜‡”ƒŽ ”ƒ†‘‹•‡† ‘–”‘ŽŽ‡† –”‹ƒŽ• ƒ† ‘„•‡”˜ƒ–‹‘ƒŽ •–—†‹‡•‹ƒ†—Ž–•Šƒ˜‡”‡˜‡ƒŽ‡†”ƒ–Š‡”†‹• ”‡’ƒ–”‡•—Ž–•ˆ‘”ǡ”‡’‘”–‹‰’”‘–‡ –‹˜‡ ‡ˆˆ‹ ƒ ‹‡• ”ƒ‰‹‰ ˆ”‘ Ͳ –‘ ͺͲΨ ȋͳͲȌǤ ƒ› ‡š’Žƒƒ–‹‘• Šƒ˜‡ „‡‡ ’—– ˆ‘”™ƒ”† –‘ ƒ ‘—– ˆ‘” –Š‹• ‘—†”—ǡ ‹ Ž—†‹‰ †‹ˆˆ‡”‡ ‡• ‹ –”‹ƒŽ ‡–Š‘†‘Ž‘‰‹‡•ǡ Š‘•– ’‘’—Žƒ–‹‘ ‰‡‡–‹ •ǡ ”‡‰‹‘ƒŽ †‹ˆˆ‡”‡ ‡• ‹ M. tuberculosis •–”ƒ‹•ƒ† †‹ˆˆ‡”‡ ‡• ‹ –Š‡   ˜ƒ ‹‡ •–”ƒ‹• —•‡†Ǥ

(11) – ‹• —””‡–Ž› „‡Ž‹‡˜‡† –Šƒ– Š‡–‡”‘Ž‘‰‘—• ‹—‹–› ‹†— ‡† „› ‡˜‹”‘‡–ƒŽ › ‘„ƒ –‡”‹ƒ ’Žƒ›• ƒ •‹‰‹ˆ‹ ƒ– ”‘Ž‡ ‹ „Ž‘ ‹‰ ‘” ƒ•‹‰  ǯ• ’”‘–‡ –‹˜‡ ‡ˆˆ‹ ƒ › ȋͳ͵ǡ ͳͶȌǤ   ƒŽ•‘ Ž‡ƒ”Ž› ˆƒ‹Ž• –‘ ’”‡˜‡–  ”‡ƒ –‹˜ƒ–‹‘ ˆ”‘ Žƒ–‡– ‹ˆ‡ –‹‘Ǥ ‘”‡‘˜‡”ǡ   ”‡˜ƒ ‹ƒ–‹‘ ‘ˆˆ‡”• ‘ ƒ††‹–‹˜‡ ’”‘–‡ –‹‘ ƒ‰ƒ‹•–  ȋͳͷȌǤ Š‡•‡ ƒ”‡ –Š‡ ’”‹ƒ”› ”‡ƒ•‘• –Šƒ–   Šƒ• Šƒ† Ž‹––Ž‡ ‹’ƒ –‘–Š‡‰Ž‘„ƒŽ’”‡˜ƒŽ‡ ‡ƒ†‡’‹†‡‹‘Ž‘‰›‘ˆǤ ‡˜‡Ž‘’‹‰„‡––‡”˜ƒ ‹‡•–Šƒ– ƒ ‘’Ž‡‡–‘””‡’Žƒ ‡  ‘•–‹–—–‡ƒƒŒ‘” ‰Ž‘„ƒŽ”‡•‡ƒ” Šƒ”‡ƒǤƒ•‹ ƒŽŽ›ǡ–Š‡”‡ƒ”‡–Š”‡‡ƒ‹•–”ƒ–‡‰‹‡•ǣ ͳȌTBsubunitvaccinesǡ„ƒ•‡†—’‘‹—‘†‘‹ƒ–› ‘„ƒ –‡”‹ƒŽƒ–‹‰‡• †‡Ž‹˜‡”‡† ‹ •‡Ž‡ –‡† ’Žƒ–ˆ‘”•ǡ ‹ Ž—†‹‰ ‘Ǧ”‡’Ž‹ ƒ–‹‰ ˜‹”—•‡• ȋǡ †‡‘˜‹”—•‡•Ȍ‘””‡ ‘„‹ƒ–’”‘–‡‹•ƒ†‹š‡†™‹–Š’‘–‡–ƒ†Œ—˜ƒ–•Ǣ ʹȌŽ‹˜‡˜ƒ ‹‡•„ƒ•‡†—’‘geneticallyimprovedBCGǢƒ† ͵ȌŽ‹˜‡˜ƒ ‹‡•„ƒ•‡†—’‘Š‹‰ŠŽ›attenuatedliveM.tuberculosis. Š‡ •—„—‹– „ƒ•‡† ƒ’’”‘ƒ Š‡• ƒ‹ –‘ ‹†— ‡ Š‹‰Š Ž‡˜‡Ž• ‘ˆ ‡ŽŽ ‡†‹ƒ–‡† ‹—‹–› ƒ† ‡‘”› –‘ ƒ •‹‰Ž‡ ‘” ”‡•–”‹ –‡† —„‡” ‘ˆ › ‘„ƒ –‡”‹ƒŽ ƒ–‹‰‡•ǡ ’”‡ˆ‡”ƒ„Ž› –Š‘•‡ –Šƒ– ƒ”‡ ‹—‘†‘‹ƒ– ƒ† ‡••‡–‹ƒŽ ˆ‘” › ‘„ƒ –‡”‹ƒŽ ˜‹”—Ž‡ ‡Ǥ Š‡ ‘ ‡’– „‡Š‹† –Š‡ —•‡ ‘ˆ Ž‹˜‡ › ‘„ƒ –‡”‹ƒŽ ˜ƒ ‹‡• ‹• –Š‡ ‹†— –‹‘ ‘ˆ ƒ „”‘ƒ†‡” ‡ŽŽ—Žƒ” ‹—‡ ”‡•’‘•‡ ƒ‰ƒ‹•– ƒ ’Ž‡–Š‘”ƒ ‘ˆ ƒ–‹‰‡• ™Š‹ Š ƒ› Š‡Ž’ ‰‡‡”ƒ–‹‰ ‘’–‹ƒŽ ’”‘–‡ –‹˜‡ ‹—‹–›Ǥ Š‡•‡ †‹ˆˆ‡”‡– ƒ’’”‘ƒ Š‡• Šƒ˜‡ „‡‡ †‹• —••‡† ‹ †‡–ƒ‹Ž”‡ ‡–Ž›ȋͳ͸ǦͳͺȌǤ Ž‘•–ƒŽŽ‡™‰‡‡”ƒ–‹‘˜ƒ ‹‡•–Šƒ–ƒ”‡ —””‡–Ž›‹ Ž‹‹ ƒŽ†‡˜‡Ž‘’‡–Šƒ˜‡ „‡‡†‡•‹‰‡†ƒ•’”‡Ǧ‡š’‘•—”‡˜ƒ ‹‡•Ǥ”‘’Š›Žƒ –‹ •—„—‹–˜ƒ ‹‡•ƒ”‡‰‡‡”ƒŽŽ› ‘•‹†‡”‡† –‘ „‡ ’ƒ”–‹ —Žƒ”Ž› ‡ˆˆ‡ –‹˜‡ ‹ „‘‘•–‹‰ ‹—‹–› ‹†— ‡† „› ’”‹‘”   ˜ƒ ‹ƒ–‹‘ǡ™Š‡”‡ƒ•Ž‹˜‡› ‘„ƒ –‡”‹ƒŽ˜ƒ ‹‡•ƒ‹–‘”‡’Žƒ ‡ „›‘”‡‡ˆˆ‹ ‹‡– ˜ƒ ‹‡ •–”ƒ‹•Ǥ Š‹Ž•– –Š‡•‡ ˜ƒ ‹‡• ƒ‹ –‘ ‹ ”‡ƒ•‡ Š‘•– ”‡•‹•–ƒ ‡ prior –‘ ‹ˆ‡ –‹‘ǡ–Š‡›ƒ”‡—Ž‹‡Ž›–‘„‡‡ˆˆ‡ –‹˜‡ƒ•’‘•–Ǧ‡š’‘•—”‡‘”–Š‡”ƒ’‡—–‹ ˜ƒ ‹‡•‹ Žƒ–‡–Ž› ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ• ȋͳͻǡ ʹͲȌǤ Š‹• ‹• —†‡”Ž‹‡† „› –Š‡ ƒˆ‘”‡‡–‹‘‡† ‹‡ˆˆ‹ ƒ ›‘ˆ ”‡˜ƒ ‹ƒ–‹‘‹ƒˆˆ‘”†‹‰ƒ††‡†’”‘–‡ –‹‘ ‘’ƒ”‡†–‘•‹‰Ž‡  ƒ†‹‹•–”ƒ–‹‘Ǥ

(12) –‹• Ž‡ƒ”–Šƒ–’‘•–Ǧ‡š’‘•—”‡‘”Dz–Š‡”ƒ’‡—–‹ dz˜ƒ ‹‡•–Šƒ– ‘–”‘Žǡ‘” ‡˜‡ „‡––‡”ǡ ‡”ƒ†‹ ƒ–‡ †‘”ƒ– ’‡”•‹•–‡– „ƒ –‡”‹ƒ ƒ› „‡ ‹’‘”–ƒ– –‘‘Ž• –‘ Š‡Ž’ ’”‘–‡ –‹‰ƒ‰ƒ‹•–”‡ƒ –‹˜ƒ–‹‘ƒ†–Š‡”‡„›‡Šƒ ‡ ‘–”‘ŽȋʹͳȌǤ  StagevariationduringM.tuberculosisinfection Ǧ˜ƒ ‹‡ †‹• ‘˜‡”› ƒ’’”‘ƒ Š‡• ”‡•– ‘ –Š‡ ƒ••—’–‹‘ –Šƒ– –Š‡ ˜ƒ ‹‡ ƒ–‹‰‡• ƒ†‹‹•–‡”‡† ƒ”‡ ‡š’”‡••‡† „› ‹ˆ‡ –‡† Š‘•– ‡ŽŽ•ǡ ™Š‡”‡ –Š‡› ƒ”‡ ”‡ ‘‰‹œ‡† „›  ‡ŽŽ• –Šƒ– ‡š‡ —–‡ –Š‡ †‡•‹”‡† ‡ˆˆ‡ –‘” ”‡•’‘•‡ǡ ‡‹–Š‡” ƒ••‹•–‹‰ ’Šƒ‰‘ ›–‡• ‹ ‘–”‘ŽŽ‹‰‘”‡Ž‹‹ƒ–‹‰Ž‹˜‡„ƒ –‡”‹ƒǡ‘”ǦƒŽ–‡”ƒ–‹˜‡Ž›Ǧ„› ›–‘Ž›•‹•‘ˆ‹ˆ‡ –‡† ‡ŽŽ•Ǥ ‡•’‹–‡ •‹‰‹ˆ‹ ƒ– ƒ†˜ƒ ‡•ǡ ”‡Žƒ–‹˜‡Ž› Ž‹––Ž‡ ‹• ‘™ ƒ„‘—– –Š‡ M. tuberculosis ƒ–‹‰‡”‡’‡”–‘‹”‡–Šƒ–‹•–”—Ž›‡š’”‡••‡†‘–Š‡•—”ˆƒ ‡‘ˆ‹ˆ‡ –‡† ‡ŽŽ•ǡƒ†™Š‹ Š‹• ‘•‹†‡”‡† ”‡Ž‡˜ƒ– –‘ Š—ƒ  ‡ŽŽ•Ǥ Š‹• ‹• ’ƒ”–‹ —Žƒ”Ž› ‡˜‹†‡– ˆ‘” ‘Ž‡ —Ž‡• ‡ ‘†‡† „› ”‡ ‡–Ž› †‹• ‘˜‡”‡† Dz‰”‘—’•dz ‘ˆ M. tuberculosis ‰‡‡• ‡š’”‡••‡† †—”‹‰ ͳͶ.

