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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)  Chapter2 HumanTcellresponsesto25novelantigens encodedbygenesofthedormancyregulonof Mycobacteriumtuberculosis          .  Ž‹ƒ‡ǤǤ‡›–‡ǡƒǡͳƒ›‘—‰‹ǡ„ǡͳ‡‡•ǤǤǤ ”ƒ‡ǡ„‡‹‡‡ Ǥ ”‹‰‰‡ǡ„‘”‹‡ ”‹•ǡƒ”‹•–ƒǤ˜ƒ‡‹Œ‰ƒƒ”†‡ǡ„ƒ”–‹

(3) Ǥ‘•—‹Žǡ ǡƒ”‹‡Ž†‹‰Šǡ†‡–‡”†‡”•‡ǡ† ƒ”›Ǥ  Š‘‘Ž‹ǡ ƒ†”ƒǤ”‡†ǡƒ‘ ǤǤ––‡Š‘ˆˆǡ„ƒ†‹ Š°ŽǤŽ‡‹„  ƒ‡’ƒ”–‡–‘ˆ

(4) ˆ‡ –‹‘—•‹•‡ƒ•‡•ƒ†„‡’ƒ”–‡–‘ˆ

(5) —‘Š‡ƒ–‘Ž‘‰›ƒ†Ž‘‘† ”ƒ•ˆ—•‹‘ǡ‡‹†‡‹˜‡”•‹–›‡†‹ ƒŽ‡–‡”ǡ‡‹†‡ǡ–Š‡‡–Š‡”Žƒ†• ‡’ƒ”–‡–‘ˆ‡†‹ ‹‡ǡ‹˜‹•‹‘‘ˆ

(6) ˆ‡ –‹‘—•‹•‡ƒ•‡•ƒ† ‡‘‰”ƒ’Š‹ ‡†‹ ‹‡ǡ–ƒˆ‘”† ‹˜‡”•‹–› Š‘‘Ž‘ˆ‡†‹ ‹‡ǡ–ƒˆ‘”†ǡǡǡ †‡’ƒ”–‡–‘ˆ

(7) ˆ‡ –‹‘—•‹•‡ƒ•‡

(8) —‘Ž‘‰›ǡ–ƒ–‡•‡”—

(9) •–‹–—–‡ǡ‘’‡Šƒ‰‡ǡ‡ƒ” ͳǤǤǤǤƒ†ǤǤǤ ‘–”‹„—–‡†‡“—ƒŽŽ›–‘–Š‹•™‘”  MicrobesInfect.2006Jul;8(8):20522060..

(10) Chapter2. Abstract Š‡ †‘”ƒ › ȋ‘•Ȍ ”‡‰—Ž‘ ‘ˆ Mycobacterium tuberculosis ‹• ‡š’”‡••‡† ‹ ˜‹–”‘ †—”‹‰Š›’‘š‹ƒƒ†Ž‘™Ǧ†‘•‡‹–”‹ ‘š‹†‡•–‹—Žƒ–‹‘Ǥ—„‡” Ž‡„ƒ ‹ŽŽ‹ƒ”‡–Š‘—‰Š––‘ ‡ ‘—–‡” –Š‡•‡ ‘†‹–‹‘•‹ Š—ƒ• †—”‹‰ Žƒ–‡– ‹ˆ‡ –‹‘Ǥ

(11)  –Š‹• •–—†›ǡ ‹—‡ ”‡•’‘•‡• ™‡”‡ ‡˜ƒŽ—ƒ–‡† –‘ –Š‡ ʹͷ ‘•– •–”‘‰Ž› ‹†— ‡† ‘•Ǧ”‡‰—Ž‘Ǧ‡ ‘†‡† ’”‘–‡‹•ǡ”‡ˆ‡””‡†–‘ƒ•Žƒ–‡ ›ƒ–‹‰‡•Ǥ”‘Ž‹ˆ‡”ƒ–‹‘ƒ••ƒ›•™‡”‡’‡”ˆ‘”‡†—•‹‰M. tuberculosis•’‡ ‹ˆ‹ Ǧ ‡ŽŽŽ‹‡•ƒ†’‡”‹’Š‡”ƒŽ„Ž‘‘†‘‘— Ž‡ƒ” ‡ŽŽ•ȋȌˆ”‘ –—„‡” —Ž‘•‹• ȋȌ ’ƒ–‹‡–•ǡ –—„‡” —Ž‹ •‹ –‡•– ’‘•‹–‹˜‡ ȋΪȌ ‹†‹˜‹†—ƒŽ• ƒ† —‹ˆ‡ –‡† ‘–”‘Ž•Ǥ ŽŽ ʹͷ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ƒ„Ž‡ –‘ ‹†— ‡ ’”‘†— –‹‘ ‘ˆ ‹–‡”ˆ‡”‘Ǧ‰ƒƒ ȋ

(12) ǦJȌ „› Ǧ ‡ŽŽ Ž‹‡•Ǥ ‹‰Š–‡‡ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ƒŽ•‘ ”‡ ‘‰‹œ‡† „›  ‘ˆ M. tuberculosis‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ•ǡ ™Š‹ Š ‹†‹ ƒ–‡• ‡š’”‡••‹‘‘ˆ–Š‡‘•Ǧ”‡‰—Ž‘†—”‹‰ƒ–—”ƒŽ‹ˆ‡ –‹‘Ǥ‹ˆˆ‡”‡–‹ƒŽƒƒŽ›•‹••Š‘™‡† –Šƒ– Ϊ ‹†‹˜‹†—ƒŽ• ”‡ ‘‰‹œ‡† ‘”‡ Žƒ–‡ › ƒ–‹‰‡• ƒ† ™‹–Š ƒ •–”‘‰‡” ——Žƒ–‹˜‡

(13) Ǧɀ”‡•’‘•‡–Šƒ’ƒ–‹‡–•ǡ™Š‹Ž‡–Š‡‘’’‘•‹–‡’”‘ˆ‹Ž‡™ƒ•ˆ‘—†ˆ‘” —Ž–—”‡ ˆ‹Ž–”ƒ–‡ ’”‘–‡‹ǦͳͲǤ

(14)  ’ƒ”–‹ —Žƒ” ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͹  ƒ† ˜ʹ͸ʹͺ ‹†— ‡† •–”‘‰

(15) Ǧɀ ”‡•’‘•‡• ‹ Ϊ ‹†‹˜‹†—ƒŽ•ǡ ™‹–Š ͸ͳΨǡ ͸ͳΨǡ ͷʹΨ ƒ† ͵ͷΨ ”‡•’‘†‡”•ǡ ”‡•’‡ –‹˜‡Ž›Ǥ

(16)  ‘ Ž—•‹‘ǡ •‡˜‡”ƒŽ ‡™ M. tuberculosis ƒ–‹‰‡• ™‡”‡ ‹†‡–‹ˆ‹‡† ™‹–Š‹ –Š‡ ‘•Ǧ”‡‰—Ž‘Ǥ ƒ”–‹ —Žƒ”Ž› •–”‘‰

(17) Ǧɀ ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ‘„•‡”˜‡† ‹ Žƒ–‡–Ž› ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ•ǡ •—‰‰‡•–‹‰ –Šƒ– ‹—‡ ”‡•’‘•‡•ƒ‰ƒ‹•––Š‡•‡ƒ–‹‰‡•ƒ› ‘–”‹„—–‡–‘ ‘–”‘ŽŽ‹‰Žƒ–‡–M.tuberculosis ‹ˆ‡ –‹‘Ǥ. Ͷʹ.