(13) Introductionandoutlineofthethesis . •’‡ ‹ˆ‹  ’Šƒ•‡• Ǧ‘” •–ƒ‰‡•Ǧ ‘ˆ M. tuberculosis ‹ˆ‡ –‹‘Ǥ ”‘–‡‹• –Šƒ– ƒ”‡ •–”‘‰Ž› ‡š’”‡••‡††—”‹‰–Š‡‡ƒ”Ž›’Šƒ•‡‘ˆ‹ˆ‡ –‹‘ ƒ„‡Š‹‰ŠŽ›‡ˆˆ‹ ƒ ‹‘—•˜ƒ ‹‡–ƒ”‰‡–• ‹‘†‡Ž•‘ˆƒ —–‡‹ˆ‡ –‹‘Ǥ”ƒ†‹–‹‘ƒŽŽ›ǡ˜ƒ ‹‡†‹• ‘˜‡”›Šƒ•ˆ‘ —•‡†‘•–Ž›‘ •— Š ƒ–‹‰‡•ǡ •‡˜‡”ƒŽ ‘ˆ ™Š‹ Š Šƒ˜‡ •Š‘™ •–”‘‰ ’”‘–‡ –‹˜‡ ‡ˆˆ‹ ƒ › ‹ ƒ‹ƒŽ ‘†‡Ž•ǡ ‹ Ž—†‹‰ –Š‡ ™‡ŽŽ ‘™ ‡ƒ”Ž› •–ƒ‰‡ ƒ–‹‰‡• ȋ‡Ǥ‰Ǥ ‡ƒ”Ž› •‡ ”‡–‡† ƒ–‹‰‡‹  –ƒ”‰‡–Ǧ͸ȋǦ͸ȌǡͳͲǤͶǡ‰ͺͷƒ†‰ͺͷȌǤ ‘™‡˜‡”ǡ‘‡ ƒ˜‡ƒ–‘ˆ–Š‹•ƒ’’”‘ƒ Š‹•–Šƒ–ƒ–‹‰‡•–Šƒ–ƒ”‡Š‹‰ŠŽ›‡š’”‡••‡††—”‹‰ ‡ƒ”Ž› ‹ˆ‡ –‹‘ Ǧ‘” —†‡” Žƒ„‘”ƒ–‘”› ‘†‹–‹‘• ‘ˆ Ž‘‰ ’Šƒ•‡ ‰”‘™–ŠǦ ƒ› ‘– ‡ ‡••ƒ”‹Ž› ‹†— ‡ ‘’–‹ƒŽ ‹—‹–› ƒ† ‘ ‘‹–ƒ– ’”‘–‡ –‹‘ †—”‹‰ –Š‡ Žƒ–‡” •–ƒ‰‡•‘ˆ‹ˆ‡ –‹‘ǡ•‹ ‡–Š‡›‹‰Š–‘–„‡‡š’”‡••‡†‘’–‹ƒŽŽ›†—”‹‰Žƒ–‡”•–ƒ‰‡•‘ˆ M.tuberculosis‹ˆ‡ –‹‘Ǥ†‡“—ƒ–‡ ‘–”‘Ž‘ˆŽƒ–‡•–ƒ‰‡‹ˆ‡ –‹‘ƒ›”‡“—‹”‡†‹ˆˆ‡”‡– •—„•‡–• ‘ˆ  ‡ŽŽ Ž‘‡•ǡ ‹ Ž—†‹‰  ‡ŽŽ• •’‡ ‹ˆ‹  ˆ‘” ƒ–‹‰‡• ‡š’”‡••‡† †—”‹‰ Žƒ–‡ •–ƒ‰‡  ‹ˆ‡ –‹‘Ǥ ‡˜‡”ƒŽ ˆƒ –‘”• ƒ› ‘–”‹„—–‡ –‘ –Š‡ Žƒ  ‘ˆ Dz‡ƒ”Ž›dz ƒ–‹‰‡• ‹ ‹†— ‹‰’”‘–‡ –‹‘ƒ‰ƒ‹•–Žƒ–‡•–ƒ‰‡‹ˆ‡ –‹‘ǡ‹ Ž—†‹‰‡šŠƒ—•–‹‘‘ˆ”‡Ž‡˜ƒ– ‡ŽŽ ‡‘”› ’‘’—Žƒ–‹‘•ǡ ‹•—ˆˆ‹ ‹‡– ‡š’”‡••‹‘ ‘ˆ ‡ƒ”Ž› ƒ–‹‰‡• ‘ ‹ˆ‡ –‡† ‡ŽŽ•ǡ ƒ† ‹—‡ ”‡‰—Žƒ–‘”› ‡ˆˆ‡ –• ƒˆˆ‡ –‹‰ –Š‡  ‡ŽŽ• •’‡ ‹ˆ‹  ˆ‘” ‡ƒ”Ž› ‹—‘Ǧ †‘‹ƒ–ƒ–‹‰‡•Ǥ ‘–Š‡”‹’‘”–ƒ–‹••—‡‹•–Šƒ–‡‹–Š‡”ƒ–—”ƒŽ‹ˆ‡ –‹‘‘” ˜ƒ ‹ƒ–‹‘ƒ›„‡ ƒ„Ž‡ –‘ ƒ Š‹‡˜‡ ‘’–‹ƒŽ ƒ –‹˜ƒ–‹‘ ‘ˆ •— Š  ‡ŽŽ• •’‡ ‹ˆ‹  ˆ‘” Žƒ–‡ •–ƒ‰‡ ƒ–‹‰‡•Ǥ ‡–ƒ‹Ž‡† ƒƒŽ›•‹• ‘ˆ –Š‡ M. tuberculosis ‰‡‡• –Šƒ– ƒ”‡ •™‹– Š‡† ‘ •‡Ž‡ –‹˜‡Ž› ȋ‘” ƒ– Ž‡ƒ•–’”‡†‘‹ƒ–Ž›Ȍ†—”‹‰Žƒ–‡•–ƒ‰‡‹ˆ‡ –‹‘ƒ›Š‡Ž’–‘‹†‡–‹ˆ›‘˜‡Žƒ–‹‰‡•–‘ ƒ –‹˜ƒ–‡  ‡ŽŽ• ™‹–Š –Š‡ ’‘–‡–‹ƒŽ –‘ ‘–”‘Ž •— Š •–ƒ‰‡• ‘ˆ ‹ˆ‡ –‹‘Ǥ ƒ”‰‡–‹‰ ƒ† ”‡†‹”‡ –‹‰–Š‡Š—ƒ‹—‡”‡•’‘•‡–‘–Š‡•‡ƒ–‹‰‡•ƒ›–Š—•Š‡Ž’’”‡˜‡–‹‰ ”‡ƒ –‹˜ƒ–‹‘Ǥ ‡ ‘ˆ –Š‡ „‡•– ‘–”‘ŽŽ‡† Žƒ„‘”ƒ–‘”› ‘†‡Ž• –‘ •–—†› ƒ†ƒ’–‹˜‡ ”‡•’‘•‡• ‘ˆ M. tuberculosis †—”‹‰ ‘Ǧ’”‘Ž‹ˆ‡”ƒ–‹‰ ‘†‹–‹‘• ‹• –Š‡ Dzƒ›‡dz ‘†‡Ž ȋʹʹȌǤ Š‹• ‘†‡Ž‹•„ƒ•‡†‘–Š‡‰”ƒ†—ƒŽ†‡’Ž‡–‹‘‘ˆ‘š›‰‡ˆ”‘M.tuberculosis —Ž–—”‡•ǡ™Š‹ Š –”‹‰‰‡”•M.tuberculosis–‘‡–‡”ƒ•–ƒ–‡‘ˆ‘”‡’Ž‹ ƒ–‹‰’‡”•‹•–‡ ‡ȋȌȋ͵ȌǤ™‘ †‹ˆˆ‡”‡–  •–ƒ‰‡• ƒ „‡ †‹• ”‹‹ƒ–‡†ǣ –Š‡ ‹ ”‘ƒ‡”‘„‹  ȋ‘š›‰‡ Ž‡˜‡Ž• ƒ’’”‘ƒ Š‹‰ ͳΨ •ƒ–—”ƒ–‹‘Ȍ ͳ •–ƒ‰‡ǡ ™Š‹ Š ‹• Šƒ”ƒ –‡”‹œ‡† „› ƒ •Ž‘™ ”ƒ–‡ ‘ˆ ‹ ”‡ƒ•‡ ‹ –—”„‹†‹–› ™‹–Š‘—– ‘””‡•’‘†‹‰ ‹ ”‡ƒ•‡ ‹  ǡ ƒ ƒ””‡•– ‘ˆ  •›–Š‡•‹• ƒ† –‘ ƒ Žƒ”‰‡ ‡š–‡– ƒŽ•‘ ”‡†— ‡† ‰‡‡”ƒŽ  •›–Š‡•‹• ȋ͵ǡʹʹȌǤ š’”‡••‹‘ ‘ˆ ‰‡‡• ‡ ‘†‹‰ ‡ƒ”Ž› •–ƒ‰‡ ’”‘–‡‹• •— Š ƒ• Ǧ͸ ƒ† ‰ͺͷ ‹• ”‡’”‡••‡††—”‹‰–Š‹••–ƒ–‹‘ƒ”›’Šƒ•‡ȋʹ͵ȌǤ—”‹‰ͳ–Š‡„ƒ ‹ŽŽ‹•–ƒ”–’”‘†— ‹‰ Žƒ”‰‡ ƒ‘—–• ‘ˆ ‰Ž› ‹‡ †‡Š›†”‘‰‡ƒ•‡ǡ ™Š‹ Š ‘–‹—‡• †—”‹‰ ˆ—”–Š‡” ͳǤ ††‹–‹‘ƒŽŽ›ǡ •–‡ƒ†›  ‘ ‡–”ƒ–‹‘• ƒ”‡ ‘„•‡”˜‡†Ǥ ‘™‡˜‡”ǡ ƒ• •‘‘ ƒ• ‘š›‰‡ •ƒ–—”ƒ–‹‘ Ž‡˜‡Ž• †‡ ”‡ƒ•‡ „‡Ž‘™ ͲǤͲ͸Ψ •ƒ–—”ƒ–‹‘ǡ M. tuberculosis ‡–‡”• –Š‡ ʹ •–ƒ‰‡Ǥ ʹ ‹• ƒ ƒƒ‡”‘„‹  •–ƒ‰‡ ™‹–Š ‘ ˆ—”–Š‡” ‹ ”‡ƒ•‡ ‹ –—”„‹†‹–›ǡ ‘  •›–Š‡•‹• ƒ† ‘•– Ž‹‡Ž› ƒŽ•‘ ‘  •›–Š‡•‹• ȋʹʹȌǤ —”–Š‡”‘”‡ǡ ‹ ‘–”ƒ•– –‘ ͳǡ†‡ ”‡ƒ•‡†Ž‡˜‡Ž•‘ˆ‰Ž› ‹‡†‡Š›†”‘‰‡ƒ•‡ƒ†ƒ†”‘’‹ ‘ ‡–”ƒ–‹‘ ƒ „‡ ‘„•‡”˜‡†Ǥ —”‹‰ –Š‡•‡  •–ƒ‰‡• „ƒ –‡”‹ƒ ƒ”‡ –›’‹ ƒŽŽ› ”‡•‹•–ƒ– –‘ –Š‡ „ƒ –‡”‹ ‹†ƒŽƒ –‹‘•‘ˆ†”—‰•–Šƒ––ƒ”‰‡–ƒ –‹˜‡Ž›”‡’Ž‹ ƒ–‹‰„ƒ ‹ŽŽ‹ȋ͵ȌǤ Š‡—•‡‘ˆ–Š‡•‡‘†‡Ž• ‘„‹‡†™‹–Š‰‡‘‡™‹†‡–”ƒ• ”‹’–‘‡’”‘ˆ‹Ž‹‰Šƒ•Ž‡† –‘ –Š‡ ‹†‡–‹ˆ‹ ƒ–‹‘ ‘ˆ M. tuberculosis ‰‡‡• –Šƒ– ƒ”‡ ’ƒ”–‹ —Žƒ”Ž› ‡š’”‡••‡† †—”‹‰ ‘†‹–‹‘• –Š‘—‰Š– –‘ ”‡’Ž‹ ƒ–‡ „ƒ –‡”‹ƒŽ †‘”ƒ ›Ǥ ‘•—‹Ž et al. ‹‹–‹ƒŽŽ› •–—†‹‡† M. tuberculosis†—”‹‰invitro ‘†‹–‹‘•‘ˆ‹–”‹ ‘š‹†‡ȋȌƒ†Š›’‘š‹ƒǡƒ†‹†‡–‹ˆ‹‡†. ͳͷ.

(14) Chapter1. ƒ”‡‰—Ž‘ ƒŽŽ‡†–Š‡‘•‘”devRȋ†‘”ƒ ›Ȍ”‡‰—Ž‘ǡ–Šƒ– ‘•‹•–•‘ˆͶͺ‰‡‡•™Š‹ Š ƒ”‡ ‘‘”†‹ƒ–‡Ž› —’Ǧ”‡‰—Žƒ–‡† ‹ M. tuberculosis —†‡” –Š‡•‡ ‘†‹–‹‘• ȋʹͶȌǤ ‘‘ ƒˆ–‡”™ƒ”†•ǡ •‡˜‡”ƒŽ •–—†‹‡• •Š‘™‡† ‡š’”‡••‹‘ ƒ† —’Ǧ”‡‰—Žƒ–‹‘ ‘ˆ ƒ› ‘ˆ –Š‡ ‘•/devR ”‡‰—Ž‘ ‰‡‡• „› M. tuberculosis ‹ –Š‡  •–ƒ‰‡• ‘ˆ –Š‡ ƒ›‡ ‘†‡Ž ȋʹͷǡ ʹ͸ȌǤ ‘” ‘ˆ Š‡”ƒ ‡– ƒŽǤ Šƒ• •Š‘™ „‡ˆ‘”‡ –Šƒ– M. tuberculosisǯ ”‡•’‘•‡ –‘ Š›’‘š‹ƒ ™ƒ• Šƒ”ƒ –‡”‹œ‡† „› •‹‰‹ˆ‹ ƒ– ƒŽ–‡”ƒ–‹‘• ‹ –Š‡ ‡š’”‡••‹‘ ‘ˆ ƒ’’”‘š‹ƒ–‡Ž›ͳͲͲ‰‡‡•ǤŠ‡‡š’”‡••‹‘‘ˆ‘˜‡”ͶͲ‰‡‡•ǡƒ‹Ž›‹ Ž—†‹‰‡„‡”• ‘ˆ–Š‡‘•”‡‰—Ž‘ǡ™ƒ•‹†— ‡†™Š‡”‡ƒ•–Šƒ–‘ˆ‘•–‘–Š‡”‰‡‡•™ƒ••‹‰‹ˆ‹ ƒ–Ž› ”‡’”‡••‡†ȋʹ͹ȌǤŠ‡•‡•–—†‹‡•–Š—••—‰‰‡•––Šƒ–M.tuberculosis‹• ƒ’ƒ„Ž‡‘ˆ•Š‘™‹‰ ’Šƒ•‡ •’‡ ‹ˆ‹  ‰‡‡ ‡š’”‡••‹‘Ǥ Š‹• ƒ› ’”‘˜‹†‡ ‘– ‘Ž› ‡™ ‹•‹‰Š–• ‹–‘ ‹–• ‹–”‹‰—‹‰‹ˆ‡ –‹‘„‹‘Ž‘‰›ǡ„—–ƒŽ•‘’”‘˜‹†‡‡™†‹”‡ –‹‘•ˆ‘”ƒ–‹‰‡†‹• ‘˜‡”›ƒ†  ˜ƒ ‹‡ ƒ† †”—‰ †‡•‹‰Ǥ

(15)  –Š‹• ‹–”‘†— –‹‘ •‡˜‡”ƒŽ ƒ•’‡ –• ‘ˆ Š‘•–Ȃ’ƒ–Š‘‰‡ ‹–‡”ƒ –‹‘•™‹ŽŽ„‡†‹• —••‡†ˆ‘ŽŽ‘™‡†„›–Š‡• ‘’‡ƒ†‘—–Ž‹‡‘ˆ–Š‹•–Š‡•‹•Ǥ  Infectionanddisease —„‡” —Ž‘•‹• ‹ˆ‡ –‹‘ ‹• ƒ “—‹”‡† –Š”‘—‰Š ‹ŠƒŽƒ–‹‘ ‘ˆ ƒ‡”‘•‘Ž‹œ‡† ‹ˆ‡ –‹‘—• ’ƒ”–‹ Ž‡• ‘–ƒ‹‹‰M.tuberculosisǡ™Š‹ Š ƒ”‡ƒ Š–Š‡ƒŽ˜‡‘Ž‹‹–Š‡†‹•–ƒŽƒ‹”™ƒ›• ȋʹͺȌǤŠ‡„ƒ –‡”‹ƒƒ”‡‰‡‡”ƒŽŽ›–ƒ‡—’„›ƒŽ˜‡‘Žƒ”ƒ ”‘’Šƒ‰‡•™Š‡”‡–Š‡›’‡”•‹•– ƒ†”‡’Ž‹ ƒ–‡•Ž‘™Ž›Ǥ Š‡ ’”‡•‡ ‡ ‘ˆ M. tuberculosis ™‹ŽŽ –”‹‰‰‡” „‘–Š –Š‡ ‹ƒ–‡ ȋ•‡‡ „‡Ž‘™Ȍ ƒ† –Š‡ ƒ†ƒ’–‹˜‡ ‹—‡ ”‡•’‘•‡•ǡ ™Š‹ Š ‹ Ž—†‡ Š‡Ž’‡” ȋͶΪȌ  ‡ŽŽ•ǡ ›–‘–‘š‹  ȋͺΪȌ  ‡ŽŽ•ǡɀɁ ‡ŽŽ•ƒ†’”‘†— –‹‘‘ˆ ›–‘‹‡•ƒ•‹–‡”ˆ‡”‘Jȋ

(16) JȌƒ†–—‘”‡ ”‘•‹• ˆƒ –‘”Dȋ DȌǡ„‘–Š˜‹–ƒŽ‹‹—‹–›–‘Ǥ•ƒ”‡•—Ž–ǡ–Š‡‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ™‹ŽŽ –›’‹ ƒŽŽ› ‘˜‡”––‘ƒ’‘•‹–‹˜‡–—„‡” —Ž‹•‹–‡•–ȋȌǡ™Š‹ Š‹•„ƒ•‡†‘ƒ “—‹”‡† •’‡ ‹ˆ‹  ‹—‹–› ȋ†‡Žƒ›‡†Ǧ–›’‡ Š›’‡”•‡•‹–‹˜‹–›Ȍ –‘ M. tuberculosisǤ ‡•’‹–‡ –Š‡ ‡••‡–‹ƒŽ ”‘Ž‡ ‘ˆ