(18) ImmuneresponsestolatencyantigensofM.tuberculosis . Introduction —„‡” —Ž‘•‹•ȋȌ‹•ƒƒŒ‘”–Š”‡ƒ––‘‰Ž‘„ƒŽŠ‡ƒŽ–Š™‹–Šƒ‡•–‹ƒ–‡‘ˆˆ‘—”’‡”•‘• †›‹‰‘ˆ‡˜‡”›‹—–‡Ǥ—”˜‡›•™‹–Š–—„‡” —Ž‹•‹–‡•–•ȋȌ•—‰‰‡•––Šƒ–‘‡Ǧ –Š‹”† ‘ˆ –Š‡ ™‘”Ž†̵• ’‘’—Žƒ–‹‘ ‹• Žƒ–‡–Ž› ‹ˆ‡ –‡† ™‹–Š Mycobacterium tuberculosisǤ Š‹•‡‘”‘—•”‡•‡”˜‘‹”‘ˆŽƒ–‡–ǡˆ”‘™Š‹ Š‘•– ƒ•‡•‘ˆƒ –‹˜‡†‹•‡ƒ•‡ƒ”‹•‡ǡ ‡„‘†‹‡• ƒ ƒŒ‘” ‘„•–ƒ Ž‡ ‹ ƒ Š‹‡˜‹‰ ™‘”Ž†™‹†‡ ‘–”‘Ž ‘ˆ  ȏͳȐǤ

(19)  ’ƒ”–‹ —Žƒ” ™Š‡ –ƒ‡ ‹–‘ ƒ ‘—– –Š‡ —””‡–Ž› ‘‰‘‹‰ 

(20)  ’ƒ†‡‹ ǡ ƒ• ‹

(21) Ǧͳ ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ• ”‹• ‘ˆ ’”‘‰”‡••‹‘ ˆ”‘ ƒ Žƒ–‡– ‹ˆ‡ –‹‘ –‘ ƒ –‹˜‡  ‹ ”‡ƒ•‡• •‹‰‹ˆ‹ ƒ–Ž›ǡ —’ –‘ ͺǦͳͲΨ ’‡” ›‡ƒ” ȏͳǡʹȐǤ Š‡ ƒ˜ƒ‹Žƒ„Ž‡ ˜ƒ ‹‡ ƒ‰ƒ‹•– ǡ M.bovis „ƒ ‹ŽŽ—•ƒŽ‡––‡Ǧ —±”‹ȋ Ȍǡ‘Ž›’”‘˜‹†‡••‹‰‹ˆ‹ ƒ–’”‘–‡ –‹‘ƒ‰ƒ‹•–•‡˜‡”‡ †‹•‡ƒ•‡‹›‘—‰‹ˆƒ–•ƒ†‡•–ƒ„Ž‹•Š‡–‘ˆM.tuberculosis‹ˆ‡ –‹‘ȏ͵Ȑǡ„—–ƒˆˆ‘”†• Ž‹‹–‡†ƒ†Š‹‰ŠŽ›˜ƒ”‹ƒ„Ž‡’”‘–‡ –‹‘ƒ‰ƒ‹•–’—Ž‘ƒ”›‹ƒ†—Ž–•ǡ™Š‹ Š‹•‘•–Ž› †—‡–‘”‡ƒ –‹˜ƒ–‹‘‘ˆŽƒ–‡–M.tuberculosisȏͶǡͷȐǤ ‘–ŠͶΪ ƒ†ͺΪǦ ‡ŽŽ•ƒ†–Š‡ ›–‘‹‡•

(22) ǦJƒ† ǦD’Žƒ›ƒ‹’‘”–ƒ–”‘Ž‡ ‹–Š‡‹—‡”‡•’‘•‡ƒ‰ƒ‹•–› ‘„ƒ –‡”‹ƒƒ†‹ ‘–”‘ŽŽ‹‰Žƒ–‡–‹ˆ‡ –‹‘ȏ͸ǡ͹ȐǤ —”‹‰ Žƒ–‡– ‹ˆ‡ –‹‘ǡ –—„‡” Ž‡ „ƒ ‹ŽŽ‹ ƒ”‡ –›’‹ ƒŽŽ› ‘–ƒ‹‡† ™‹–Š‹ ‹—‡Ǧ ‡†‹ƒ–‡† ‰”ƒ—Ž‘ƒ• ȏͺȐǤ ‘™‡˜‡”ǡ „‡ˆ‘”‡ –Š‡ ‡”ƒ ‘ˆ Š‡‘–Š‡”ƒ’›ǡ ‹– Šƒ• „‡‡ •Š‘™ –Šƒ– Ž‹˜‡ –—„‡” Ž‡ „ƒ ‹ŽŽ‹ ƒ ƒŽ•‘ „‡ ’”‡•‡– ‹ ƒ ”‘• ‘’‹ ƒŽŽ› ‘”ƒŽ Ž—‰ –‹••—‡ȏͻȐǤŠ‹•ˆ‹†‹‰™ƒ•”‡ ‡–Ž› ‘ˆ‹”‡†„›‹Ǧ•‹–—ȏͳͲȐǡ„—––Š‡•‡–—„‡” Ž‡ „ƒ ‹ŽŽ‹ ‘—Ž†‘–„‡˜‹•—ƒŽ‹œ‡†—•‹‰‹‡ŠŽǦ‡‡Ž•‡•–ƒ‹‹‰Ǥ

(23) –Šƒ•„‡‡”‡’‘”–‡†–Šƒ– –Š‹• ‹• ƒ—•‡† „› †‹•–‹ – ‡ŽŽǦ™ƒŽŽ ƒŽ–‡”ƒ–‹‘• ‘ˆ –—„‡” Ž‡ „ƒ ‹ŽŽ‹ †—”‹‰ ’‡”•‹•–‡ ‡ ȏͳͳȐǤ

(24) – ‹• ‰‡‡”ƒŽŽ› –Š‘—‰Š– –Šƒ– ’‡”•‹•–‹‰ –—„‡” Ž‡ „ƒ ‹ŽŽ‹ ƒ”‡ •—„Œ‡ –‡† –‘ —–”‹‡– ƒ† ‘š›‰‡†‡’”‹˜ƒ–‹‘ǡ‹ ”‘„‹ ‹†ƒŽ‘Ž‡ —Ž‡••— Šƒ•”‡ƒ –‹˜‡‘š›‰‡‹–‡”‡†‹ƒ–‡•ƒ† ‹–”‘‰‡‹–‡”‡†‹ƒ–‡•ǡƒ†‹—‡Ǧ‡†‹ƒ–‡†‹ŽŽ‹‰ȋ”‡˜‹‡™‡†‹ȏͳʹǡͳ͵ȐȌǤ ‘™‡˜‡”ǡ Ž‹––Ž‡ ‹• ‘™ ƒ„‘—– ƒ–‹‰‡Ǧ•’‡ ‹ˆ‹  Š—ƒ Ǧ ‡ŽŽ ”‡•’‘•‡• ƒ‰ƒ‹•– ’‡”•‹•–‹‰ › ‘„ƒ –‡”‹ƒǡ’ƒ”–‹ —Žƒ”Ž›‹–Š‡ ‘–‡š–‘ˆŽƒ–‡–‹ˆ‡ –‹‘ƒ†’”‘–‡ –‹‘ƒ‰ƒ‹•– †‹•‡ƒ•‡Ǥ ”‡˜‹‘—• •–—†‹‡• ‘ˆ –—„‡” Ž‡ „ƒ ‹ŽŽ‹ —Ž–—”‡† —†‡” Ž‘™ ‘š›‰‡ ”‡’‘”– –Šƒ– •’ǡ ƒŽ•‘ ‘™ ƒ• ͳ͸Ǧƒ ƒŽ’ŠƒǦ ”›•–ƒŽŽ‹ Š‘‘Ž‘‰—‡ ȋ ”Ȍ ‘” ˜ʹͲ͵ͳ ǡ ‹• Š‹‰ŠŽ› ‡š’”‡••‡††—”‹‰ –Š‡•‡ ‘†‹–‹‘• ȏͳͶǡͳͷȐǤ ‡ŽŽ—Žƒ” ‹—‡ ”‡•’‘•‡• –‘ •’Šƒ˜‡ „‡‡ ‘„•‡”˜‡† ‹ Žƒ–‡–Ž› ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ•ǡ ™Š‹Ž‡ ƒ–‹„‘†‹‡• –‘ –Š‹• ƒ–‹‰‡ ™‡”‡ ’”‡†‘‹ƒ–Ž›ˆ‘—†‹’‡”•‘•™‹–Šƒ –‹˜‡†‹•‡ƒ•‡ȏͳ͸ȐǤ‘”‡”‡ ‡–Ž›ǡ •’™ƒ• ˆ‘—† –‘ „‡ ’ƒ”– ‘ˆ –Š‡ •‘Ǧ ƒŽŽ‡† †‘”ƒ › ȋ‘•Ȍ ”‡‰—Ž‘ ‘ˆ M. tuberculosis ‘’”‹•‹‰Ͷͺ‰‡‡•ȏͳͷǡͳ͹ǦʹͲȐǤš’”‡••‹‘‘ˆ–Š‡‘•”‡‰—Ž‘‹•‘„•‡”˜‡†ƒ•’ƒ”–‘ˆ –Š‡ ƒ†ƒ’–‹˜‡ ”‡•’‘•‡ ‘ˆ M. tuberculosis –‘ Š›’‘š‹ƒǡ ‹ Ž—†‹‰ ‰”ƒ†—ƒŽ ‘š›‰‡ †‡’Ž‡–‹‘ǡ ™Š‹ Š ”‡•—Ž–• ‹ †‹•–‹ – •–ƒ‰‡• ‘ˆ ‘Ǧ”‡’Ž‹ ƒ–‹‰ ’‡”•‹•–‡ ‡ ‹ –Š‡ •‘Ǧ ƒŽŽ‡†ƒ›‡‘†‡ŽȏʹͳȐǡƒ†–‘Ž‘™Ǧ†‘•‡‹–”‹ ‘š‹†‡•–‹—Žƒ–‹‘ȏͳͻȐǤŠ‡•‡‹˜‹–”‘ —Ž–—”‡ ‘†‡Ž• ”‡’”‡•‡– ’”‘š‹‡• ‘ˆ ‘†‹–‹‘• –Šƒ– –—„‡” Ž‡ „ƒ ‹ŽŽ‹ ƒ”‡ –Š‘—‰Š– –‘ ‡ ‘—–‡” ‹ ˜‹˜‘ †—”‹‰ ’‡”•‹•–‡ ‡ ‹ ‹—‡ ‘’‡–‡– Š‘•–• ȏͳ͵ǡʹʹȐǤ Š‹• ‹• •—’’‘”–‡† „› ‘„•‡”˜ƒ–‹‘• –Šƒ– ‰‡‡• ‘ˆ –Š‡ ‘• ”‡‰—Ž‘ ƒ”‡ —’”‡‰—Žƒ–‡† ‹