(17) J ‹ Š‘•– ”‡•‹•–ƒ ‡ –‘ M. tuberculosisǡ ‡˜‹†‡ ‡ ‹• ƒ ——Žƒ–‹‰ –Šƒ–

(18) J‹‹–•‡Žˆ‹•‘–ƒ•—ˆˆ‹ ‹‡– ‘””‡Žƒ–‡‘ˆ’”‘–‡ –‹˜‡‹—‹–›–‘M.tuberculosis ȋʹͻȌǤ ‡ ‡–Ž›ǡ ‹– Šƒ• „‡ ‘‡ ‡˜‹†‡– –Šƒ– •‘Ǧ ƒŽŽ‡† —Ž–‹ˆ— –‹‘ƒŽ  ‡ŽŽ• ‹Ǥ‡Ǥ •‹—Ž–ƒ‡‘—•Ž›’”‘†— ‹‰

(19) Jǡ Dƒ†

(20) Ǧʹǡ†‡ˆ‹‡ƒ ‘””‡Žƒ–‡‘ˆ˜ƒ ‹‡Ǧ‡†‹ƒ–‡† ’”‘–‡ –‹‘ƒ‰ƒ‹•–Leishmaniamajorȋ͵ͲȌƒ†M.tuberculosisȋ͵ͳȌǤ††‹–‹‘ƒŽŽ›ǡ

(21) ǦͳͲ ’‘••‹„Ž› ‹ ‘„‹ƒ–‹‘ ™‹–Š

(22) Ǧʹ Šƒ˜‡ „‡‡ ’—– ˆ‘”™ƒ”† ƒ• ‡™ „‹‘ƒ”‡”• ˆ‘”  ‡Ǥ‰Ǥ ‹ –Š‡ †‹ƒ‰‘•‹• ‘ˆ Žƒ–‡–  ȋ͵ʹȌǤ ›‡”‰‹•–‹  ‹–‡”ƒ –‹‘• „‡–™‡‡ †‹ˆˆ‡”‡– ’ƒ–Š™ƒ›•ǡ •— Š ƒ• ‡˜‹†‡– ˆ‘”

(23) Jǡ  D ƒ†

(24) Ǧʹǡ ƒ› ƒ• –Š‡ ‡••‡–‹ƒŽ ”‘Ž‡ ‘ˆ •‹‰Ž‡ ‹†‹˜‹†—ƒŽ ‘’‘‡–• ‹ ˜ƒ ‹‡ ‹†— ‡† ‹—‹–›Ǥ Š‹• ‹ŽŽ—•–”ƒ–‡• –Š‡ ‡ ‡••‹–› ‘ˆ ‡š’Ž‘”‹‰ ƒ† †‡–‡”‹‹‰ ‘”‡ ‘’Ž‡šǡ —Ž–‹Ǧˆƒ –‘”‹ƒŽ „‹‘ƒ”‡” ’”‘ˆ‹Ž‡•‹’”‘–‡ –‹‘‘ˆǤ  DiagnosisofM.tuberculosisinfection Š‡ –›’‹ ƒŽ •›’–‘• ‘ˆ ’—Ž‘ƒ”›  ƒ”‡’”‘†— –‹˜‡ ’”‘Ž‘‰‡† ‘—‰Šǡ Š‡•– ’ƒ‹ǡ ˆ‡˜‡”ǡ ‡ƒ•› ˆƒ–‹‰ƒ„‹Ž‹–›ǡ ‹‰Š– •™‡ƒ–‹‰ ƒ† ™‡‹‰Š– Ž‘••Ǥ  ƒ ‘Ž›„‡ ‘ˆ‹”‡†„› ‡‹–Š‡” ”ƒ†‹‘‰”ƒ’Š‹  ‡šƒ‹ƒ–‹‘ ƒ†Ȁ‘” †‹ƒ‰‘•–‹  ‹ ”‘„‹‘Ž‘‰›Ǥ ƒ–‡–  ‹• ‘”‡ †‹ˆˆ‹ —Ž– –‘ †‹ƒ‰‘•‡Ǥ ”‘ –Š‡ Žƒ–‡ ͳͻ͵Ͳǯ•ǡ †‡–‡ –‹‘ ‘ˆ Žƒ–‡–  ‹ˆ‡ –‹‘ Šƒ• Žƒ••‹ ƒŽŽ› ”‡Ž‹‡† ‘ –Š‡ ǡ ™Š‹ Š ‹• ’‡”ˆ‘”‡† „› ‹–”ƒ†‡”ƒŽ ƒ†‹‹•–”ƒ–‹‘ ‘ˆ ’—”‹ˆ‹‡† ’”‘–‡‹ †‡”‹˜ƒ–‹˜‡ ȋ ‘” –—„‡” —Ž‹Ȍ ‘ˆ M. tuberculosisǤ ‡ ‘ˆ –Š‡ ƒŒ‘”. ͳ͸.

(25) Introductionandoutlineofthethesis . •Š‘”– ‘‹‰• ‘ˆ –Š‡  ‹• ‹–• Ž‹‹–‡† •’‡ ‹ˆ‹ ‹–› †—‡ –‘ ”‘••Ǧ”‡ƒ –‹˜‹–› ™‹–Š ‡˜‹”‘‡–ƒŽ› ‘„ƒ –‡”‹ƒƒ•™‡ŽŽƒ•™‹–Š Ǥ ‘‘˜‡” ‘‡–Š‹•’”‘„Ž‡ǡ–Š‡”‡ —””‡–Ž›ƒ”‡–™‘ ‘‡” ‹ƒŽˆ‹”•–‰‡‡”ƒ–‹‘ƒ••ƒ›• ƒ˜ƒ‹Žƒ„Ž‡ ƒ‹‹‰ ƒ– ‹’”‘˜‡† †‡–‡ –‹‘ ‘ˆ Žƒ–‡– –—„‡” —Ž‘•‹• ‹ˆ‡ –‹‘Ǥ ‘–Š –Š‡ —ƒ–‹ ̹Ǧ ‘Ž† ƒ••ƒ› ƒ† ǦǤ –‡•– ƒ”‡ „ƒ•‡† ‘ †‡–‡ –‹‰

(26) J ”‡•’‘•‡•–‘–Š‡M.tuberculosis ‘’Ž‡š•’‡ ‹ˆ‹ ƒ–‹‰‡•Ǧ͸ƒ† —Ž–—”‡ˆ‹Ž–”ƒ–‡ ’”‘–‡‹ ͳͲ ȋ ǦͳͲȌ ƒ† ƒ”‡ „‡‹‰ ’”‘‘–‡† ƒ• ‡™ †‹ƒ‰‘•–‹  –‡•–• ‹  ȋ͵͵ȌǤ – –Š‹••–ƒ‰‡ǡŠ‘™‡˜‡”ǡ‹•—ˆˆ‹ ‹‡–ˆ‘”ƒ–‹‘‹•ƒ˜ƒ‹Žƒ„Ž‡–‘‡˜ƒŽ—ƒ–‡–Š‡’”‡ ‹•‡’‘–‡–‹ƒŽ ‘–”‹„—–‹‘ ‘ˆ –Š‡•‡ –‡•–• –‘  †‹ƒ‰‘•‹•ǡ †‡•’‹–‡ –Š‡‹” ‡Šƒ ‡† •’‡ ‹ˆ‹ ‹–›Ǥ Š‹• ’ƒ”–‹ —Žƒ”Ž› Š‘Ž†• ˆ‘” ƒ•‡• ‹ ƒ”‡ƒ• ™‹–Š Š‹‰Š  ‡†‡‹ ‹–›Ǥ

(27)  ƒ”‡ƒ• ™‹–Š Ž‘™ ‡†‡‹ ‹–›ǡ–Š‡•‡ƒ••ƒ›•ƒ›†‡–‡ –”‡ ‡–Ž›„—–‘–•‘— Š‘”‡†‹•–ƒ–Ž›‡š’‘•‡† ‹†‹˜‹†—ƒŽ•Ǥ  TreatmentofTB  –”‡ƒ–‡– ”‡“—‹”‡• Ž‘‰Ǧ–‡” –”‡ƒ–‡– ™‹–Š ƒ ‘„‹ƒ–‹‘ ‘ˆ †”—‰•ǡ ƒ• ”‡ ‘‡†‡†„›–Š‡‘”Ž† ‡ƒŽ–Š”‰ƒ‹•ƒ–‹‘ȋ ȌǤ‹”‡ –Ž›‘„•‡”˜‡†–”‡ƒ–‡– •Š‘”– ‘—”•‡ ȋȌ ‹• –Š‡ ‹–‡”ƒ–‹‘ƒŽŽ› ”‡ ‘‡†‡† –—„‡” —Ž‘•‹• –”‡ƒ–‡– „—‹Ž†‹‰ ‘ ˆ‹˜‡ ‡› ‡Ž‡‡–•ǣ ’‘Ž‹–‹ ƒŽ ‘‹–‡–ǡ ƒ•‡ †‡–‡ –‹‘ǡ •–ƒ†ƒ”†‹•‡† ‘„•‡”˜‡†–Š‡”ƒ’›ǡ‡ˆˆ‡ –‹˜‡†”—‰•—’’Ž›ƒ†‘‹–‘”‹‰ƒ†‡˜ƒŽ—ƒ–‹‘ȋ͵ͶȌǤ‡•’‹–‡ –Š‡‡‘”‘—•‹’ƒ –‘ˆ—Ž–‹’Ž‡†”—‰–Š‡”ƒ’›ȋȌ‘’”‡˜ƒŽ‡ ‡ǡŽ‹‹–‡††”—‰ ƒ˜ƒ‹Žƒ„‹Ž‹–› ƒ† ‘’Ž‹ƒ ‡ ’”‘„Ž‡• Šƒ˜‡ ƒŽŽ‘™‡† †”—‰ ”‡•‹•–ƒ ‡ –‘ ƒ”‹•‡ ‹ Ǥ —‡”‘—•—Ž–‹Ǧ†”—‰”‡•‹•–ƒ–ȋȌƒ†ƒŽ•‘‡š–‡•‹˜‡Ž›†”—‰”‡•‹•–ƒ–ȋȌȋ͵ͷȌ M. tuberculosis •–”ƒ‹• ƒ”‡ ”ƒ’‹†Ž› ƒ”‹•‹‰ ™Š‹ Š ‹ •‘‡ ƒ•‡• ƒ”‡ ˜‹”–—ƒŽŽ› —–”‡ƒ–ƒ„Ž‡™‹–Š —””‡–†”—‰•Ǥ

(28) ˆ–Š‡•‡‡• ƒ’‡˜ƒ”‹ƒ–•™‹ŽŽ–—”‘—––‘„‡‹ˆ‡ –‹‘Ǧ ƒ† –”ƒ•‹••‹‘ ‘’‡–‡–ǡ ™Š‹ Š ‹• •—’’‘”–‡† „› —””‡– †ƒ–ƒǡ –Š‹• ™‹ŽŽ ’‘•‡ •‡”‹‘—• ŠƒŽŽ‡‰‡• –‘ –Š‡ ˆ—–—”‡ ‘–”‘Ž ‘ˆ  ƒ† ƒ› „”‹‰ —• „ƒ  –‘ –Š‡ ’”‡Ǧ ƒ–‹„‹‘–‹ ‡”ƒǤŠ‡• ƒ” ‹–›‘ˆ‡™†”—‰ƒ„Ž‡–ƒ”‰‡–•ˆ‘”‹–”ƒ ‡ŽŽ—Žƒ”’ƒ–Š‘‰‡••— Šƒ• › ‘„ƒ –‡”‹ƒ ƒ† Salmonella ȋ͵͸Ȍ —†‡”Ž‹‡• –Š‡ ‡‡† ˆ‘” ‘’Ž‡–‡Ž› ‡™ ƒ’’”‘ƒ Š‡•‹†”—‰†‹• ‘˜‡”›ˆ‘”–Š‡ ‘–”‘Ž‘ˆ‹–”ƒ ‡ŽŽ—Žƒ”„ƒ –‡”‹ƒŽ†‹•‡ƒ•‡•Ǥ  GeneticpredispositionofTBdisease

(29) –Šƒ•Ž‘‰„‡‡”‡ ‘‰‹œ‡†–Šƒ–„‘–Š‡˜‹”‘‡–ƒŽƒ†‰‡‡–‹ ˆƒ –‘”• ‘–”‹„—–‡–‘ –Š‡•—• ‡’–‹„‹Ž‹–›–‘‹Š—ƒ•ǤŠ‡Š‘•–‰‡‡•‹˜‘Ž˜‡†ƒ”‡’”‘„ƒ„Ž›—‡”‘—•ǡ ƒ† ƒŽ‘•– ‡”–ƒ‹Ž› ‹˜‘Ž˜‡ ‘’Ž‡š ‰‡‡Ǧ‰‡‡ ‹–‡”ƒ –‹‘•Ǥ Š—•ǡ •›‡”‰‹•–‹  ‹–‡”ƒ –‹‘• „‡–™‡‡ †‹ˆˆ‡”‡– ‰‡‡• ƒ† †‘™•–”‡ƒ ’ƒ–Š™ƒ›• ƒ”‡ Ž‹‡Ž› –‘ ‡š‹•–ǡ ™Š‹ Š ƒ› ƒ• –Š‡ ‘–”‹„—–‹‘ ‘ˆ •‹‰Ž‡ ‹†‹˜‹†—ƒŽ ‘’‘‡–•. ‡•’‹–‡ –Š‡ Ž‹‹–ƒ–‹‘• ’‘•‡† „› –Š‡•‡ ’”‘„Ž‡• ‘ Ǧ•—• ‡’–‹„‹Ž‹–› ‰‡‡ †‹• ‘˜‡”› •‡ƒ” Š‡•ǡ ‘•‹•–‡–ƒ••‘ ‹ƒ–‹‘•Šƒ˜‡„‡‡”‡’‘”–‡†ˆ‘”•‡˜‡”ƒŽ‰‡‡•™‹–ŠŠ‘•–•—• ‡’–‹„‹Ž‹–› –‘ǤŠ‡•‡‹ Ž—†‡ƒ–—”ƒŽ”‡•‹•–ƒ ‡ƒ••‘ ‹ƒ–‡†ƒ ”‘’Šƒ‰‡’”‘–‡‹Ǧͳ‘”NRAMP1 ȋ͵͹Ǧ͵ͻȌǡ –Š‡ ˜‹–ƒ‹Ǧ ”‡ ‡’–‘” ȋVDRȌ ‰‡‡ ƒ†   ‰‡‡•ǡ ’ƒ”–‹ —Žƒ”Ž› HLADRB1 ȋͶͲȌǤ ‡ˆ‹ ‹‡ ‹‡•‹•‹‰ƒŽŽ‹‰’ƒ–Š™ƒ›•‘ˆƒ†ƒ’–‹˜‡ƒ†‹ƒ–‡‹—‹–› ƒƒŽ•‘”‡•—Ž–‹ ”‡ƒ”ƒ„Ž› •‡Ž‡ –‹˜‡ •—• ‡’–‹„‹Ž‹–› –‘ › ‘„ƒ –‡”‹ƒǤ ƒ–‹‡–• •—ˆˆ‡”‹‰ ˆ”‘ •‡˜‡”‡ ‹ˆ‡ –‹‘• †—‡ –‘ ‘–Š‡”™‹•‡ ’‘‘”Ž› ’ƒ–Š‘‰‡‹  › ‘„ƒ –‡”‹ƒ ȋ‡Ǥ‰Ǥ ‘ –—„‡” —Ž‘—• › ‘„ƒ –‡”‹ƒ ‘”  Ȍ Šƒ˜‡ „‡‡ †‹ƒ‰‘•‡† ™‹–Š ‘Ž‡ —Žƒ” †‡ˆ‡ –• ‹ ‡••‡–‹ƒŽ ’”‘–‡‹• ‘ˆ –Š‡ –›’‡ ͳ ›–‘‹‡ ƒš‹• ȋ

(30) ǦͳʹȀʹ͵’ͶͲǡ

(31) ǦͳʹȀʹ͵Ⱦͳǡ

(32) ǦJͳǡ

(33) ǦJʹǡ ͳ͹.

(34) Chapter1. –ƒ–Ǧͳǡ ›ʹȌ ȋͶͳǡͶʹȌǤ

(35)  Ž‹‡ ™‹–Š –Š‹•ǡ ƒŠ‹”ƒ–ƒ†Œƒ ‡– ƒŽǤ •Š‘™‡† –Šƒ– •‘‡ ’‘Ž›‘”’Š‹•• ‹

(36) ǦͳʹȀ

(37) J ’ƒ–Š™ƒ› ‰‡‡• ™‡”‡ ƒ••‘ ‹ƒ–‡† ™‹–Š •—• ‡’–‹„‹Ž‹–› –‘ ’—Ž‘ƒ”›–—„‡” —Ž‘•‹•‹

(38) †‘‡•‹ƒȋͶ͵ȌǤ Ž•‘ †‡ˆ‹ ‹‡ ‹‡• ‹ ‹ƒ–‡ ‡ŽŽ •‹‰ƒŽŽ‹‰ –Š”‘—‰Š ‘ŽŽ Ž‹‡ ”‡ ‡’–‘” ȋǦ•‡‡ „‡Ž‘™Ȍ ’ƒ–Š™ƒ›• •‡‡ ‹˜‘Ž˜‡† ‹  •—• ‡’–‹„‹Ž‹–›Ǥ Š‡ ƒ†ƒ’–‘” ’”‘–‡‹ ƒŽǡ ™Š‹ Š

(39)  ‡ ‘†‡† „› TIRAPǡ ‹• ‹˜‘Ž˜‡† ‹ –Š‡ †‘™•–”‡ƒ •‹‰ƒŽŽ‹‰ ‘ˆ ʹ ƒ† Ͷ ƒ† ˜ƒ”‹ƒ–• ‹ –Š‹• ‰‡‡ Šƒ˜‡ „‡‡ ƒ••‘ ‹ƒ–‡† ™‹–Š  ‹ ‘‡ •–—†› ȋͶͶȌǢ Š‘™‡˜‡”ǡ ƒ Žƒ”‰‡”•–—†›™ƒ•—ƒ„Ž‡–‘ ‘ˆ‹”–Š‹•ȋͶͷȌǤ††‹–‹‘ƒŽŽ›ǡƒ‰‡‡–‹ ƒ••‘ ‹ƒ–‹‘•–—†› ’‡”ˆ‘”‡†‹

(40) †‘‡•‹ƒƒ†—••‹ƒ•Š‘™‡†–Šƒ–’‘Ž›‘”’Š‹••‹–Š‡ͺ’ƒ–Š™ƒ› ƒ”‡‹’Ž‹‡†‹–Š‡‹ ”‡ƒ•‡†•—• ‡’–‹„‹Ž‹–›–‘ƒ†—Ž–’—Ž‘ƒ”›ȋͶ͸ȌǤ

(41) –‡”‡•–‹‰Ž›ǡŠ—ƒ

(42) Ǧͳ”‡ ‡’–‘”Ǧƒ••‘ ‹ƒ–‡†‹ƒ•‡Ͷȋ

(43) ͶȌ†‡ˆ‹ ‹‡ ›ǡŽ‡ƒ†‹‰–‘ ‹’ƒ‹”‡†Ȁ

(44) Ǧͳ”‡ ‡’–‘”†‡’‡†‡–•‹‰ƒŽŽ‹‰ǡ†‘‡•‘–‡Šƒ ‡•—• ‡’–‹„‹Ž‹–›–‘ › ‘„ƒ –‡”‹ƒ„—–”ƒ–Š‡”–‘’›‘‰‡‹ „ƒ –‡”‹ƒȋͶ͹ǡͶͺȌǤ ‡˜‡”ƒŽ‘–Š‡”‰‡‡•Šƒ˜‡„‡‡ƒ••‘ ‹ƒ–‡†–‘–Š‡’”‡†‹•’‘•‹–‹‘–‘†‹•‡ƒ•‡Ǥƒet al. ‹†‡–‹ˆ‹‡† –Š‡ Ipr1 ȋ‹–”ƒ ‡ŽŽ—Žƒ” ’ƒ–Š‘‰‡ ”‡•‹•–ƒ ‡ ͳȌ Ž‘ —• ƒ• ƒ ƒŒ‘” ‡™  •—• ‡’–‹„‹Ž‹–› Ž‘ —• ‹ ‹ ‡ ȋͶͻȌǤ —„•‡“—‡– •–—†‹‡• ‹˜‡•–‹‰ƒ–‡† –Š‡ Ž‘•‡•– Š—ƒ Š‘‘Ž‘‰—‡‘ˆIpr1ƒ‡Ž› ͳͳͲƒ†‹–•”‘Ž‡‹‰‡‡–‹ •—• ‡’–‹„‹Ž‹–›‹Ǥ

(45) †‡‡†ǡ ’‘Ž›‘”’Š‹•• ‹ SP110 ™‡”‡ ƒ••‘ ‹ƒ–‡† ™‹–Š •—• ‡’–‹„‹Ž‹–› –‘  ‹ Š—ƒ• ȋͷͲȌǤ ‘” ‘ˆ ƒ‰Š†ƒ†‹et al. ”‡˜‡ƒŽ‡† –Š‡ ‡š‹•–‡ ‡ ‘ˆƒ ƒŒ‘” –—„‡” —Ž‘•‹• •—• ‡’–‹„‹Ž‹–› Ž‘ —•ȋͺ“ͳʹǦ“ͳ͵Ȍ ‘–ƒ‹‹‰ƒƒ—–‘•‘ƒŽ†‘‹ƒ–•—• ‡’–‹„‹Ž‹–›‰‡‡ȋͷͳȌǤ ‹ ‡ •—• ‡’–‹„‹Ž‹–› ƒ••‘ ‹ƒ–‡† ‰‡‡ ’‘Ž›‘”’Š‹•• ƒ”‡ ‘ˆ–‡ †‹ˆˆ‡”‡– „‡–™‡‡ †‹ˆˆ‡”‡– •–—†‹‡•ǡ ‹– ‹• Ž‹‡Ž› –Šƒ– —Ž–‹’Ž‡ ‰‡‡• ƒ† ‰‡‡–‹  ’‘Ž›‘”’Š‹•• ‘Ǧ ‘”†‹ƒ–‡Ž›†‡–‡”‹‡Š‘•–•—• ‡’–‹„‹Ž‹–›–‘Ǥ ‹‰Š†‡•‹–›–›’‹‰–‡ Š‘Ž‘‰‹‡• ‘„‹‡† ™‹–Š Žƒ”‰‡ • ƒŽ‡ ’‘’—Žƒ–‹‘ •–—†‹‡• ™‹ŽŽ •Š‡† ‡™ Ž‹‰Š– ‘ –Š‡ ‰‡‡–‹  ‡Ž‡‡–•ƒ†–Š‡†‘™•–”‡ƒ’ƒ–Š™ƒ›•–Šƒ–”‡‰—Žƒ–‡Š‘•–•—• ‡’–‹„‹Ž‹–›–‘Ǥ‘•– ‹’‘”–ƒ–Ž›ǡŠ‘™‡˜‡”ǡ‘•–‰‡‡–‹ ˆƒ –‘”•‹†‡–‹ˆ‹‡†–‘†ƒ–‡Šƒ˜‡•‹‰‹ˆ‹ ƒ–”‘Ž‡•‹ ‘–”‘ŽŽ‹‰‹ƒ–‡ƒ†ƒ†ƒ’–‹˜‡ ‘’‘‡–•‘ˆ–Š‡ ‡ŽŽ‡†‹ƒ–‡†‹—‡”‡•’‘•‡‹ ‰‡‡”ƒŽǡ ƒ† –‘ ‹–”ƒ ‡ŽŽ—Žƒ” ’ƒ–Š‘‰‡• ‹ ’ƒ”–‹ —Žƒ” ȋ”‡˜‹‡™‡† „› ȋͶͳǡͶ͹ȌȌǤ Š—•ǡ ‰‡‡–‹  ˆƒ –‘”• –Šƒ– ‘–”‘Ž –Š‡ „ƒŽƒ ‡ ‘ˆ –Š‡ ‡ŽŽ ‡†‹ƒ–‡† ‹—‡ ”‡•’‘•‡ ƒ”‡ Ž‹‡Ž›–‘‹’ƒ –‘”‡•‹•–ƒ ‡ƒ†•—• ‡’–‹„‹Ž‹–›Ǥ  Facetoface:hostresponsestoM.tuberculosis  InnateimmunitytoM.tuberculosis ƒ ”‘’Šƒ‰‡•ƒ††‡†”‹–‹  ‡ŽŽ•ȋ•Ȍƒ”‡–Š‡ˆ‹”•–Š‘•– ‡ŽŽ•–ƒ”‰‡–‡†„›‹˜ƒ†‹‰M. tuberculosis „ƒ –‡”‹ƒǤ Š‡› ƒ”‡ –Š‡ ‡› ‡†‹ƒ–‘”• ‘ˆ ‹ƒ–‡ ‹—‹–› –‘ M. tuberculosisǡ ƒ† ”‡ ‘‰‹œ‡ ’ƒ–Š‘‰‡ ‘’‘‡–• –Š”‘—‰Š Š‹‰ŠŽ› ‘•‡”˜‡† ’ƒ––‡” ”‡ ‘‰‹–‹‘ ”‡ ‡’–‘”• ȋ•Ȍǡ ‹ Ž—†‹‰ ‡„‡”• ‘ˆ –Š‡ ‘ŽŽǦŽ‹‡ ”‡ ‡’–‘” ˆƒ‹Ž› ȋȌǤ ƒ Š ‘ˆ –Š‡ –‡ Š—ƒ  ˆƒ‹Ž› ‡„‡”• ”‡ ‘‰‹œ‡• ƒ †‹•–‹ – Žƒ•• ‘ˆ ‘•‡”˜‡†‹ ”‘„‹ƒŽ‘Ž‡ —Ž‡•Ǥ ‘”‡šƒ’Ž‡ǡʹǡ‹ ‘Œ— –‹‘™‹–Šͳ‘”͸ǡ ”‡ ‘‰‹œ‡•‹ ”‘„‹ƒŽŽ‹’‘Ǧ’”‘–‡‹•ȋȌǡŽ‹’‘Ǧƒƒ•ȋȌƒ†Ž‹’‘Ǧƒ”ƒ„‹‘ƒƒ• ȋȌǡ ƒŽŽ ‘ˆ ™Š‹ Š ƒ”‡ Šƒ”ƒ –‡”‹•–‹  ‘’‘‡–• ‘ˆ › ‘„ƒ –‡”‹ƒǤ  ƒ –‹˜ƒ–‹‘ ‹†— ‡•–Š‡ǣͳȌ”‡Ž‡ƒ•‡‘ˆ ›–‘‹‡•ȋ‡Ǥ‰Ǥ

(46) ǦͳʹȌƒ† Š‡‘‹‡•ǢʹȌ†‹ˆˆ‡”‡–‹ƒ–‹‘‘ˆ •Ǣ ͵Ȍ ”‡‰—Žƒ–‹‘ ‘ˆ ’Šƒ‰‘ ›–‘•‹•Ǣ ƒ† ͶȌ –”‹‰‰‡”‹‰ ‘ˆ ƒ–‹Ǧ‹ ”‘„‹ƒŽ ƒ –‹˜‹–‹‡• ȋͷʹǡ ͷ͵ȌǤ. ͳͺ.

(47) Introductionandoutlineofthethesis . Š‡”‘Ž‡‘ˆ•‹ƒ–‹Ǧ› ‘„ƒ –‡”‹ƒŽƒ –‹˜‹–›Šƒ•„‡‡Ž‹‡†–‘˜‹–ƒ‹ǣ‹–ƒ‹ ‡†‹ƒ–‡†ƒ–‹‹ ”‘„‹ƒŽƒ –‹˜‹–›–‘M.tuberculosisis™ƒ•ˆ‘—†–‘„‡†‡’‡†‡–‘–Š‡ ƒ–‹‹ ”‘„‹ƒŽ ’‡’–‹†‡ ƒ–Š‡Ž‹ ‹†‹ ȋ͵͹Ȍ ™Š‹ Š ‡‡†• –‘ „‡ ƒ –‹˜ƒ–‡† „› ʹȀͳ •‹‰ƒŽŽ‹‰ȋͷͶȌǤ –Š‡” ”‡Ž‡˜ƒ– • ‹ Ž—†‡ ƒ‘•‡ ”‡ ‡’–‘”• ȋȌǡ ‹–”ƒ ‡ŽŽ—Žƒ” Ȁ ”‡ ‡’–‘”• ȋͷͷȌ ƒ† Ǧ–›’‡ Ž‡ –‹• Ž‹‡ †‡†”‹–‹  ‡ŽŽǦ•’‡ ‹ˆ‹ 

(48)  ‰”ƒ„„‹‰ ‘‹–‡‰”‹ȋǦ

(49) ȌǤ

(50) –Šƒ•„‡‡”‡’‘”–‡†–Šƒ–M.tuberculosis‹•ƒ„Ž‡–‘’”‡˜‡– ƒ–—”ƒ–‹‘ „› –Š‡ „‹†‹‰ ‘ˆ ƒ‘•›Žƒ–‡†  ȋƒǦȌ ȋƒ• ™‡ŽŽ ƒ• ‘–Š‡” ‘’‘‡–•Ȍ –‘ Ǧ

(51) ǡ –Š‡”‡„› ‹†— ‹‰ –Š‡ ’”‘†— –‹‘ ‘ˆ

(52) ǦͳͲ ȋͷ͸Ȍ ™Š‹ Š •—’’”‡••‡• ‹—‹–› ƒ†  ‡ŽŽ ƒ –‹˜ƒ–‹‘Ǥ

(53)  ƒ††‹–‹‘ǡ ƒ ”‘’Šƒ‰‡• ‡š’”‡•• J ”‡ ‡’–‘”• ƒ† ‘’Ž‡‡– ”‡ ‡’–‘”• ȋȌ ™Š‹ Š ’”‘‘–‡ ”‡ ‘‰‹–‹‘ ‘ˆ ‘’•‘‹•‡† „ƒ –‡”‹ƒȋͷ͹ǡͷͺȌǤ