(25) Ǧɀ ƒ –‹˜ƒ–‡† M. tuberculosis‹ˆ‡ –‡† —”‹‡ ƒ ”‘’Šƒ‰‡• ƒ† ‹ Ž—‰• ‘ˆ Š”‘‹ ƒŽŽ› ‹ˆ‡ –‡†‹ ‡ȏʹͲǡʹʹǡʹ͵ȐǤ

(26) Š—ƒ•ǡ‹ ”‡ƒ•‡†Ž‡˜‡Ž•‘ˆ‘ˆ •’™‡”‡ˆ‘—†‹ Ž—‰•‘ˆ’ƒ–‹‡–•™‹–Š Š”‘‹ ƒ –‹˜‡ȏʹ͵ȐǤ. Ͷ͵.

(27) Chapter2. Š‡ ˆ— –‹‘• ‘ˆ ‘•– ‘• ”‡‰—Ž‘ ‡ ‘†‡† ’”‘–‡‹• ƒ”‡ —‘™ ȏͳͶǡʹͶȐǤ – ’”‡•‡– ‹– ‹• ƒŽ•‘ ‘– ‘™ –‘ ™Š‹ Š ‡š–‡– ‘• ”‡‰—Ž‘ ‡ ‘†‡† ’”‘–‡‹• ƒ”‡ ‡š’”‡••‡† †—”‹‰ –Š‡ †‹ˆˆ‡”‡– •–ƒ‰‡• ‘ˆ ƒ–—”ƒŽ M. tuberculosis ‹ˆ‡ –‹‘ ‹ Š—ƒǡ ‘”‹•‹–‘™™Š‡–Š‡”–Š‡•‡’”‘–‡‹•ƒ”‡–ƒ”‰‡–‡†ƒ•’ƒ”–‘ˆ–Š‡’”‘–‡ –‹˜‡‹—‡ ”‡•’‘•‡–‘M.tuberculosisǤ‘•–ƒ”–ƒ††”‡••‹‰–Š‡•‡“—‡•–‹‘•™‡Šƒ˜‡•‡Ž‡ –‡†ʹͷ ‘ˆ –Š‡ ‘•– •–”‘‰Ž› ‡š’”‡••‡† ’”‘–‡‹• ‘ˆ –Š‡ ‘• ”‡‰—Ž‘ǡ ˆ—”–Š‡” ”‡ˆ‡””‡† –‘ ƒ• Žƒ–‡ ›ƒ–‹‰‡•ǡƒ†‡˜ƒŽ—ƒ–‡†

(28) Ǧɀ”‡•’‘•‡•ƒ†’”‘Ž‹ˆ‡”ƒ–‹‘‘ˆŠ—ƒǦ ‡ŽŽ•‹ ’ƒ–‹‡–•ǡ’‘•‹–‹˜‡ȋΪȌ‹†‹˜‹†—ƒŽ•ƒ†M.tuberculosis—‹ˆ‡ –‡† ‘–”‘Ž•Ǥ  . MaterialsandMethods Studysubjects —” ’”‹ƒ”› ‰‘ƒŽ ™ƒ• –‘ ƒ••‡•• –Š‡ ’‘–‡–‹ƒŽ ‹—‘‰‡‹ ‹–› ‘ˆ ‘˜‡Ž ƒ†‹†ƒ–‡ M. tuberculosis Žƒ–‡ › ƒ–‹‰‡•Ǥ Š‡”‡ˆ‘”‡ǡ ™‡ •‡Ž‡ –‡† ƒ ™‹†‡ •’‡ –”— ‘ˆ M. tuberculosis ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ•ǡ ƒ• ‹• †‡• ”‹„‡† ‹ †‡–ƒ‹Ž „‡Ž‘™Ǥ 

(29)  –‘–ƒŽǡ –Š”‡‡ ’‘’—Žƒ–‹‘• ™‡”‡ •–—†‹‡†ǣ  ’ƒ–‹‡–•ǡ Ϊ Š‡ƒŽ–Š› ‹†‹˜‹†—ƒŽ• ƒ† M. tuberculosis —‹ˆ‡ –‡†Š‡ƒŽ–Š›‹†‹˜‹†—ƒŽ•Ǥ Š‡ ‰”‘—’ ‘ˆ  ’ƒ–‹‡–• ȋαʹͲȌ ‘•‹•–‡† ‘ˆ ͳͳ ’‡”•‘• ™‹–Š  †—”‹‰ –”‡ƒ–‡– ȋ‡ƒ†—”ƒ–‹‘‘ˆ–”‡ƒ–‡–ǣͳͲ™‡‡•ǡ”ƒ‰‡ʹǦʹͷȌƒ†ͻ™‹–Š —”‡†™Š‘™‡”‡ –”‡ƒ–‡† „‡–™‡‡ ͶǦ͸͵ ›‡ƒ”• „‡ˆ‘”‡ „Ž‘‘† •ƒ’Ž‹‰ ȋ‡ƒ ‹–‡”˜ƒŽ ʹͻ ›‡ƒ”•ȌǤ Ž‡˜‡ ’ƒ–‹‡–•Šƒ†’—Ž‘ƒ”›ƒ†ͻŠƒ†‡š–”ƒǦ’—Ž‘ƒ”›ǤŠ‡‡ƒƒ‰‡™ƒ•Ͷ͸›‡ƒ”• ȋ”ƒ‰‡ͳ͹Ǧ͹ͷ›‡ƒ”•ȌǡͳͶ™‡”‡ƒŽ‡Ǥ‹‰Š–’ƒ–‹‡–•™‡”‡‘ˆ—– Š‘”‹‰‹ǡͻ‘ˆˆ”‹ ƒ ƒ† ͵ ‘ˆ •‹ƒ ‘”‹‰‹Ǥ  ’ƒ–‹‡–• ™‡”‡ ‡‹–Š‡”

(30) Ǧͳ •‡”‘‡‰ƒ–‹˜‡ ‘” Šƒ† ‘ ”‹• ˆƒ –‘”•ˆ‘”‡š’‘•—”‡–‘

(31) Ǥ ŽŽ ʹ͵ Ϊ Š‡ƒŽ–Š› ‹†‹˜‹†—ƒŽ• ™‡”‡ ‘ˆ —– Š ‘”‹‰‹ ƒ† ™‡”‡ ‘–   ˜ƒ ‹ƒ–‡†Ǥ Š‡›Šƒ†ƒ†‘ —‡–‡†”‡•—Ž–‘ˆtͳͲ‹†—”ƒ–‹‘ǡ‘•–Ž›ȋαͳͶȌƒˆ–‡” ‘–ƒ – ™‹–Šƒ ƒ•‡‘ˆ•‡ƒ”Ǧ’‘•‹–‹˜‡’—Ž‘ƒ”›ǤŠ‡‡ƒƒ‰‡™ƒ•͵͹›‡ƒ”•ȋ”ƒ‰‡ʹͳȂ ͸͵Ȍǡ ͳͶ ™‡”‡ ƒŽ‡Ǥ ”‘ ͳʹ ’‡”•‘•ǡ „Ž‘‘† ™ƒ• †”ƒ™ ™‹–Š‹ ͸ ‘–Š• ƒˆ–‡”  ‘˜‡”•‹‘ǡ ‘ˆ ™Š‘ ‘Ž› ͷ ™‡”‡ –”‡ƒ–‡† ™‹–Š ‹•‘‹ƒœ‹†Ǥ

(32)  –Š‡ ”‡ƒ‹‹‰ ͳͳ Ϊ ‹†‹˜‹†—ƒŽ•ǡ–Š‡‡ƒ‹–‡”˜ƒŽ„‡–™‡‡ ‘˜‡”•‹‘ƒ†„Ž‘‘†•ƒ’Ž‹‰™ƒ•ͷǤͶ›‡ƒ”• ȋ”ƒ‰‡ʹǦͺȌǤŽ›ʹ‘ˆ–Š‡•‡”‡‘–‡ ‘˜‡”–‡”•Šƒ†”‡ ‡‹˜‡†‹•‘‹ƒœ‹†Ǥ’–‘–Š‡ –‹‡ ‘ˆ –Š‹• ™”‹–‹‰ǡ ‘‡ ‘ˆ –Š‡ Ϊ ‹†‹˜‹†—ƒŽ• Šƒ† †‡˜‡Ž‘’‡† ƒ –‹˜‡  ƒˆ–‡” ƒ ‡ƒ’‡”‹‘†‘ˆͷǤͷ›‡ƒ”•ȋ”ƒ‰‡ʹǤͷǦͳͳȌ•‹ ‡ ‘˜‡”•‹‘ǤŠ‡•‡‹†‹˜‹†—ƒŽ•ƒ”‡ ”‡‰ƒ”†‡†ƒ•Žƒ–‡–Ž›‹ˆ‡ –‡†’‡”•‘•™Š‘‘•–Ž‹‡Ž›Šƒ˜‡ƒ “—‹”‡†ƒ–—”ƒŽ‹—‹–› ƒ‰ƒ‹•–†‡˜‡Ž‘’‡–‘ˆ†‹•‡ƒ•‡Ǥ • ƒ ‘–”‘Ž ‰”‘—’ǡ ʹͳ —‹ˆ‡ –‡† Š‡ƒŽ–Š› ‹†‹˜‹†—ƒŽ• ™‡”‡ •–—†‹‡†Ǣ ‘‡ ‘ˆ ™Š‘ ™‡”‡   ˜ƒ ‹ƒ–‡† ‘” Šƒ† Šƒ† ƒ› ‘™ ‡š’‘•—”‡ –‘ Ǥ Š‡› ™‡”‡ ‡‹–Š‡”  ‡‰ƒ–‹˜‡ ȋαͳͺǢ ‹ –Š‡ ‘–Š‡”• ‘  ™ƒ• †‘‡Ȍ ƒ†Ȁ‘” †‹† ‘– ”‡•’‘† –‘ M. tuberculosis•’‡ ‹ˆ‹ ’”‘–‡‹•Ǧ͸ƒ† ǦͳͲ‹ƒ

(33) Ǧɀ

(34) ȋ‘™ˆ”‘ƒ ’”‡˜‹‘—• ’”‘Œ‡ – ȏʹͷȐȌǤ ŽŽ ‘–”‘Ž• ™‡”‡ ‘ˆ —– Š ‘”‹‰‹ ™‹–Š ƒ ƒ˜‡”ƒ‰‡ ƒ‰‡ ‘ˆ ͵Ͳ ›‡ƒ”•ȋ”ƒ‰‡ʹʹǦͶͶȌǡ͹™‡”‡ƒŽ‡Ǥ Ž‘‘† •ƒ’Ž‡• ™‡”‡ ‘ŽŽ‡ –‡† ƒˆ–‡” ™”‹––‡ ‹ˆ‘”‡† ‘•‡– ™ƒ• ‘„–ƒ‹‡†Ǥ  ™‡”‡ ‹•‘Žƒ–‡† ƒ† •–‘”‡† ‹ Ž‹“—‹† ‹–”‘‰‡ ƒ• ’”‡˜‹‘—•Ž› †‡• ”‹„‡† ȏʹ͸ȐǤ Š‡ •–—†›. ͶͶ.

(35) ImmuneresponsestolatencyantigensofM.tuberculosis . ’”‘–‘ ‘Ž ȋʹͲ͹ȀͻͻȌ ™ƒ• ƒ’’”‘˜‡† „› –Š‡ ‹•–‹–—–‹‘ƒŽ ”‡˜‹‡™ „‘ƒ”† ‘ˆ –Š‡ ‡‹†‡ ‹˜‡”•‹–›‡†‹ ƒŽ‡–‡”Ǥ  M.tuberculosisantigensandpeptides M. tuberculosis ͵͹˜ ™ƒ• ‰”‘™ ˆ‘” ʹͶ Š‘—”• ‹ –—„‡• ™‹–Š –‹‰Š–Ž› • ”‡™‡† ƒ’•ǡ Šƒ”˜‡•–‡† ƒ† Ž›•‡† ƒ• ’”‡˜‹‘—•Ž› †‡• ”‹„‡† ȏͳͷȐǤ Š‡ —Ž–—”‡ ˆ‹Ž–”ƒ–‡ ‘ˆ –Š‹• Ž‘™ ‘š›‰‡ —Ž–—”‡ ™ƒ• ‘ ‡–”ƒ–‡† ™‹–Š ƒ ‡–”‹’”‡’Ǧ ‘ ‡–”ƒ–‘” ƒ† ’”‘–‡‹ ‘ ‡–”ƒ–‹‘™ƒ•†‡–‡”‹‡†„›–Š‡–‡•–ȋ‹‡” ‡ǡ‘ ˆ‘”†ǡ

(36) ŽŽ‹‘‹•ȌǤŠ‡Ž›•ƒ–‡ ˆ”‘M.tuberculosis —Ž–—”‡†—†‡”•–ƒ†ƒ”†ƒ‡”ƒ–‡† ‘†‹–‹‘•™ƒ•’”‘˜‹†‡†„›–Š‡ 

(37) ȋ‹Ž–Š‘˜‡ǡ–Š‡‡–Š‡”Žƒ†•ȌǤ ‘•”‡‰—Ž‘‡ ‘†‡†‰‡‡•™‡”‡•‡Ž‡ –‡†‘„ƒ•‹•‘ˆ–Š‡‹”‡š’”‡••‹‘Ž‡˜‡Ž‹ ‹ ”‘ƒ””ƒ›‡š’‡”‹‡–•ȏͳͻȐǡƒ•‘•–‘ˆ–Š‡•‡Ͷͺ‰‡‡•ƒ”‡Š›’‘–Š‡–‹ ƒŽ‘’‡”‡ƒ†‹‰ ˆ”ƒ‡• ™‹–Š —‘™ „‹‘Ž‘‰‹ ƒŽˆ— –‹‘Ǥ Š‡ ʹͷ ‘•– •–”‘‰Ž› ‹†— ‡†‰‡‡• ™‡”‡ •‡Ž‡ –‡† ƒ† •‡“—‡ ‡• ™‡”‡ ‘„–ƒ‹‡† ˆ”‘ Š––’ǣȀȀ‰‡‘Ž‹•–Ǥ’ƒ•–‡—”Ǥˆ”Ȁ—„‡” —‹•– ȋƒ„Ž‡ͳȌǤ ‡‡•™‡”‡ Ž‘‡†ƒ†’”‘–‡‹•™‡”‡‘˜‡”‡š’”‡••‡†‹Escherichiacoliƒ† ’—”‹ˆ‹‡†ǡ ƒ• ’”‡˜‹‘—•Ž› †‡• ”‹„‡† ȏʹ͹ȐǤ ‹œ‡ ƒ† ’—”‹–› ™‡”‡ Š‡ ‡† „› ‰‡Ž ‡Ž‡ –”‘’Š‘”‡•‹• ƒ† ‡•–‡” „Ž‘––‹‰ ™‹–Š ƒ–‹Ǧ ‹• ƒ–‹„‘†‹‡•Ǥ ‡•‹†—ƒŽ ‡†‘–‘š‹ Ž‡˜‡Ž•™‡”‡†‡–‡”‹‡†™‹–Šƒ‹—Ž—•‡„‘ ›–‡›•ƒ–‡ƒ••ƒ›ȋƒ„”‡šȌƒ†™‡”‡ ˆ‘—† –‘ „‡ „‡Ž‘™ ͷͲ

(38) Ȁ‰ ”‡ ‘„‹ƒ– ’”‘–‡‹Ǥ ”‘–‡‹ „ƒ– Š‡• ™‡”‡ –‡•–‡† ˆ‘” ‘Ǧ•’‡ ‹ˆ‹ Ǧ ‡ŽŽ•–‹—Žƒ–‹‘‹Ž›’Š‘ ›–‡•–‹—Žƒ–‹‘ƒ••ƒ›•—•‹‰‘ˆ Ǧ —˜ƒ ‹ƒ–‡†ǡǦ‡‰ƒ–‹˜‡Š‡ƒŽ–Š›†‘‘”•. ›–Š‡–‹  ’‡’–‹†‡• ˆ”‘ —Ž–—”‡ ˆ‹Ž–”ƒ–‡ ’”‘–‡‹ ͳͲ ȋ ǦͳͲȌ ™‡”‡ ’”‘†— ‡† ƒ• ’”‡˜‹‘—•Ž›†‡• ”‹„‡†ȏʹ͸ȐǤ  Tcelllines ‹‰Š–Ž‘‰Ǧ–‡”Ǧ ‡ŽŽŽ‹‡•™‡”‡‰‡‡”ƒ–‡†™‹–Š‡‹–Š‡”Ž›•ƒ–‡ȋαͶȌ‘” —Ž–—”‡ˆ‹Ž–”ƒ–‡ ȋαͶȌ ‘ˆ M. tuberculosis ‰”‘™ —†‡” Ž‘™ ‘š›‰‡ ‘†‹–‹‘•ǡ —•‹‰  ‘„–ƒ‹‡† ˆ”‘–™‘ —”‡†’ƒ–‹‡–•ƒ†–™‘Ϊ‹†‹˜‹†—ƒŽ•‘™–‘”‡•’‘†–‘ •’Ǥ