(54)  –Š‡ ‘—”•‡ ‘ˆ ‹ˆ‡ –‹‘ǡ ‹ ”‡ƒ•‹‰ —„‡”• ‘ˆ ƒ ”‘’Šƒ‰‡• ƒ† ”‡•‹†‡– • ƒ”‡ ”‡ ”—‹–‡†–‘–Š‡•‹–‡‘ˆ‹ˆ‡ –‹‘Ǥƒ–—”‡•”‡ǦŽ‘ ƒ–‡–‘–Š‡Ž›’Š‘†‡•™Š‡”‡–Š‡› ’”‘†— ‡ ‹ˆŽƒƒ–‘”› ›–‘‹‡• ƒ† ’”‹‡ ͶΪ ƒ† ͺΪ Ǧ ‡ŽŽ• ƒ‰ƒ‹•– › ‘„ƒ –‡”‹ƒȋ͹ǡͷͻȌǤ  TheTcellresponsetoM.tuberculosis M. tuberculosis ’”‹ƒ”‹Ž› ”‡•‹†‡• ‹ ˜ƒ —‘Ž‡• ™‹–Š‹ ƒ ”‘’Šƒ‰‡•ǡ ƒ† ’”‡•‡–• ƒ–‹‰‡•˜‹ƒ–Š‡‡†‘ ›–‹ •›•–‡‹–Š‡ ‘–‡š–‘ˆ  Žƒ••

(55)

(56) ‘Ž‡ —Ž‡•–‘ͶΪ ‡ŽŽ•Ǥ ’Ž‡ ‡˜‹†‡ ‡ ’‘‹–• –‘ –Š‡ ‹†‹•’‡•ƒ„Ž‡ ”‘Ž‡ ‘ˆ ͶΪ Ž›’Š‘ ›–‡• ‹ ’”‘–‡ –‹˜‡ ‹—‹–› –‘ M. tuberculosisǤ

(57)  Š—ƒ•ǡ Ž‘•• ‘ˆ ͶΪ  ‡ŽŽ• †—‡ –‘ ’”‘‰”‡••‹‰

(58)  †‹•‡ƒ•‡ ‰”‡ƒ–Ž› ‹ ”‡ƒ•‡• –Š‡ Šƒ ‡ ‘ˆ  ”‡ƒ –‹˜ƒ–‹‘ ƒ†  ”‡Ǧ ‹ˆ‡ –‹‘ȋ͸ȌǤ‹ ‡†‡ˆ‹ ‹‡–‹ͶΪ ‡ŽŽ•Šƒ˜‡‹’ƒ‹”‡†ƒ„‹Ž‹–›–‘ ‘–”‘Ž‹ˆ‡ –‹‘ ƒ†‡˜‡–—ƒŽŽ›†‹‡ˆ”‘ȋ͸ͲȌǤ

(59) ƒ‹ƒŽ‘†‡Ž•ǡƒ†‘’–‹˜‡–”ƒ•ˆ‡”‘ˆͶΪ ‡ŽŽ• –ƒ‡ ƒ– –Š‡ Š‡‹‰Š– ‘ˆ –Š‡ ’”‹ƒ”› ‹—‡ ”‡•’‘•‡ –‘ M. tuberculosis ‘ˆ‡””‡† ’”‘–‡ –‹‘ƒ‰ƒ‹•–M.tuberculosis‹ ‡ŽŽ†‡ˆ‹ ‹‡–‹ ‡ȋ͸ͳȌǤ ͶΪ ‡ŽŽ• ‘’”‹•‡•‡˜‡”ƒŽ•—„ Žƒ••‡•ǡƒ‘‰™Š‹ ŠŠ‡Ž’‡”ͳȋŠͳȌ ‡ŽŽ•ƒ”‡–Š‡ ‘•–ƒ„—†ƒ–ƒ†’”‘‹‡–ǤŠͳ ‡ŽŽ•ƒ”‡ Šƒ”ƒ –‡”‹œ‡†„›–Š‡’”‘†— –‹‘‘ˆ

(60) J ƒ†   ȋ͸ʹǦ͸ͶȌǢ ‘–Š‡” ͶΪ  ‡ŽŽ •—„•‡–• ‡ ‘’ƒ•• Šʹ ‡ŽŽ•ǡ Ǧ”‡‰—Žƒ–‘”› ‡ŽŽ• ȋ”‡‰•Ȍ ƒ† Šͳ͹ ‡ŽŽ•Ǥ Šʹ ‡ŽŽ• ’”‘†— ‡

(61) ǦͶǡ

(62) ǦͳͲ ƒ†  E ƒ† ‹ˆŽ—‡ ‡ ‹—‹–› –‘ M. tuberculosis ’‘••‹„Ž› „› ƒ–ƒ‰‘‹œ‹‰ Šͳ ‡ŽŽ• –Š”‘—‰Š

(63) ǦͶ ȋ͸ͷȌǤ ”‡‰• ‘’”‹•‡ —Ž–‹’Ž‡ •—„•‡–• ƒ† ƒ”‡ ‹’‘”–ƒ– ‹ ‘–”‘ŽŽ‹‰ ‹—‹–› ƒ† ‹ˆŽƒƒ–‹‘Ǥ

(64)  M. tuberculosis ‹ˆ‡ –‹‘ ”‡‰• ™‡”‡ •Š‘™ –‘ „‡ ƒ••‘ ‹ƒ–‡† ™‹–Š ƒ –‹˜‡†‹•‡ƒ•‡ȋ͸͸Ȍ„—––Š‡›ƒ”‡ƒŽ•‘‹†— ‡†‡ˆˆ‹ ‹‡–Ž›„› ȋ͸͹Ȍƒ†M.leprae ȋ͸ͺȌǤ ‡ ‡–Ž›ǡ ƒ ‡™Ž› †‡–‡ –‡† •—„•‡– ‘ˆ ͶΪ  ‡ŽŽ•ǡ Šͳ͹ ‡ŽŽ•ǡ ™ƒ• †‡• ”‹„‡†Ǥ Š‡•‡ ‡ŽŽ•ƒ”‡ Šƒ”ƒ –‡”‹œ‡†„›–Š‡’”‘†— –‹‘‘ˆ–Š‡’”‘Ǧ‹ˆŽƒƒ–‘”› ›–‘‹‡

(65) Ǧ ͳ͹ƒ†

(66) ǦʹʹǤ

(67) ‹ ‡ǡŠǦͳ͹ ‡ŽŽ•ƒ”‡ƒ••‘ ‹ƒ–‡†™‹–Š‹ˆŽƒƒ–‘”›†‹•‡ƒ•‡••— Šƒ• ”Š‡—ƒ–‘‹† ƒ”–Š”‹–‹•ǡ ‘ŽŽƒ‰‡ ‹†— ‡† ƒ”–Š”‹–‹• ƒ† ‡š’‡”‹‡–ƒŽ ƒ—–‘‹—‡ ‡ ‡’ŠƒŽ‹–‹•ȋ͸ͻȌǤŠƒ†‡”etalǤ•Š‘™‡†–Šƒ–

(68) Ǧʹ͵‹•”‡“—‹”‡†ˆ‘”–Š‡‡•–ƒ„Ž‹•Š‡–‘ˆ

(69) Ǧͳ͹ ’”‘†— ‹‰ ͶΪ  ‡ŽŽ• ‹ –Š‡ Ž—‰• ‘ˆ ‹ ‡ ‹ˆ‡ –‡† ™‹–Š M. tuberculosisǤ

(70) – ‹• –Š‘—‰Š––Šƒ–Šͳ͹ ‡ŽŽ•ƒ› ‘–”‹„—–‡–‘–Š‡•‡ ‘†ƒ”›‹—‡ȋ”‡ ƒŽŽȌ”‡•’‘•‡„› ’”‘‘–‹‰–Š‡‡š’”‡••‹‘‘ˆ Š‡‘‹‡”‡ ‡’–‘”•‹–Š‡Ž—‰ƒ†–Š‡”‡ ”—‹–‡–‘ˆ

(71) J ’”‘†— ‹‰  ‡ŽŽ• ȋ͹Ͳǡ ͹ͳȌǤ Ž•‘ –Š‡ ƒ––”ƒ –‹‘ ‘ˆ ‡—–”‘’Š‹Ž• ™Š‹ Š ƒ ‹ŽŽ M. tuberculosis,ƒ› ‘–”‹„—–‡–‘

(72) Ǧͳ͹†‡’‡†‡–’”‘–‡ –‹‘Ǥ•›‡–ǡ–Š‡‡šƒ –”‘Ž‡•ƒ†. ͳͻ.

(73) Chapter1. ‘†‡•‘ˆƒ –‹‘‘ˆ–Š‡•‡Žƒ––‡”–Š”‡‡’‘’—Žƒ–‹‘•‘ˆͶΪ ‡ŽŽ•‹Š—ƒ”‡ƒ‹ –‘„‡‡•–ƒ„Ž‹•Š‡†Ǥ  ‹˜‘Ž˜‡‡– ‘ˆ ͺΪ  ‡ŽŽ• ‹ –Š‡ ‘–ƒ‹‡– ‘ˆ M. tuberculosis Šƒ• „‡‡ •—‰‰‡•–‡†„›–Š‡”ƒ’‹†‹‰”ƒ–‹‘‘ˆ•— Š ‡ŽŽ•–‘–Š‡•‹–‡•‘ˆ‹ˆ‡ –‹‘ȋ͹ʹȌƒ†–Š‡‹” ’”‡•‡ ‡‹‰”ƒ—Ž‘ƒ•ȋ͹͵ȌǤ› ‘„ƒ –‡”‹ƒ•’‡ ‹ˆ‹ ͺΪ ‡ŽŽ• ƒ’”‘†— ‡

(74) Jǡ„—– ƒ”‡ ‘•–Ž› ”‡ ‘‰‹œ‡† ˆ‘” –Š‡‹” ›–‘–‘š‹  ˆ— –‹‘ ȋ͹ͶȌǤ ͺΪ  ‡ŽŽ• ƒ”‡ –›’‹ ƒŽŽ› ƒ –‹˜ƒ–‡†„›ƒ–‹‰‡•†‡”‹˜‡†ˆ”‘–Š‡ ›–‘’Žƒ•ǡ™Š‹ Š‹–Š‡ˆ‘”‘ˆ’‡’–‹†‡•Šƒ˜‡ „‡‡–”ƒ•Ž‘ ƒ–‡†–‘–Š‡ƒ† ‘’Ž‡š‡†–‘  Žƒ••

(75) ‘Ž‡ —Ž‡•Ǥ ‘”Ž‘‰ǡ‹–Šƒ• „‡‡ — Ž‡ƒ” Š‘™ ƒ–‹‰‡• ˆ”‘ –Š‡ ’Šƒ‰‘•‘‡ ‹ ™Š‹ Š M. tuberculosis ”‡•‹†‡•ǡ ‘—Ž†ƒ ‡••–Š‡  Žƒ••

(76) ”‘—–‡Ǥ™‘’ƒ–Š™ƒ›•Šƒ˜‡‘™„‡‡‹†‡–‹ˆ‹‡†„›™Š‹ Š –Š‹•ƒ›–ƒ‡’Žƒ ‡ȋ͹ͷȌǣˆ‹”•–ǡ› ‘„ƒ –‡”‹ƒƒ”‡ƒ„Ž‡–‘‹†— ‡ƒ’‘’–‘•‹•‹‹ˆ‡ –‡† ƒ ”‘’Šƒ‰‡•ǡ–Š—•‹‹–‹ƒ–‹‰”‡Ž‡ƒ•‡‘ˆƒ’‘’–‘–‹ ˜‡•‹ Ž‡•Ǣ–Š‡•‡ ƒ–Š‡„‡–ƒ‡—’ „›•ǡ’”‘ ‡••‡†ƒ†•Š—––Ž‡†‹–‘–Š‡ ƒ‘‹ ƒŽ  Žƒ••

(77) ’”‡•‡–ƒ–‹‘’ƒ–Š™ƒ›ǡƒ ’”‘ ‡•• ‘‘Ž› ”‡ˆ‡””‡† –‘ ƒ• Dz ”‘••Ǧ’”‹‹‰dzǤ  •‡ ‘†ǡ ƒŽ–Š‘—‰Š ƒ• ›‡– ‘–”‘˜‡”•‹ƒŽ‡ Šƒ‹•ǡ‹˜‘Ž˜‡•–Š‡’‘••‹„Ž‡”‡ ”—‹–‡–‘ˆ‡„”ƒ‡•–‘–Š‡ ’Šƒ‰‘ ›–‹  —’Ǥ Š‹• ™‘—Ž† ƒŽŽ‘™ƒ ‡••‘ˆ–Š‡   Žƒ••

(78)  ’”‘ ‡••‹‰ ƒ Š‹‡”› –‘ ‹–”ƒ ‡ŽŽ—Žƒ” „ƒ –‡”‹ƒǡ ’”‘˜‹†‹‰ ƒ •‘—” ‡ ‘ˆ ’‡’–‹†‡• ˆ‘” ‘—’Ž‹‰ –‘   Žƒ••

(79)  ‘Ž‡ —Ž‡•Ǥ ˆ‹–‡”‡•–ǡͺΪ ‡ŽŽ•Šƒ˜‡„‡‡•Š‘™–‘’”‡ˆ‡”‡–‹ƒŽŽ›”‡ ‘‰‹œ‡Š‡ƒ˜‹Ž›‹ˆ‡ –‡† ‡ŽŽ•™Š‡”‡ƒ•ͶΪ ‡ŽŽ• †‘‘–•Š‘™ƒ‡–Š‹•†‹•–‹ –‹‘ȋ͹͸ȌǤ

(80) –Šƒ•ƒŽ•‘„‡‡ •—‰‰‡•–‡†–Šƒ–ͺΪ ‡ŽŽ• ‘–”‘ŽŽƒ–‡”•–ƒ‰‡M.tuberculosis‹ˆ‡ –‹‘™Š‡”‡ƒ•ͶΪ  ‡ŽŽ•ƒ”‡‹’‘”–ƒ–†—”‹‰‡ƒ”Ž›•–ƒ‰‡•ȋ͹͹ȌǤ —”–Š‡”‘”‡ǡ•‹ ‡M.tuberculosis ƒ ƒŽ•‘‹ˆ‡ –‘’Šƒ‰‘ ›–‹  ‡ŽŽ••— Šƒ•–›’‡

(81)

(82) ƒŽ˜‡‘Žƒ”‡’‹–Š‡Ž‹ƒŽ ‡ŽŽ•ȋ͹ͺȌǡ™Š‹ Šƒ”‡ –›’‹ ƒŽŽ›†‡˜‘‹†‘ˆ  Žƒ••

(83)

(84) ‡š’”‡••‹‘„—–†‘‡š’”‡••  Žƒ••

(85) ‘Ž‡ —Ž‡•ǡͺΪ  ‡ŽŽ• ƒ› „‡ ‡†‘™‡† ™‹–Š –Š‡ —‹“—‡ ƒ’ƒ ‹–› –‘ ”‡ ‘‰‹•‡ ƒ† ‡Ž‹‹ƒ–‡ –Š‹• —‹“—‡ •—„ Žƒ•• ‘ˆ ‹ˆ‡ –‡† ‡ŽŽ•Ǥ Š—•ǡ ƒ ‰”‘™‹‰ „‘†› ‘ˆ ‡˜‹†‡ ‡ ‡’Šƒ•‹œ‡• ƒ ‹’‘”–ƒ– ƒ† ’‡”Šƒ’• —‹“—‡ ”‘Ž‡ ‘ˆ ͺΪ  ‡ŽŽ• ‹ †‹ˆˆ‡”‡– •–ƒ‰‡• ‘ˆ ƒ†ƒ’–‹˜‡ ‹—‹–›‹M.tuberculosis‹ˆ‡ –‹‘ȋ͹ͻȌ. DEΪͺΪ ‡ŽŽ•ƒ†ͶΪ ‡ŽŽ•”‡ ‘‰‹œ‡ƒ–‹‰‡•‹–Š‡ ‘–‡š–‘ˆ  Žƒ••