(39)  ƒ††‹–‹‘ǡ Ͷ Ǧ ‡ŽŽ Ž‹‡• ™‡”‡ ƒ†‡ „› •–‹—Žƒ–‹‰  ˆ”‘ –Š”‡‡  ’ƒ–‹‡–• ƒ† ‘‡Ϊ‹†‹˜‹†—ƒŽ™‹–ŠŽ›•ƒ–‡ˆ”‘M.tuberculosis —Ž–—”‡†—†‡”•–ƒ†ƒ”†ƒ‡”ƒ–‡† ‘†‹–‹‘•ǤǦ ‡ŽŽŽ‹‡•™‡”‡‰‡‡”ƒ–‡†ƒ•’”‡˜‹‘—•Ž›†‡• ”‹„‡†ȏʹ͸ȐǤ  ProliferationassaysandIFNdetection Ǧ ‡ŽŽ•ȋͳǤͷšͳͲͶȀ™‡ŽŽȌ™‡”‡ —Ž–—”‡†™‹–Šƒ—–‘Ž‘‰‘—•‘” Ǧƒ– Š‡†‹””ƒ†‹ƒ–‡† ȋͷšͳͲͶȀ™‡ŽŽȌˆ‘”͵†ƒ›•ƒ†ȋͳǤͷšͳͲͷȀ™‡ŽŽȌ™‡”‡ —Ž–—”‡†ˆ‘”͸†ƒ›•‹ –Š‡’”‡•‡ ‡‘”ƒ„•‡ ‡‘ˆƒ–‹‰‡ǡƒ•’”‡˜‹‘—•Ž›†‡• ”‹„‡†ȏʹ͸ȐǤŽŽŽƒ–‡ ›ƒ–‹‰‡• ȋƒ„Ž‡

(40) Ȍ ™‡”‡ –‡•–‡† ƒ– ƒ ˆ‹ƒŽ ‘ ‡–”ƒ–‹‘ ‘ˆ ͲǤ͵͵ P ȋƒ˜‡”ƒ‰‡ ‘ ‡–”ƒ–‹‘ ͻǤ͵ P‰ȀŽǡ ”ƒ‰‡ ͵ǤͳǦʹͶȌ ‹ ‘”†‡” –‘ ƒŽŽ‘™ ˆ‘” †‹”‡ – ‘’ƒ”‹•‘ ‘ˆ ‹—‘‰‡‹ ‹–› „‡–™‡‡’”‘–‡‹•™Š‹ Š˜ƒ”› ‘•‹†‡”ƒ„Ž›‹•‹œ‡ȋͻǦ͹ͶƒȌǤ–ƒ†ƒ”†M.tuberculosis Ž›•ƒ–‡ǡŠ›’‘š‹ Ž›•ƒ–‡ƒ† —Ž–—”‡ˆ‹Ž–”ƒ–‡™‡”‡—•‡†ƒ–ͳP‰ȀŽƒ†–Š‡’‡’–‹†‡Ǧ’‘‘Ž‘ˆ  ǦͳͲ ƒ– ͳ P‰ȀŽȀ’‡’–‹†‡Ǥ Š‡ •ƒ‡ ƒ–‹‰‡• ƒ† ‹†‡–‹ ƒŽ „ƒ– Š‡• ™‡”‡ —•‡† –Š”‘—‰Š‘—– ƒŽŽ ‡š’‡”‹‡–•Ǥ —‡ –‘ ƒ •Š‘”–ƒ‰‡ ‘ˆ –Š‡ ˜ͳ͹͵͵  „ƒ– Š –Š‡ —„‡” ‘ˆ •–—†›•—„Œ‡ –•–Šƒ– ‘—Ž†„‡–‡•–‡†ˆ‘”–Š‹•ƒ–‹‰‡™ƒ•Ž‹‹–‡†–‘ͳ͹ ‘–”‘Ž•ǡͳͺΪ ’‡”•‘• ƒ† ͳ͸  ’ƒ–‹‡–•Ǥ ˆ–‡” —Ž–—”‡ǡ •—’‡”ƒ–ƒ–• ™‡”‡ ‘ŽŽ‡ –‡† ˆ‘” –Š‡ †‡–‡ –‹‘ ‘ˆ

(41) ǦJ ƒ† ’”‘Ž‹ˆ‡”ƒ–‹‘ ‘ˆ Ǧ ‡ŽŽ• ™ƒ• ‡ƒ•—”‡† „› >͵ @Ǧ–Š›‹†‹‡ ‹ ‘”’‘”ƒ–‹‘ƒ•†‡• ”‹„‡†‡Ž•‡™Š‡”‡ȏʹ͸ȐǤŠ‡ ‘ ‡–”ƒ–‹‘‘ˆ

(42) ǦJ™ƒ•‡ƒ•—”‡† Ͷͷ.

(43) Chapter2. „›

(44) ȋǦ›‡ Šǡ–”‡ Š–ǡŠ‡‡–Š‡”Žƒ†•Ǣ†‡–‡ –‹‘Ž‹‹–‘ˆʹͲ’‰ȀŽȌǤŠ‡‡ƒ ˜ƒŽ—‡ ‘ˆ —•–‹—Žƒ–‡† —Ž–—”‡• ™ƒ• •—„–”ƒ –‡† ˆ”‘ –Š‡ ‡ƒ ˜ƒŽ—‡ ‘ˆ •–‹—Žƒ–‡† —Ž–—”‡•Ǥ  Statisticalanalysis ‘” ‘’ƒ”‹•‘ ‘ˆ–Š‡ ’”‘’‘”–‹‘‘ˆ ”‡•’‘†‡”• ‹ ‡ƒ Š •–—†› ‰”‘—’ǡ –Š‡ Š‹Ǧ•“—ƒ”‡ –‡•–™ƒ•—•‡†Ǥ ‘”ƒŽŽ•–—†›•—„Œ‡ –•™Š‘™‡”‡ƒ„Ž‡–‘”‡•’‘†–‘ƒƒ–‹‰‡ǡŽ‡˜‡Ž•‘ˆ

(45) ǦJ’”‘†— –‹‘™‡”‡‡˜ƒŽ—ƒ–‡†‘Ǧ’ƒ”ƒ‡–”‹ ƒŽŽ›—•‹‰”—•ƒŽǦƒŽŽ‹•ƒ†ƒǦ Š‹–‡› –‡•–• ˆ‘” ‘’ƒ”‹•‘ ‘ˆ •–—†› ‰”‘—’•Ǥ Š‡ ‹Ž ‘š‘Ǧ•‹‰‡†Ǧ”ƒ –‡•– ™ƒ• ’‡”ˆ‘”‡† –‘ ‘’ƒ”‡ –Š‡ •–”‡‰–Š ‘ˆ –Š‡ ”‡•’‘•‡ „‡–™‡‡ –™‘ ƒ–‹‰‡• ˆ‘” ‡ƒ Š ‹†‹˜‹†—ƒŽǤ

(46)  ‘–”‘Ž•”‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡•™‡”‡ ‘””‡Žƒ–‡†–‘–Š‡”‡•’‘•‡ –‘M.tuberculosisŽ›•ƒ–‡—•‹‰ƒ’‡ƒ”ƒ”ƒ ‘””‡Žƒ–‹‘Ǥ”‡‰”‡••‹‘ƒƒŽ›•‹•™ƒ• †‘‡–‘ ‘’ƒ”‡–Š‡ ——Žƒ–‹˜‡