(86)  ƒ†

(87)

(88) ”‡•’‡ –‹˜‡Ž›ǡ›‡–„ƒ –‡”‹ƒŽ‰Ž› ‘Ž‹’‹†ƒ–‹‰‡•ƒ”‡–›’‹ ƒŽŽ›’”‡•‡–‡†–‘ ‡ŽŽ• „›ͳ‘Ž‡ —Ž‡•–Šƒ–ƒ”‡ƒ„—†ƒ–Ž›‡š’”‡••‡†‘•ȋͺͲȌǤŠ‡”‡ƒ”‡ˆ‘—”Š—ƒ ‹•‘ˆ‘”•‘ˆͳǣͳƒǡ„ǡ ǡƒ††™Š‹ Š ƒ„‡•‡‰”‡‰ƒ–‡†‹–‘–™‘‰”‘—’•ǤŠ‡‰”‘—’ ͳ ‘” ͳƒǡ „ ƒ†  ‹•‘ˆ‘”• ’”‡•‡– Ž‹’‹† ƒ–‹‰‡• –‘  ‡ŽŽ•ǡ ™Š‡”‡ƒ• ‰”‘—’ ʹ ͳ ‘Ž‡ —Ž‡• ƒ”‡ ‘’‘•‡† ‘ˆ ͳ† ƒ† –Š‡ —”‹‡ ‘”–Š‘Ž‘‰—‡ ͳǡ ƒ† ’”‡•‡– Ž‹’‹† ƒ–‹‰‡•–‘ ‡ŽŽ•ȋͺͳǡͺʹȌǤ‡ ‡–Ž›ǡ†‹ƒ ›Žƒ–‡†•—Žˆ‘‰Ž› ‘Ž‹’‹†•™‡”‡‹†‡–‹ˆ‹‡†ƒ• Š‹‰ŠŽ›’‘–‡–‘’”‘–‡‹› ‘„ƒ –‡”‹ƒŽƒ–‹‰‡•–Šƒ–ƒ”‡’”‡•‡–‡†‹–Š‡ ‘–‡š–‘ˆ ͳ ”‡•–”‹ –‡†  ‡ŽŽ• ȋͺ͵ȌǤ JGΪ  ‡ŽŽ• ”‡ ‘‰‹œ‡ ’Š‘•’Šƒ–‡Ǧ‰”‘—’ ‘–ƒ‹‹‰ ‘Ǧ ’”‘–‡‹ ƒ–‹‰‡• ‹ –Š‡ ƒ„•‡ ‡ ‘ˆƒƒ–‹‰‡ ’”‡•‡–‹‰ ‘Ž‡ —Ž‡ ȋͳ͸ȌǤ Š‡•‡ Žƒ––‡” –™‘ ’‘’—Žƒ–‹‘• ƒ”‡ ‘‘Ž› ”‡ˆ‡””‡†–‘ƒ• — ‘˜‡–‹‘ƒŽ ‡ŽŽ• ƒ† ƒ‡ —’ ƒ •ƒŽŽ‡”ˆ”ƒ –‹‘‘ˆ ‹” —Žƒ–‹‰ ‡ŽŽ•Ǥ ‘˜‡–‹‘ƒŽ ‡ŽŽ•Š‘™‡˜‡”ƒ› ‘–”‹„—–‡ –‘ƒ–‹„ƒ –‡”‹ƒŽ‹—‹–›ǡ’ƒ”–‹ —Žƒ”Ž›‹–Š‡‡ƒ”Ž›’Šƒ•‡‘ˆ‹ˆ‡ –‹‘Ǥ ’‘ ƒ –‹˜ƒ–‹‘ǡ „‘–Š ͶΪ ƒ† ͺΪ  ‡ŽŽ• ’”‘†— ‡ •‡˜‡”ƒŽ ‡ˆˆ‡ –‘” ‘Ž‡ —Ž‡•Ǥ • ‡–‹‘‡†ǡ

(89) J •›‡”‰‹œ‡• ™‹–Š  D ‹ ƒ –‹˜ƒ–‹‰ M. tuberculosis ‹ˆ‡ –‡† ƒ ”‘’Šƒ‰‡•ƒ†•—„•‡“—‡–‹ŽŽ‹‰‘ˆM.tuberculosisȋͺͶȌǤ Š‡ ‹’‘”–ƒ ‡ ‘ˆ

(90) J ‹ ‘–”‘ŽŽ‹‰ › ‘„ƒ –‡”‹ƒŽ ‹ˆ‡ –‹‘• ‹ Ž—†‹‰ M. tuberculosis‹•‡’Šƒ•‹œ‡†„›–Š‡‡š–”‡‡•—• ‡’–‹„‹Ž‹–›‘ˆ‹†‹˜‹†—ƒŽ•‰‡‡–‹ ƒŽŽ›ƒ†. ʹͲ.

(91) Introductionandoutlineofthethesis . ˆ— –‹‘ƒŽŽ› †‡ˆ‹ ‹‡– ‹ –Š‡

(92) ǦͳʹȀ

(93) Ǧʹ͵Ȁ

(94) J ƒš‹•Ǥ Š‡ ˜‹–ƒŽ ”‘Ž‡ ‘ˆ  D ‹ –Š‡ ‘–”‘Ž ‘ˆ ȋŽƒ–‡–Ȍ  ‹ˆ‡ –‹‘ ™ƒ• ”‡ ‡–Ž› ‡’Šƒ•‹œ‡† ƒ‰ƒ‹ „› –Š‡ —•‡ ‘ˆ   „Ž‘ ‡”• ‹ Š”‘‹  ‹ˆŽƒƒ–‘”› †‹•‡ƒ•‡• Ž‹‡ ”Š‡—ƒ–‘‹† ƒ”–Š”‹–‹• ƒ† ”‘Šǯ• †‹•‡ƒ•‡ǣ ‡—–”ƒŽ‹œƒ–‹‘ ‘ˆ   „› ƒ–‹Ǧ  ƒ–‹„‘†‹‡• Ž‡† –‘ †‹•’”‘’‘”–‹‘ƒŽŽ› ˆ”‡“—‡– ”‡ƒ –‹˜ƒ–‹‘ ‘ˆ Žƒ–‡– M. tuberculosis ‹ˆ‡ –‹‘ ƒ† †‹••‡‹ƒ–‹‰  ‹ –”‡ƒ–‡†‹†‹˜‹†—ƒŽ•ȋͺͷǡͺ͸ȌǤ

(95) Ž‹‡™‹–Š–Š‹•ǡM.tuberculosis‹ˆ‡ –‡†‹ ‡‡—–”ƒŽ‹œ‡† ˆ‘”  Dǡ ‘” †‡ˆ‹ ‹‡– ‹   ”‡ ‡’–‘” •‹‰ƒŽ‹‰ǡ ƒŽ•‘ ”ƒ’‹†Ž› †‹‡† ™‹–Š ƒ”‡†Ž› Š‹‰Š‡” „ƒ –‡”‹ƒŽ „—”†‡ ȋͺ͹ȌǤ • ‡–‹‘‡† „‡ˆ‘”‡ǡ ‹– ‹• Ž‡ƒ” –Šƒ– –Š‡ ”‘Ž‡ ‘ˆ •›‡”‰‹•–‹  ‹–‡”ƒ –‹‘• „‡–™‡‡ †‹ˆˆ‡”‡– ›–‘‹‡ ’ƒ–Š™ƒ›• —•– „‡ ‡š’Ž‘”‡† ƒ• ™‡ŽŽǤ  –‹˜ƒ–‡† ‡ŽŽ•ƒ”‡ƒ„Ž‡–‘‡š‡”–†‹”‡ – ›–‘Ž›–‹ ƒ†‹ ”‘„‹ ƒŽ‡ˆˆ‡ –‘”ˆ— –‹‘•„› –Š‡ ’”‘†— –‹‘ ‘ˆ ’‡”ˆ‘”‹ǡ ‰”ƒœ›‡• ƒ† ‰”ƒ—Ž›•‹ ȋͺͺǡ ͺͻȌǤ Š‡•‡ ‘Ž‡ —Ž‡• ƒ”‡ •‡ ”‡–‡† ˆ”‘ ‰”ƒ—Ž‡• ƒ† ƒ”‡ ”‡Ž‡ƒ•‡† ‹ –Š‡ ‹—‘Ž‘‰‹ ƒŽ •›ƒ’•‡ „‡–™‡‡ ‡ˆˆ‡ –‘”  ‡ŽŽ ƒ† ‹ˆ‡ –‡† –ƒ”‰‡– ‡ŽŽǤ ‡”ˆ‘”‹ ˆ‘”• ’‘”‡• ‹ –Š‡ –ƒ”‰‡– ‡ŽŽ ‡„”ƒ‡ǡ ƒ—•‹‰Ž›•‹•„›–Š‡‹ˆŽ—š‘ˆ™ƒ–‡”ƒ†‹‘•Ǥ‘”‡‘˜‡”ǡ’‡”ˆ‘”‹‡†‹ƒ–‡• –”ƒ•Ž‘ ƒ–‹‘ ‘ˆ ‰”ƒœ›‡•ǡ ™Š‹ Š ‡–‡” –Š‡ — Ž‡—• ƒ† ‹†— ‡ ƒ’‘’–‘•‹• ȋͻͲȌǤ. ”ƒ—Ž›•‹ †‹”‡ –Ž› ‹†— ‡• ƒ’‘’–‘•‹• ȋͻͳȌǢ ™Š‡ ƒ ‡••‹‰ „ƒ –‡”‹ƒǡ ‹– ƒ ƒŽ–‡” –Š‡ ‡„”ƒ‡‹–‡‰”‹–›Ǥ

(96) –‹•–Š‘—‰Š––Šƒ–’‡”ˆ‘”‹Š‡Ž’•‰”ƒ—Ž›•‹–‘ƒ ‡••’Šƒ‰‘•‘ƒŽ „ƒ –‡”‹ƒ •— Š ƒ• M. tuberculosisǡ –Š‡”‡„› ‡˜‡–—ƒŽŽ› ”‡†— ‹‰ › ‘„ƒ –‡”‹ƒŽ ˜‹ƒ„‹Ž‹–› ȋͻʹȌǤƒ††‹–‹‘ƒŽ‡ Šƒ‹•–‘‹†— ‡–ƒ”‰‡–Ǧ ‡ŽŽƒ’‘’–‘•‹•‘ —”•„›–Š‡Ž‹‰ƒ–‹‘‘ˆ –ƒ”‰‡–Ǧ ‡ŽŽ ‡š’”‡••‡† ƒ• ȋͻͷȌ –‘ ƒ• ȋͻͷȌ ‘ –Š‡ ‡ˆˆ‡ –‘”  ‡ŽŽ ȋͺͺǡ ͻ͵ȌǤ ’‘’–‘•‹•‹•ƒ‹’‘”–ƒ–Š‘•–†‡ˆ‡ ‡‡ Šƒ‹•ƒ‰ƒ‹•–‹–”ƒ ‡ŽŽ—Žƒ”„ƒ –‡”‹ƒǡƒ† ˜‹”—Ž‡–M.tuberculosis‹•ƒ„Ž‡–‘”‡•‹•–ƒ’‘’–‘•‹•‹†— –‹‘‹Š—ƒ ‡ŽŽ•ȋͻͶǦͻ͸ȌǤ  Thegranuloma:M.tuberculosis’hideout

(97)  ‘•– ƒ•‡• –Š‡ ‡ŽŽ ‡†‹ƒ–‡† ”‡•’‘•‡ ‹• ƒ„Ž‡ –‘ ‘–ƒ‹ M. tuberculosis ‹ ™‡ŽŽǦ ‘”‰ƒ‹•‡† ‰”ƒ—Ž‘ƒ•ǡ ‹ ™Š‹ Š ‹– ƒ ’‡”•‹•– ˆ‘” †‡ ƒ†‡• ™‹–Š‘—– ƒ—•‹‰ ƒ› •›’–‘•Ǥ

(98) – ‹• ’‘••‹„Ž‡ –Šƒ– ‹ –Š‡•‡ Ž‡•‹‘• –”—Ž› †‘”ƒ– „ƒ ‹ŽŽ‹ ƒ”‡ ’”‡•‡– –Šƒ– ’‡”•‹•– ‹ ƒ ‡–ƒ„‘Ž‹ ƒŽŽ› ”‡†— ‡† ‘” ‹ƒ –‹˜‡ •–ƒ–‡ ȋͺͲȌǤ Ž–‡”ƒ–‹˜‡Ž›ǡ ȋƒ •—„’‘’—Žƒ–‹‘ ‘ˆȌ ’‡”•‹•–‹‰ „ƒ –‡”‹ƒ ‹‰Š– ‘–‹—‡ –‘ ”‡’Ž‹ ƒ–‡ •Ž‘™Ž›Ǥ ‡‰ƒ”†Ž‡••ǡ ‹„‘–Š ƒ•‡•Žƒ–‡–‹ˆ‡ –‹‘ƒ”‹•‡•ǡ”‡’”‡•‡–‹‰ƒ„ƒŽƒ ‡„‡–™‡‡Š‘•–†‡ˆ‡•‡ƒ† „ƒ –‡”‹ƒŽ †‘”ƒ ›Ȁ•Ž‘™ ”‡’Ž‹ ƒ–‹‰ ’‡”•‹•–‡ ‡ǡ ™Š‹ Š ƒ „‡ ƒ‹–ƒ‹‡† ˆ‘” ƒ› †‡ ƒ†‡•Ǥ. ”ƒ—Ž‘ƒˆ‘”ƒ–‹‘‹•ƒŠƒŽŽƒ”‘ˆŽƒ–‡–M.tuberculosis‹ˆ‡ –‹‘ǡƒ†’”‘˜‹†‡•ƒ ‹ ”‘‡˜‹”‘‡–‹™Š‹ Š‹–‡”ƒ –‹‘•„‡–™‡‡ ‡ŽŽ•ǡƒ ”‘’Šƒ‰‡•ƒ† ›–‘‹‡• ƒ”‡ ˆƒ ‹Ž‹–ƒ–‡† ƒ† „ƒ –‡”‹ƒ ƒ”‡ •‡“—‡•–‡”‡† ˆ”‘ •’”‡ƒ†‹‰ ˆ—”–Š‡” ‹–‘ –Š‡ Š‘•–Ǥ ‹•”—’–‹‘‘ˆ–Š‡•‡‘”‰ƒ‹œ‡†•–”— –—”‡•‹•ƒ–›’‹ ƒŽˆ‡ƒ–—”‡‘ˆ”‡ƒ –‹˜ƒ–‹‘Ǥ —‡–‘ Š”‘‹ •–‹—Žƒ–‹‘ǡƒ ”‘’Šƒ‰‡•‹–Š‡•‡Ž‡•‹‘•‡˜‡–—ƒŽŽ›ˆ—•‡–‘ˆ‘”‰‹ƒ– ‡ŽŽ• –Šƒ– ƒ”‡ Šƒ”ƒ –‡”‹•–‹  ˆ‘” ‰”ƒ—Ž‘ƒ•Ǥ Š‡ ‰”ƒ—Ž‘ƒ ‹• ƒ Š‹‰ŠŽ› †›ƒ‹  •–”— –—”‡‹™Š‹ ŠͶΪƒ†ͺΪ ‡ŽŽ•‘ —’›†‹• ”‡–‡ƒ††‹ˆˆ‡”‡–•‹–‡•–Šƒ–ƒ”‡ ‘•–Ž‹‡Ž›ƒ••‘ ‹ƒ–‡†™‹–Š–Š‡‹”ˆ— –‹‘•‹†‹ˆˆ‡”‡–•–ƒ‰‡•‘ˆ‹ˆ‡ –‹‘ƒ††‹•‡ƒ•‡ ȋͻ͹ǡ ͻͺȌǤ ‹•–‹ – –‡’‘”ƒŽ ƒ ——Žƒ–‹‘• ‘ˆ ‹—‡ ‡ŽŽ• ‹ Ž—†‹‰  ‡ŽŽ•ǡ ƒ ”‘’Šƒ‰‡•ǡ‡—–”‘’Š‹Ž•ǡ ‡ŽŽ•ƒ†•‹–Š‡Ž—‰•‘ˆ‹ ‡†—”‹‰’”‘‰”‡••‹‘‘ˆ ƒ —–‡–‘ Š”‘‹ •–ƒ–‡‘ˆ‹ˆ‡ –‹‘Šƒ˜‡„‡‡‘„•‡”˜‡†Ǣƒ ”‘’Šƒ‰‡•ƒ†‡—–”‘’Š‹Ž• ™‡”‡’”‡†‘‹ƒ–Ž›’”‡•‡–†—”‹‰–Š‡ƒ —–‡’Šƒ•‡‘ˆ‹ˆ‡ –‹‘™Š‡”‡ƒ•—„‡”•‘ˆ ͵Ϊ ‡ŽŽ•”ƒ’‹†Ž›‡š’ƒ†‡†‹–Š‡Ž—‰•†—”‹‰–Š‡ ‘—”•‡‘ˆ‹ˆ‡ –‹‘ȋʹǦͶ™‡‡• ʹͳ.