(47) Ǧɀ”‡•’‘•‡–‘Žƒ–‡ ›ƒ–‹‰‡•„‡–™‡‡‰”‘—’•ǡ ™Š‹Ž‡ ‘–”‘ŽŽ‹‰ ˆ‘” –Š‡ ‡ˆˆ‡ – ‘ˆ ƒ‰‡ǡ ‰‡‡”ƒŽ ”‡•’‘•‹˜‡‡•• ‘ˆ Ǧ ‡ŽŽ• ƒ† –‹‡ „‡–™‡‡‹‹–‹ƒŽ‹ˆ‡ –‹‘ƒ†„Ž‘‘†•ƒ’Ž‹‰Ǥ . Results HumanTcelllinesrecognizelatencyantigens ‘‰Ǧ–‡” Ǧ ‡ŽŽ Ž‹‡• ™‡”‡ ‰‡‡”ƒ–‡† ƒ‰ƒ‹•– ‡‹–Š‡” Ž›•ƒ–‡ ȋαͶȌ ‘” —Ž–—”‡ ˆ‹Ž–”ƒ–‡ ȋαͶȌ ‘ˆ M. tuberculosis ‰”‘™ —†‡” Ž‘™ ‘š›‰‡ ‘†‹–‹‘• ‘” •–ƒ†ƒ”† ƒ‡”ƒ–‡† ‘†‹–‹‘• ȋαͶȌǤ ŽŽ Ž‹‡• ”‡•’‘†‡† •–”‘‰Ž› –‘ –Š‡ ’”‡’ƒ”ƒ–‹‘• ‘ˆ M. tuberculosis ‰”‘™ —†‡” Š›’‘š‹  ‘†‹–‹‘•Ǥ ‡ƒ†‘—–• ‹ Ž—†‡† Ǧ ‡ŽŽ ’”‘Ž‹ˆ‡”ƒ–‹‘ ȋdata not shownȌ ƒ†

(48) ǦJ ’”‘†— –‹‘Ǥ ‹‰—”‡ ͳƒ •Š‘™• –Š‡ ‹†‹˜‹†—ƒŽ

(49) ǦJ ”‡•’‘•‡• –‘ ʹͷ Žƒ–‡ ›ƒ–‹‰‡•‘ˆƒŽŽ‰‡‡”ƒ–‡†M.tuberculosis•’‡ ‹ˆ‹ Ǧ ‡ŽŽŽ‹‡•Ǥ‘–ŠǦ ‡ŽŽŽ‹‡• ‰‡‡”ƒ–‡† ˆ”‘ —”‡†  ’ƒ–‹‡–• ƒ• ™‡ŽŽ ƒ• ˆ”‘ Ϊ ‹†‹˜‹†—ƒŽ• ™‡”‡ ƒ„Ž‡ –‘ ”‡ ‘‰‹œ‡ƒŽƒ”‰‡—„‡”‘ˆŽƒ–‡ ›ƒ–‹‰‡•Ǥ

(50) ‘”†‡”–‘‡•—”‡–Š‡•‡Ž‡ –‹‘‘ˆƒŽŽ’”‘–‡‹•™‹–Š’‘••‹„Ž‡‹—‘‰‡‹  ƒ’ƒ ‹–›ˆ‘” ˆ—”–Š‡”‡˜ƒŽ—ƒ–‹‘ȋ•‡‡„‡Ž‘™Ȍǡ™‡—•‡†ƒ”‡Žƒ–‹˜‡Ž›Ž‘™Ž‡˜‡Ž‘ˆ

(51) Ǧɀƒ• —–Ǧ‘ˆˆ˜ƒŽ—‡ ȋͷͲ ’‰ȀŽ ƒ„‘˜‡ „ƒ ‰”‘—†Ȍ ƒ† ƒŽ —Žƒ–‡† –Š‡ —„‡” ‘ˆ Ǧ ‡ŽŽ Ž‹‡• –Šƒ– ”‡•’‘†‡† –‘ ‡ƒ Š Žƒ–‡ › ƒ–‹‰‡ ȋ ‹‰—”‡ ͳ„ȌǤ Š‹• ˆ‹‰—”‡ •Š‘™• –Šƒ– ƒŽŽ ʹͷ Žƒ–‡ › ƒ–‹‰‡•™‡”‡”‡ ‘‰‹œ‡†„›ƒ–Ž‡ƒ•–ͳ‘—–‘ˆͳʹǦ ‡ŽŽŽ‹‡•–‡•–‡†ƒ†ʹͳƒ–‹‰‡•„› ƒ–Ž‡ƒ•–ͶǦ ‡ŽŽŽ‹‡•Ǥƒ–‡ ›ƒ–‹‰‡˜ʹͲ͵ͳ ȋ •’Ȍǡƒ†˜ʹͲ͵ʹȋ ‰Ȍ™‡”‡‘•– ˆ”‡“—‡–Ž› ”‡ ‘‰‹œ‡† „› ͹ͷΨ ‘ˆ –‡•–‡† Ǧ ‡ŽŽ Ž‹‡• ȋ‡†‹ƒ

(52) ǦJ Ž‡˜‡Ž• ƒ‘‰ ”‡•’‘†‹‰Ž‹‡•ǣͷͲ͹ƒ†ͳʹͻ’‰ȀŽ”‡•’‡ –‹˜‡Ž›ȌǤŠ‡‘„•‡”˜‡†”‡•’‘•‡•–‘Žƒ–‡ › ƒ–‹‰‡•„›Ǧ ‡ŽŽŽ‹‡•‰‡‡”ƒ–‡†™‹–Š–Š‡•–ƒ†ƒ”†Ǧƒ‡”ƒ–‡†M.tuberculosisŽ›•ƒ–‡ƒ”‡ ‡š’Žƒ‹‡†„›–Š‡ˆ‹†‹‰‘ˆ •’‹–Š‹•’”‡’ƒ”ƒ–‹‘ȋ‡•–‡”„Ž‘–ƒƒŽ›•‹•Ǣdatanot shownȌǡ ‹†‹ ƒ–‹‰ –Š‡ ‡š’”‡••‹‘ ‘ˆ –Š‡ ‘• ”‡‰—Ž‘Ǥ ‘•– Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ”‡ ‘‰‹œ‡† „› Ǧ ‡ŽŽ Ž‹‡• ”ƒ‹•‡† ™‹–Š Š›’‘š‹ ǦŽ›•ƒ–‡ ƒ• ™‡ŽŽ ƒ• ™‹–Š Š›’‘š‹  —Ž–—”‡ ˆ‹Ž–”ƒ–‡ǡ •—‰‰‡•–‹‰ –Šƒ– •‘‡ Žƒ–‡ › ƒ–‹‰‡• ‹‰Š– ƒŽ•‘ „‡ ˆ‘—† ‡š–”ƒǦ ‡ŽŽ—Žƒ”Ž›Ǥ Š‹• ‹• ‹ Ž‹‡ ™‹–Š ’”‡˜‹‘—• ˆ‹†‹‰• •Š‘™‹‰ –Šƒ– ˜Ͳͷ͸ͻǡ ˜ʹ͸ʹ͵ ƒ† ˜ʹ͸ʹ͸  ’”‘–‡‹• ™‡”‡ ’”‡•‡– ‹ —Ž–—”‡ ˆ‹Ž–”ƒ–‡ ‘ˆ M. tuberculosis ‰”‘™ —†‡” Š›’‘š‹  ‘†‹–‹‘•ȏͳͷȐǤ

(53)  ‘ Ž—•‹‘ǡ—•‹‰Š—ƒǦ ‡ŽŽŽ‹‡••’‡ ‹ˆ‹ ˆ‘”M.tuberculosisǡ™‡ •Š‘™ –Šƒ– ƒŽŽ ʹͷ ‘˜‡Ž › ‘„ƒ –‡”‹ƒŽ Žƒ–‡ › ƒ–‹‰‡• ƒ”‡ ’‘–‡–‹ƒŽŽ› ƒ„Ž‡ –‘ ‡Ž‹ ‹– ‡ŽŽ—Žƒ”‹—‡”‡•’‘•‡•‹M.tuberculosis‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•Ǥ. Ͷ͸.