(99) Chapter1. ’‘•–Ǧ‹ˆ‡ –‹‘ȌǤ ‹—Ž–ƒ‡‘—•Ž›ǡ –‘–ƒŽ —„‡”• ‘ˆ ƒ ”‘’Šƒ‰‡• ‹ ”‡ƒ•‡† ƒ• ™‡ŽŽǤ ‡—–”‘’Š‹Ž—„‡”•†‡ ”‡ƒ•‡†–‘™ƒ”†•–Š‡ Š”‘‹ ’Šƒ•‡‘ˆ‹ˆ‡ –‹‘ƒ†‡˜‡–—ƒŽŽ› ͵Ϊ  ‡ŽŽ• ƒ† ƒ ”‘’Šƒ‰‡• ™‡”‡ •Š‘™ –‘ Šƒ”ƒ –‡”‹œ‡ –Š‡ Š”‘‹  –—„‡” —Ž‘—• Ž—‰ȋͻ͹ȌǤ. ”ƒ—Ž‘ƒ• ƒ „‡ ˆ‘”‡† ƒ›™Š‡”‡ ‹ –Š‡ Ž—‰ǡ ›‡– ͻͲΨ ‘ˆ –Š‡ ’‘•–Ǧ’”‹ƒ”›  ƒ•‡• ‘ —”• ‹ –Š‡ —’’‡” Ž‘„‡• ȋͻͻȌǤ ”‡˜‹‘—•Ž› ‹– ™ƒ• ”‡’‘”–‡† –Šƒ– ‹ ˆ‡™‡” –Šƒ ͳͲΨ‘ˆ–Š‡–—„‡” —Ž‘—•Ž‡•‹‘•˜‹ƒ„Ž‡„ƒ –‡”‹ƒ ‘—Ž†„‡†‡–‡ –‡†™Š‡”‡ƒ•‹ͷͲΨ‘ˆ ‘”ƒŽ Ž—‰ –‹••—‡ –Š‡•‡ „ƒ –‡”‹ƒ ‘—Ž† „‡ ”‡ ‘˜‡”‡† ȋͳͲͲȌǤ

(100)  ‘ ‘”†ƒ ‡ǡ M. tuberculosis™ƒ•†‡–‡ –‡†‹–Š‡—’’‡”Ž‘„‡•‘ˆ‘”ƒŽŽ—‰–‹••—‡†—”‹‰Žƒ–‡ › ȋͳͲͳȌǤ‘‰‡–Š‡”ǡ–Š‡•‡•–—†‹‡••—‰‰‡•––Šƒ–M.tuberculosisƒ›ƒŽ•‘’‡”•‹•–‹Š—ƒ Ž—‰–‹••—‡‘—–•‹†‡–Š‡ Žƒ••‹ –—„‡” —Ž‘—•‰”ƒ—Ž‘ƒ•„—––Š‹•‹’‘”–ƒ–‹••—‡‡‡†• •—„•–ƒ–‹ƒŽˆ—”–Š‡”‹˜‡•–‹‰ƒ–‹‘Ǥ ™‘‡„‡”•‘ˆ–Š‡ •—’‡”ˆƒ‹Ž›ȋ‘™ ‘’”‹•‹‰ƒ–‘–ƒŽ—„‡”‘ˆͳͻŽ‹‰ƒ†• ƒ†ʹͻ”‡ ‡’–‘”•ȋͳͲʹȌƒ”‡’ƒ”–‹ —Žƒ”Ž›‹˜‘Ž˜‡†‹ ‘–”‘ŽŽ‹‰‰”ƒ—Ž‘ƒˆ‘”ƒ–‹‘ǣ  Dƒ†›’Š‘–‘š‹DȋDȌǤ‘–‘Ž›ƒ ”‘’Šƒ‰‡•„—–ƒŽ•‘ͶΪŠͳƒ†Šͳ͹ ‡ŽŽ•’”‘†— ‡–Š‡•‡‘Ž‡ —Ž‡•ǤD„‹†•–‘–Š‡ ”‡ ‡’–‘”‘Ž‡ —Ž‡ ͳǤ‹ ‡ Žƒ ‹‰DƒŽ•‘‡šŠ‹„‹–ƒ†‹•–‹ –•—• ‡’–‹„‹Ž‹–›–‘‹ˆ‡ –‹‘†‡•’‹–‡‘”ƒŽ D Ž‡˜‡Ž•ȋͳͲ͵ȌǤ   ˆƒ‹Ž› ‡„‡”• ƒ”‡ ƒŽ•‘ ‹˜‘Ž˜‡† ‹ ”‡‰—Žƒ–‹‰ Š‡‘‹‡ ƒ† Š‡‘‹‡ ”‡ ‡’–‘”‡š’”‡••‹‘ǡ™Š‹ Šƒ”‡”‡•’‘•‹„Ž‡ˆ‘”–Š‡”‡ ”—‹–‡–‘ˆ‹ˆŽƒƒ–‘”› ‡ŽŽ•Ǥ Ž‡˜ƒ–‡† Ž‡˜‡Ž• ‘ˆ –Š‡ Š‡‘‹‡• Ǧͳǡ 

(101) ͳDȀEǡ ǡ

(102) Ǧͺ ƒ†

(103) ǦͳͲ ‹ „”‘ Š‹ƒŽƒŽ˜‡‘Žƒ”Žƒ˜ƒ‰‡‘ˆ’ƒ–‹‡–• ‘’ƒ”‡†–‘Š‡ƒŽ–Š› ‘–”‘Ž•ǡƒ”‡ ‘•‹•–‡– ™‹–Š ƒ ”‘Ž‡ ˆ‘” –Š‡•‡ ‘Ž‡ —Ž‡• ‹ –Š‡ ‹—‘’ƒ–Š‘Ž‘‰› ‹  †‹•‡ƒ•‡ ȋͳͲͶȌǤ Ž•‘ ƒ†‡“—ƒ–‡

(104) ǦͳʹȀ

(105) Ǧʹ͵Ȁ

(106) J •‹‰ƒŽŽ‹‰ ‹• ”‡“—‹”‡† ˆ‘” „‘–Š –Š‡ ‘–”‘Ž ‘ˆ M. tuberculosis ‹ˆ‡ –‹‘• ƒ† ˆ‘” †‡˜‡Ž‘’‡– ‘ˆ ƒ–—”‡ ‰”ƒ—Ž‘ƒ•ǡ •‹ ‡ •—„Œ‡ –• ‰‡‡–‹ ƒŽŽ› †‡ˆ‹ ‹‡– ‹ –Š‹• ƒš‹• ‘ˆ–‡ ˆƒ‹Ž –‘ †‡˜‡Ž‘’ ƒ–—”‡ ‰”ƒ—Ž‘ƒ• ȋͶͳǡ ͶʹȌǤ ‹‡™‹•‡ǡ ‹ ‡ †‡ˆ‹ ‹‡– ‹

(107) J •‹‰ƒŽŽ‹‰ ˆƒ‹Ž –‘ ˆ‘” ‰”ƒ—Ž‘ƒ• ˆ‘ŽŽ‘™‹‰ M. tuberculosis‹ˆ‡ –‹‘ȋͳͲͷȌǤ Š‡ ‘–ƒ‹‡– ‘ˆ –Š‡ „ƒ –‡”‹ƒ ƒ† –Š‡ Ž‘ ƒŽ ‹–”ƒǦ‰”ƒ—Ž‘ƒ ‹–‡”ƒ –‹‘• „‡–™‡‡ –Š‡Š‘•–ƒ†M.tuberculosis‡˜‡–—ƒŽŽ›†‡–‡”‹‡•–Š‡‘—– ‘‡‘ˆ†‹•‡ƒ•‡Ǥ  Facetoface:M.tuberculosis’evasivemanoeuvresfromimmunekillinginside thehostilemacrophageenvironment.  Š‡ ƒŽ˜‡‘Žƒ” ƒ ”‘’Šƒ‰‡ǯ• ’Šƒ‰‘•‘‡ ‹• –Š‡ ˆƒ˜‘—”‡† ‹Ž‹‡— ˆ‘” M. tuberculosisǯ ”‡’Ž‹ ƒ–‹‘ ƒ† ’‡”•‹•–‡ ‡ǡ ƒ† ’‡”Šƒ’• ƒŽ•‘ ˆ‘” –Š‡ •—”˜‹˜ƒŽ ‘ˆ †‘”ƒ–  „ƒ ‹ŽŽ‹Ǥ

(108) –”ƒ ‡ŽŽ—Žƒ”„ƒ ‹ŽŽ‹ƒ”‡—•—ƒŽŽ›†‡‰”ƒ†‡†‹Š‹‰ŠŽ›„ƒ –‡”‹ ‹†ƒŽƒ ‹†‹ ’Šƒ‰‘Ž›•‘•‘‡•Ǥ ‘™‡˜‡”ǡ M. tuberculosis Šƒ• ƒ†‘’–‡† ’‘™‡”ˆ—Ž •–”ƒ–‡‰‹‡• –‘ ”‡•‹•–ǡ ‘” ‡• ƒ’‡ ˆ”‘ǡ –Š‡•‡‘–Š‡”™‹•‡‹ ”‘„‹ ‹†ƒŽ’ƒ–Š™ƒ›•Ǥ  EscapefromReactiveNitrogenIntermediates(RNI)  –‹˜ƒ–‹‘ ‘ˆ ƒ ”‘’Šƒ‰‡• „›

(109) J ƒ†   ‹†— ‡• –Š‡ ƒ –‹˜‹–› ‘ˆ ‹–”‹  ‘š‹†‡ •›–Šƒ•‡ʹȋʹȌǤʹ ƒ–ƒŽ›œ‡•–Š‡ ‘˜‡”•‹‘‘ˆǦƒ”‰‹‹‡‹–‘ƒ†”‡Žƒ–‡† ‹–”‘‰‡‹–‡”‡†‹ƒ–‡•ȋ

(110) ȌȋͳͲ͸Ȍ™Š‹ Š ƒƒ –ƒ•’‘–‡– ›–‘–‘š‹ ƒ‰‡–•Ǥ

(111) ˜‹–”‘ •–—†‹‡•™‹–Š‘—•‡†‡”‹˜‡†ƒ ”‘’Šƒ‰‡•Šƒ˜‡•Š‘™–Šƒ––Š‡Ǧƒ”‰‹‹‡Ǧ†‡’‡†‡– ’”‘†— –‹‘ ‘ˆ 

(112)  ‹• –Š‡ ’”‹ ‹’ƒŽ ‡ˆˆ‡ –‘” ‡ Šƒ‹• ‹ ƒ –‹˜ƒ–‡† —”‹‡. ʹʹ.

(113) Introductionandoutlineofthethesis . ƒ ”‘’Šƒ‰‡•ǡ ”‡•’‘•‹„Ž‡ ˆ‘” ‹Š‹„‹–‹‰ ˜‹”—Ž‡– M. tuberculosis ȋͳͲ͹ȌǤ ‘– •—”’”‹•‹‰Ž›ǡ –Š‡”‡ˆ‘”‡ǡ M. tuberculosis ƒ’’‡ƒ”• –‘ Šƒ˜‡ ƒ”‡† ‹–•‡Žˆ ƒ‰ƒ‹•– •— Š ‘š‹†ƒ–‹˜‡ƒ†‹–”‘•ƒ–‹˜‡Š‘•–”‡•’‘•‡•–Š”‘—‰Š–Š‡’”‡•‡ ‡‘ˆnoxR1ȋͳͲͺȌǡnoxR3 ȋͳͲͻȌƒ†ahpCȋͳͳͲȌ‰‡‡•ǡ™Š‹ ŠƒŽŽŠƒ˜‡„‡‡•Š‘™–‘ƒ‹†‹”‡•‹•–ƒ ‡–‘