(54) ImmuneresponsestolatencyantigensofM.tuberculosis . 10 3. hypoxic CF. Rv3134c. 2568 450. 12 10. 507 129 167. 195 92. 209 102. 94 215. 108. 59. 122. 6. 145 131. 170 215 211. 4. 66. hypoxic CF. hypoxic lysate. Rv3134c. Rv3133c. Rv3130c. Rv3129. Rv3127. Rv3126c. Rv2628. Rv2627c. Rv2626c. Rv2624c. Rv2623. Rv2032. Rv2031c. Rv2029c. Rv2007c. Rv1996. Rv1813c. Rv1738. Rv1733c. Rv0569. Rv0079. Rv3132c. 55. 63. 0. 71. 77. Rv3131. 2. 100. 109. 89. Rv2030c. 8. hypoxic lysate. Rv3133c. Rv3132c. Rv3131. Rv3130c. Rv3129. Rv3127. Rv3126c. Rv2628. Rv2627c. Rv2626c. Rv2624c. Rv2623. Rv2032. Rv2031c. Rv2030c. Rv2029c. Rv2007c. Rv1996. Rv1813c. Rv1738. Rv1733c. Rv0572c. Rv0569. 10 2. Rv0572c. Responding T-cell lines.        (b) „  . 10 4. Rv0079. IFN-J (pg/ml).  ƒ   . Figure1.LongtermTcelllines(n=12)respondingto25M.tuberculosislatencyantigens,hypoxicM. tuberculosis lysate and culture filtrate (CF). Hypoxic lysate and CF were prepared from M. tuberculosis H37Rvwhichwasgrownfor24hoursintubeswithtightlyscrewedcaps.8linesweregeneratedbystimulating PBMC obtained from TST converters (n=2) or cured TB patients (n=2) with either hypoxicCF (n=4, cross hatchedbar)orhypoxiclysate(n=4,whitebar). Additionally,PBMCfromoneTSTconverterand3curedTB patientswerestimulatedwithlysateofM.tuberculosis,whichwasgrownunderstandard,aeratedconditions (n=4, dotted bar).  (a) IFN responses of all 12 M. tuberculosisspecific Tcell lines. Dots indicate the IFN responseminustheIFNvaluein theunstimulatedcultures.LineswereeithergeneratedfromPBMCofTST converters (closed circles (x)) or cured TB patients (open circles (o)). (b) Bars indicate the number of lines respondingtoalatencyantigenwithanIFNproductionofatleast50pg/ml.Thenumberatthetopofeach barindicatesthemedianIFNproductionoftheserespondinglines.. RecognitionoflatencyantigensbyPBMCofM.tuberculosisinfectedindividuals —„•‡“—‡–Ž›ǡ †‹”‡ – ’‡”‹’Š‡”ƒŽ „Ž‘‘† ‡šǦ˜‹˜‘ •–‹—Žƒ–‹‘ ƒ••ƒ›• ™‡”‡ ’‡”ˆ‘”‡† —•‹‰ˆ”‘ʹͲ’ƒ–‹‡–•ǡʹ͵Ϊ‹†‹˜‹†—ƒŽ•ƒ†ʹͳ—‹ˆ‡ –‡† ‘–”‘Ž•Ǥ

(55)  ‘”†‡”–‘‹†‡–‹ˆ›–Š‘•‡’”‘–‡‹•™‹–Šƒ•–”‘‰ ƒ’ƒ ‹–›–‘‹†— ‡

(56) ǦJ’”‘†— –‹‘ǡ™‡ ƒŽ —Žƒ–‡† ˆ‘” ‡ƒ Š ƒ–‹‰‡ –Š‡ ’”‘’‘”–‹‘ ‘ˆ ‹†‹˜‹†—ƒŽ• ™Š‘ ”‡•’‘†‡† –‘ –Š‡ ƒ–‹‰‡™‹–Šƒ

(57) ǦJ’”‘†— –‹‘Ž‡˜‡Ž‡š ‡‡†‹‰ͳͲͲ’‰ȀŽȋƒ„Ž‡ͳȌǤŠ‹•ƒƒŽ›•‹• ”‡˜‡ƒŽ‡†–Šƒ–ͳͺ‘ˆ–Š‡ʹͷŽƒ–‡ ›ƒ–‹‰‡•™‡”‡”‡ ‘‰‹œ‡†„›ƒ–Ž‡ƒ•–ͳͲΨ‘ˆ‡‹–Š‡” ’ƒ–‹‡–•‘”Ϊ‹†‹˜‹†—ƒŽ•ȋƒ„Ž‡ͳȌǤˆ–Š‡•‡ǡ˜ͳ͹͵͵ ǡ˜ʹͲʹͻ ƒ†˜ʹ͸ʹ͹ ǡ ™‡”‡‡˜‡”‡ ‘‰‹œ‡†„›–Š‡ƒŒ‘”‹–›‘ˆΪ‹†‹˜‹†—ƒŽ•ǤŠ‡”‡ƒ‹‹‰͹ƒ–‹‰‡• –‡•–‡†ȋ˜Ͳͷ͹ʹ ǡ˜ʹͲͲ͹ ǡ˜ʹ͸ʹ͵ǡ˜ʹ͸ʹͶ ǡ˜͵ͳʹ͹ǡ˜͵ͳ͵ͳǡ˜͵ͳ͵Ͷ Ȍ™‡”‡‘–‘” ˜‡”›’‘‘”Ž›”‡ ‘‰‹œ‡†„›ˆ”‘M.tuberculosis‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•ǤŠ‡•‡. Ͷ͹.

(58) Chapter2 ƒ„Ž‡ͳǤ

(59) —‘‰‡‹ ‹–›‘ˆŽƒ–‡ ›ƒ–‹‰‡•a ƒ–‡ › ‡‡ ƒ–‹‰‡ ƒ‡. ”‘†— –. ˜ͲͲ͹ͻ ˜Ͳͷ͸ͻ ˜Ͳͷ͹ʹ ˜ͳ͹͵͵ ˜ͳ͹͵ͺ ˜ͳͺͳ͵ ˜ͳͻͻ͸ ˜ʹͲͲ͹ ˜ʹͲʹͻ ˜ʹͲ͵Ͳ ˜ʹͲ͵ͳ ˜ʹͲ͵ʹ ˜ʹ͸ʹ͵ ˜ʹ͸ʹͶ ˜ʹ͸ʹ͸ ˜ʹ͸ʹ͹ ˜ʹ͸ʹͺ ˜͵ͳʹ͸ ˜͵ͳʹ͹ ˜͵ͳʹͻ ˜͵ͳ͵Ͳ ˜͵ͳ͵ͳ ˜͵ͳ͵ʹ ˜͵ͳ͵͵ ˜͵ͳ͵Ͷ .     ’‘••‹„Ž‡–”ƒ•‡„”ƒ‡’”‘–‡‹       ’”‘„ƒ„Ž‡ˆ‡””‡†‘š‹  ’”‘„ƒ„Ž‡’Š‘•’Š‘ˆ”— –‘‹ƒ•‡ˆ   Š‡ƒ–•Š‘ ’”‘–‡‹ •’   ‰  ͵ͳǤ͹                 ʹǦ ‘’‘‡–•‡•‘”Š‹•–‹†‹‡‹ƒ•‡ ʹǦ ‘’‘‡––”ƒ• ”‹’–‹‘ƒŽ”‡‰—Žƒ–‘”›’”‘–‡‹  . fdxA pfkB hspX acg TB31.7. devS dosR. ‡•’‘•‡ȋΨȌb   Ϊ ȋαʹͳȌ ȋαʹͲȌ ȋαʹ͵Ȍ ͳͶ Ǧ ͳͲ Ͷͳ Ǧ ͳͶ ͳͶ Ǧ ʹͻ ͳͶ ͷ ͳͶ Ǧ Ǧ ͳͶ ͵ͺ ͳͲ ͳͻ Ǧ ͳͻ Ǧ Ǧ ʹͶ ͳͶ. Ǧ. ͳͲ ͷ ͷ ͷͲ ͳͳ ͳͷ ͳͳ Ǧ ʹͷ ͳͷ ʹͲ ʹͲ Ǧ Ǧ ͳͲ ͵Ͳ ͳ͸ ͳͲ Ǧ ʹͳ Ǧ Ǧ ͳͷ ͵ʹ Ǧ. ʹ͸ ʹʹ Ǧ ͸ͳ ͳ͵ ͳ͹ Ͷ ͻ ͸ͳȗ ʹ͸ Ǧȗ ͵Ͳ Ǧ Ǧ ͵Ͳ ͷʹ ͵ͷ ͵Ͳ Ͷ ͵ͷ ͳ͵ Ͷ ͳ͹ ͵Ͳ Ͷ. ƒ. „„”‡˜‹ƒ–‹‘•ǣ ǡŠ‡ƒŽ–Š› ‘–”‘Ž•Ǣǡ’ƒ–‹‡–•ǢΪǡ–—„‡” —Ž‹•‹–‡•–’‘•‹–‹˜‡‹†‹˜‹†—ƒŽ•Ǣ ǡŠ›’‘–Š‡–‹ ƒŽ’”‘–‡‹Ǣ ǡ ‘•‡”˜‡†Š›’‘–Š‡–‹ ƒŽ’”‘–‡‹Ǥ‘–ƒ–‹‘•ƒ”‡ˆ”‘Š––’ǣȀȀ‰‡‘Ž‹•–Ǥ’ƒ•–‡—”Ǥˆ”Ȁ—„‡” —‹•–ȀǤ „ ‡” ‡–ƒ‰‡‘ˆ‹†‹˜‹†—ƒŽ•™‹–Šƒ

(60) J”‡•’‘•‡‘ˆͳͲͲ’‰ȀŽǤ Ǧǡ‹‘‡‘ˆ–Š‡•–—†›•—„Œ‡ –•ƒ

(61) J”‡•’‘•‡‘ˆηͳͲͲ’‰ȀŽ™ƒ•‘„•‡”˜‡†Ǥ ȗP δͲǤͲͷǡ ʹ–‡•– ‘’ƒ”‹‰’ƒ–‹‡–•™‹–ŠΪ‹†‹˜‹†—ƒŽ•Ǥ.  ƒ–‹‰‡•™‡”‡ƒŽ•‘–Š‡™‡ƒ‡•–‹†— ‡”•‘ˆ