(114) •Ǥ  EscapeofM.tuberculosisfromphagolysosomalfusion ˆ–‡” —’–ƒ‡ ‘ˆ ‹–”ƒ ‡ŽŽ—Žƒ” „ƒ –‡”‹ƒ „› ’”‘ˆ‡••‹‘ƒŽ ’Šƒ‰‘ ›–‡• ‹–‘ Žƒ••‹ ƒŽ ’Šƒ‰‘•‘‡•ǡ–Š‡Žƒ––‡”–›’‹ ƒŽŽ›ˆ—•‡™‹–ŠŽ›•‘•‘‡•–‘ˆ‘”’Šƒ‰‘Ž›•‘•‘‡•ǤŠ‡•‡ ‘’ƒ”–‡–• ƒ”‡ Š‹‰ŠŽ› ƒ ‹†‹ ǡ †‡’”‹˜‡† ‘ˆ —–”‹‡–• ȋDz•–ƒ”˜ƒ–‹‘dz •–”‡••Ȍǡ Š›’‘š‹  ƒ† ”‹ Š ‹ Š›†”‘Ž›–‹  ‡œ›‡• –Šƒ– †‡‰”ƒ†‡ ƒ† ‹ŽŽ „ƒ –‡”‹ƒ ȋͳͳͳȌǤ Ž”‡ƒ†› ‹ –Š‡ ‡ƒ”Ž›ͳͻ͹Ͳǯ•‹–™ƒ•”‡ ‘‰‹œ‡†–Šƒ–‹‘”†‡”–‘‡˜ƒ†‡‹ŽŽ‹‰ǡM.tuberculosisƒ””‡•–‡† ’Šƒ‰‘•‘‡ ƒ–—”ƒ–‹‘ „› ’”‡˜‡–‹‰ ˆ—•‹‘ ™‹–Š Ž›•‘•‘‡• ȋͳͳʹȌǤ ”‘–‡‹• ƒ† ‘Ž‡ —Žƒ” ‡ Šƒ‹•• ƒ••‘ ‹ƒ–‡† ™‹–Š –Š‹• ’Šƒ‰‘•‘ƒŽ ƒ–—”ƒ–‹‘ „Ž‘  ‹ Ž—†‡ ͳǡ ƒ•‡• ‘ˆ –Š‡ ƒ„ ˆƒ‹Ž› ƒ† –Š‡ ƒŽ ‹— „‹†‹‰ ’”‘–‡‹ ƒŽ‘†—Ž‹ǡ ‘”‘‹Ǧͳȋ‘”Ȍȋͳͳ͵ǡͳͳͶȌǤ‘”‡”‡ ‡–Ž›ǡ—•‹‰ Š‡‹ ƒŽ‰‡‡–‹ •ǡƒ‡–™‘”‘ˆ Š—ƒ ‹ƒ•‡• ™ƒ• †‡‘•–”ƒ–‡† –‘ „‡ ‡••‡–‹ƒŽ ‹ ’Šƒ‰‘•‘‡ ƒ–—”ƒ–‹‘Ǥ — –‹‘ƒŽ†‹•”—’–‹‘‘ˆ‹ƒ•‡•‹–Š‡–ͳ‡–™‘”„›‹‘” Š‡‹ ƒŽ‹Š‹„‹–‘”• Ž‡† –‘ ‡Šƒ ‡† ‹ŽŽ‹‰ ‘ˆ ‹–”ƒ ‡ŽŽ—Žƒ” „ƒ –‡”‹ƒǡ ‹ Ž—†‹‰ M. tuberculosis ȋ͵͸ȌǤ

(115)  ƒ††‹–‹‘ǡ ‹–‡”ƒ –‹‘• ‘ˆ › ‘„ƒ –‡”‹ƒ ȋ‘•–Ž›  Ȍ ™‹–Š Š‘Ž‡•–‡”‘Ž Šƒ˜‡ „‡‡ •Š‘™–‘ƒŽŽ‘™‡–”›‘ˆ› ‘„ƒ –‡”‹ƒ‹–‘ƒ ”‘’Šƒ‰‡•ȋͳͳͷȌǤŠ‡•‡’ƒ–Š™ƒ›•Šƒ˜‡ ”‡ ‡–Ž›„‡‡”‡˜‹‡™‡†‹†‡–ƒ‹Žȋͳͳ͵ǡͳͳ͸ǡͳͳ͹ȌǤ ”‡ ‡–’”‘˜‘ ƒ–‹˜‡•–—†›Šƒ••—‰‰‡•–‡†–Šƒ–M.tuberculosisƒ†M.lepraeǦ„—–‘–  Ǧ ƒ ‡• ƒ’‡ ˆ”‘ –Š‡ ’Šƒ‰‘•‘‡ǡ ƒ– Ž‡ƒ•– —’‘ Ž‘‰‡”Ǧ–‡” —Ž–—”‡ ‹ Š—ƒ ‡ŽŽ•ǣM.tuberculosis ‘–ƒ‹‹‰’Šƒ‰‘•‘‡•ˆ—•‡†™‹–ŠŽ›•‘•‘‡•ǡ„—–M.tuberculosis •—„•‡“—‡–Ž› –”ƒ•Ž‘ ƒ–‡† ˆ”‘ –Š‡ ’Šƒ‰‘Ž›•‘•‘‡• ‹–‘ –Š‡ ›–‘•‘ŽǤ Š‹• ’”‘ ‡•• ™ƒ•†‡’‡†‡–‘ƒ„ƒ ‹ŽŽƒ”›•‡ ”‡–‹‘•›•–‡‹˜‘Ž˜‹‰ ǦͳͲȋͳͳͺȌǤŠ‡•—„Œ‡ –‘ˆ ’‘••‹„Ž‡ –”ƒ•Ž‘ ƒ–‹‘ ‘ˆ M. tuberculosis ”‡ƒ‹• ƒ ƒ––‡” ‘ˆ †‡„ƒ–‡ǡ ƒ† ˆ—”–Š‡” •–—†‹‡•ƒ”‡‡‡†‡†–‘†‹••‡ ––Š‹•’”‘ ‡••ˆ—”–Š‡”Ǥ  Thequestfornoveltargetsforantituberculosisintervention  Š‡ ƒ˜ƒ‹Žƒ„‹Ž‹–› ‘ˆ •‡˜‡”ƒŽ ‘’Ž‡–‡ M. tuberculosis ‰‡‘‡ •‡“—‡ ‡• ȋͳͳͻȌǡ ȋ™™™ǤǤ‘”‰Ȍ ‘„‹‡† ™‹–Š –Š‡ ’‘••‹„‹Ž‹–› –‘ •–—†› ‰‡‘‡ ™‹†‡ ‡š’”‡••‹‘ ’”‘ˆ‹Ž‡• —†‡” ‘–”‘ŽŽ‡† M. tuberculosis ‹ˆ‡ –‹‘Ǧ’Šƒ•‡ •‹—Žƒ–‹‰ ‘†‹–‹‘• ™‹ŽŽ ƒŽŽ‘™ ‹•‹‰Š– ‹–‘ –Š‡ „Ž—‡’”‹– ‘ˆ ‹ ”‘„‹ƒŽ ’‡”•‹•–‡ ‡ ‹ Š—ƒ•ǡ ƒ† Š‡Ž’ ‹†‡–‹ˆ›‹‰‘˜‡Ž–ƒ”‰‡–•ˆ‘”‹–‡”˜‡–‹‘‹ȋŽƒ–‡–ȌǤ ‡˜‡”ƒŽ •–—†‹‡• Šƒ˜‡ ƒ’’Ž‹‡†  ‹ ”‘ƒ””ƒ›–‡ Š‹“—‡• –‘•–—†› –Š‡ –”ƒ• ”‹’–‘‡ ‘ˆ M. tuberculosis ‹ ‘†‡Ž• –Šƒ– ƒ”‡ ”‡’”‡•‡–ƒ–‹˜‡ ‘ˆ †‹•–‹ – ’Šƒ•‡• ‘ˆ M. tuberculosis‹ˆ‡ –‹‘Ǥ

(116) ƒ”‡ ‡–•–—†›ǡ—”’Š›ƒ†”‘™†‡• ”‹„‡†–Š‡”‡•—Ž–•‘ˆƒ ‡–ƒǦƒƒŽ›•‹•‘†‹ˆˆ‡”‡–‰‡‡‡š’”‡••‹‘’”‘ˆ‹Ž‡•–Šƒ–Šƒ†„‡‡•’‡ ‹ˆ‹ ƒŽŽ›•–—†‹‡† ‹ ‘†‡Ž• •‹—Žƒ–‹‰ „ƒ –‡”‹ƒŽ †‘”ƒ ›Ǥ Š‡‹” ƒƒŽ›•‹• •‡– ‘—– –‘ ‹†‡–‹ˆ› ‘˜‡Ž  †”—‰–ƒ”‰‡–•ƒ‰ƒ‹•–†‘”ƒ–’Šƒ•‡M.tuberculosis‹ˆ‡ –‹‘•„ƒ•‡†‘–Š‡‡š’”‡••‹‘ †ƒ–ƒ ‘„‹‡† ™‹–Š ‰‡‘‡Ǧ™‹†‡ ‹•‡”–‹‘ƒŽ —–ƒ‰‡‡•‹• ƒ• ‹†‹ ƒ–‹˜‡ ˆ‘” ‰‡‡ ‹†‹•’‡•ƒ„‹Ž‹–›Ǥ ‘˜‡Ž ƒ–‹Ǧ –ƒ”‰‡–• ™Š‹ Š ‘—Ž† –Š—• „‡ ‹†‡–‹ˆ‹‡† ‹ Ž—†‡† ”‡‰—Žƒ–‘”›‰‡‡•ȋdevRȀdevSǡrelAǡmprABȌƒ†•‡˜‡”ƒŽ‡œ›‡•‹˜‘Ž˜‡†‹„ƒ –‡”‹ƒŽ ‡–ƒ„‘Ž‹•ȋͳʹͲȌǤ ʹ͵.

(117) Chapter1. •‹‰ ‹ ”‘Ǧƒ””ƒ› „ƒ•‡† ƒ’’”‘ƒ Š‡•ǡ ‰‡‡• ‡š’”‡••‡† „› M. tuberculosis †—”‹‰ ‘š›‰‡ †‡’”‹˜ƒ–‹‘ Šƒ˜‡ „‡‡ ‹†‡–‹ˆ‹‡†ǡ ƒ• †‹• —••‡† ‹ ‘”‡ †‡–ƒ‹Ž „‡Ž‘™Ǥ ‡•‹†‡• ‘š›‰‡ †‡’”‹˜ƒ–‹‘ǡ Ž‘™ ’ Ǧ ƒ† 

(118) Ȁ

(119) Ǧ ‡š’‘•—”‡ǡ ‹–”ƒ ‡ŽŽ—Žƒ” › ‘„ƒ –‡”‹ƒ ƒ”‡ ƒŽ•‘ ‡š’‘•‡† –‘ —–”‹‡– •–ƒ”˜ƒ–‹‘ ȋe.g. ‡ǡ ƒ”„‘ȌǤ

(120) – ‹• ‹–‡”‡•–‹‰ –Šƒ– M. tuberculosis ƒ†ƒ’–• –‘ –Š‡•‡ •’‡ ‹ˆ‹  Ž‹‹–ƒ–‹‘• „› —‹“—‡Ž› ƒŽ–‡”ƒ–‹‘• ‹ ‹–• ‰‡‡ ‡š’”‡••‹‘ ’ƒ––‡”• ȋͳʹͳȌǤ ”ƒ• ”‹’–‹‘ƒŽ ’”‘ˆ‹Ž‹‰ ƒŽ•‘ ƒŽŽ‘™• –Š‡ ‰ƒ–Š‡”‹‰ ‘ˆ †‡–ƒ‹Ž‡†‹ˆ‘”ƒ–‹‘‹†‹”‡ – ”‘••Ǧ–ƒŽ„‡–™‡‡M.tuberculosisƒ†‹ˆ‡ –‡†Š—ƒ •ƒ†ƒ ”‘’Šƒ‰‡•ȋͳʹʹȌǤ‡˜‡”–Š‡Ž‡••ǡ–Š‡„ƒ –‡”‹ƒŽˆƒ –‘”•–Šƒ–ƒŽ–‡”–Š‡„ƒŽƒ ‡ ˆ”‘–‘”‡ƒ –‹˜ƒ–‹‘ƒ†’”‘Ž‹ˆ‡”ƒ–‹‘•–‹ŽŽ”‡ƒ‹—‘™Ǥ‡ ‡–Ž›ǡƒˆƒ‹Ž›‘ˆ M.tuberculosis‰”‘™–Šˆƒ –‘”•ȋ”‡•—• ‹–ƒ–‹‘’”‘‘–‹‘ˆƒ –‘”•ǡ’ˆ•Ȍ™ƒ•‹†‡–‹ˆ‹‡†ǡ ™Š‹ Šƒ’’‡ƒ”‡†–‘„‡”‡“—‹”‡†ˆ‘”–Š‡˜‹”—Ž‡ ‡ƒ†”‡•—• ‹–ƒ–‹‘‘ˆ†‘”ƒ–„ƒ –‡”‹ƒ ȋͳʹ͵ǡͳʹͶȌǤ‡Ž‡–‹‘•‘ˆrpf‰‡‡•”‡•—Ž–‡†‹†‡ˆ‡ –‹˜‡‰”‘™–Š‘ˆ–Š‡„ƒ –‡”‹ƒ‹˜‹˜‘ǡ †‡ˆ‡ –‹˜‡”‡•—• ‹–ƒ–‹‘‹˜‹–”‘ȋͳʹͷȌƒ††‡Žƒ›‡†”‡ƒ –‹˜ƒ–‹‘ˆ”‘ Š”‘‹ ‹˜‹˜‘ ȋͳʹ͸ȌǤ

(121) ƒ††‹–‹‘ǡ’ˆƒ’’‡ƒ”–‘„‡ƒ••‘ ‹ƒ–‡†‹‘”ƒŽ ‡ŽŽ†‹˜‹•‹‘‹M.smegmatis ȋͳʹ͹ȌǤ Š‡–Š‡” –Š‹• ƒ „‡ ‡š–”ƒ’‘Žƒ–‡† –‘ M. tuberculosis ”‡ƒ‹• –‘ „‡ •‡‡Ǥ Š‡ ‡ Šƒ‹••‹˜‘Ž˜‡†‹ ‘–”‘Žƒ†‡š’”‡••‹‘‘ˆ’ˆ•‹ƒ”‡Žƒ”‰‡Ž›— Ž‡ƒ”„—–ƒ ‰”‘™‹‰ „‘†› ‘ˆ ‡˜‹†‡ ‡ ’‘‹–• –‘™ƒ”†• ƒ ”‘Ž‡ ˆ‘” ’ˆ• ‹ „ƒ –‡”‹ƒŽ ˜‹”—Ž‡ ‡ǡ ’‡”•‹•–‡ ‡ǡ‹—‡‘†—Žƒ–‹‘ƒ†”‡ƒ –‹˜ƒ–‹‘ȋͳʹͶǡͳʹͺȌǤ „˜‹‘—•Ž›ǡ ‘Ž‡ —Ž‡• ‹˜‘Ž˜‡† ‹ M. tuberculosis’ ”‡ƒ”ƒ„Ž‡ ƒ† ƒ„—†ƒ– Ž‹’‹† ‡–ƒ„‘Ž‹•ƒ”‡Š‹‰ŠŽ›ƒ––”ƒ –‹˜‡ƒ–‹„‹‘–‹ –ƒ”‰‡–•ǤŠ‡•‡‹ Ž—†‡‡–Š›Ž–”ƒ•ˆ‡”ƒ•‡•ǡ › Ž‘’”‘’ƒ‡•›–Šƒ•‡•ȋ‹˜‘Ž˜‡†‹–Š‡•›–Š‡•‹•‘ˆ› ‘„ƒ –‡”‹—•’‡ ‹ˆ‹ › ‘Ž‹  ƒ ‹†•Ȍȋͳʹͻǡͳ͵ͲȌƒ•™‡ŽŽƒ•Ž‹’‘Ž›–‹ ‘Ž‡ —Ž‡•ȋ†‡‰”ƒ†ƒ–‹‘‘ˆŽ‹’‹†•Ȍȋͳ͵ͳȌǤ‡‘ˆ–Š‡ ‘•– ‡ˆˆ‡ –‹˜‡ ƒ–‹Ǧ †”—‰•ǡ ‹•‘‹ƒœ‹† ȋ

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