(62) ǦJ’”‘†— –‹‘ƒ‘‰–Š‡ƒ„‘˜‡–‡•–‡† Ǧ ‡ŽŽŽ‹‡•Ǥ‹‹Žƒ””‡•—Ž–•™‡”‡‘„–ƒ‹‡†™Š‡’”‘Ž‹ˆ‡”ƒ–‹‘™ƒ•ƒƒŽ›•‡†ȋdatanot shownȌǤ Š‡ ‘’ƒ”‹‰ –Š‡ ’”‘’‘”–‹‘ ‘ˆ •–”‘‰ ”‡•’‘†‡”• ƒ‘‰ •–—†› ‰”‘—’•ǡ ‘•– Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ”‡ ‘‰‹œ‡† „› ƒ Žƒ”‰‡” ’”‘’‘”–‹‘ ‘ˆ Ϊ ‹†‹˜‹†—ƒŽ• ƒ• ‘’ƒ”‡† –‘  ’ƒ–‹‡–• ƒ† ‘–”‘Ž• ȋƒ„Ž‡ ͳȌǢ –Š‹• –”‡† ™ƒ• ‘Ž› •–ƒ–‹•–‹ ƒŽŽ› •‹‰‹ˆ‹ ƒ–ˆ‘”˜ʹͲʹͻ ™Š‡ ‘’ƒ”‹‰Ϊ’‡”•‘•™‹–Š’ƒ–‹‡–•ȋPαͲǤͲʹȌǤ •’ ™ƒ• ”‡Žƒ–‹˜‡Ž› ’‘‘”Ž› ”‡ ‘‰‹œ‡†ǡ ƒ† ‘”‡ ˆ”‡“—‡–Ž› „›  ’ƒ–‹‡–• –Šƒ „› Ϊ ‹†‹˜‹†—ƒŽ• ȋPαͲǤͲʹȌ ȋƒ„Ž‡ ͳȌǤ Ž–Š‘—‰Š ‘ ˆ—”–Š‡” •–ƒ–‹•–‹ ƒŽ ƒƒŽ›•‹• ™ƒ• ’‘••‹„Ž‡ „‡ ƒ—•‡ ‘ˆ •ƒŽŽ —„‡”•ǡ ‹– ™ƒ• ‹–‡”‡•–‹‰ –‘ ‘–‡ –Šƒ– Ϊ ‹†‹˜‹†—ƒŽ• ™Š‘ •Š‘™‡† ƒ– Ž‡ƒ•– •‘‡ ”‡•’‘•‡ –‘ •’ ȋ

(63) Ǧɀ ‘ˆ ʹͲǦͳͲͲ ’‰ȀŽȌ ƒŽŽ Šƒ† Šƒ† ”‡ ‡– ‘˜‡”•‹‘ȋδ͸‘–ŠȌǤ  Recognitionoflatencyantigensbyuninfectedcontrols ‘‡™Šƒ–—‡š’‡ –‡†Ž›ǡͳ͸‘ˆ–Š‡ʹͷŽƒ–‡ ›ƒ–‹‰‡•™‡”‡ƒŽ•‘”‡ ‘‰‹œ‡†„›Ǧ ‡ŽŽ• ˆ”‘ƒ‹‘”‹–›‘ˆM.tuberculosis—‹ˆ‡ –‡† ‘–”‘Ž•ȋƒ„Ž‡ͳȌǤ‘–”‘Ž•™‡”‡ Ǧ —˜ƒ ‹ƒ–‡†ǡ ™‡”‡ Ǧ‡‰ƒ–‹˜‡ ƒ† †‹† ‘– ”‡ ‘‰‹œ‡  ǦͳͲ ƒ† Ǧ͸ ȋ‘™ ˆ”‘ƒ’”‡˜‹‘—•’”‘Œ‡ –ȏʹͺȐȌǤŠ‡”‡ˆ‘”‡ǡ™‡Š›’‘–Š‡•‹œ‡†–Šƒ–‘„•‡”˜‡†”‡•’‘•‡•–‘  Ͷͺ.

(64) ImmuneresponsestolatencyantigensofM.tuberculosis . IFN-J (pg/ml).  ‘–”‘Ž•ǢŽ‘™”‡•’‘•‡–‘Ž›•ƒ–‡  ƒ  10     10   ‘–”‘Ž•ǢŠ‹‰Š”‡•’‘•‡–‘Ž›•ƒ–‡ „   10    10     Figure 2. IFN responses of M. tuberculosis uninfected healthy controls to 25 latency antigens, M. tuberculosis(MTB)lysateandCFP10.(a)ControlswithalowIFNresponse(<100pg/ml)tostandardM. tuberculosislysate(n=8)(b)ControlswithastrongIFNresponse(>100pg/ml)tostandardM.tuberculosis lysate(n=13).NoneofthecontrolsrespondedtotheM.tuberculosisspecificantigenCFP10.MTBlysate,M. tuberculosislysate.  Žƒ–‡ ›ƒ–‹‰‡•‹ ‘–”‘Ž•™‡”‡‘– ƒ—•‡†„›‹ˆ‡ –‹‘™‹–ŠM.tuberculosis ‘’Ž‡š •’‡ ‹‡•ǡ„—–‘”‡Ž‹‡Ž›„›’”‡˜‹‘—•‡š’‘•—”‡–‘‘–Š‡”› ‘„ƒ –‡”‹ƒǤ

(65) †‡‡†ǡ–Š‹”–‡‡ ͸ʹΨȌ ‘ˆ ʹͳ M. tuberculosisǦ—‹ˆ‡ –‡† ‘–”‘Ž• ƒ’’‡ƒ”‡† –‘ •–”‘‰Ž› ”‡•’‘† –‘ M. tuberculosisŽ›•ƒ–‡ȋ

(66) ǦJεͳͲͲ’‰ȀŽǢ‡†‹ƒŽ‡˜‡Žͷͻͳ’‰ȀŽ

(67) ǦɀȌǡ™Š‹ Š‹•‘•– Ž‹‡Ž› †—‡ –‘ ‡š’‘•—”‡ –‘ ‘Ǧ–—„‡” —Ž‘—• › ‘„ƒ –‡”‹ƒǤ ‹‰‹ˆ‹ ƒ– ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ƒŽ‘•– ‡š Ž—•‹˜‡Ž› ‘„•‡”˜‡† ‹ –Š‹• ‰”‘—’ ‘ˆ ‘–”‘Ž •—„Œ‡ –• ȋ ‹‰—”‡ ʹ„Ȍǡ ™Š‹Ž‡ ‹ –Š‡ ”‡ƒ‹‹‰ ͺ ‘–”‘Ž •—„Œ‡ –• ™‹–Š Ž‘™ ”‡•’‘•‡• –‘ › ‘„ƒ –‡”‹ƒŽ Ž›•ƒ–‡ ‘Ž› •’‘”ƒ†‹ ƒŽŽ› Ž‘™ ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ‘„•‡”˜‡†ȋ ‹‰—”‡ʹƒȌǤ‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡•‹†‡‡† ‘””‡Žƒ–‡†•‹‰‹ˆ‹ ƒ–Ž›–‘ –Š‡”‡•’‘•‡–‘M.tuberculosisŽ›•ƒ–‡ȋ’‡ƒ”ƒRαͲǤͷ͸ǡPαͲǤͲʹȌǤ  IFNJJresponsestofrequentlyrecognizedlatencyantigensandCFP10 ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͹  ƒ† ˜ʹ͸ʹͺ ™‡”‡ ’ƒ”–‹ —Žƒ”Ž› „”‘ƒ†Ž› ”‡ ‘‰‹œ‡†ǡ ’”‡†‘‹ƒ–Ž› „› Ϊ ‹†‹˜‹†—ƒŽ•Ǥ

(68) ǦJ ”‡•’‘•‡• –‘ –Š‘•‡ Ͷ ƒ–‹‰‡• ™‡”‡ ƒƒŽ›•‡†‹‘”‡†‡–ƒ‹Žƒ••Š‘™‹ ‹‰—”‡͵Ǥ ‘” ‘’ƒ”‹•‘‘ˆ–Š‡ƒ‰‹–—†‡‘ˆ–Š‡

(69) Ǧɀ”‡•’‘•‡„‡–™‡‡‰”‘—’•ǡ‘Ž›–Š‘•‡‹†‹˜‹†—ƒŽ•™‡”‡ƒƒŽ›•‡†™Š‘™‡”‡ƒ„Ž‡ –‘”‡ ‘‰‹œ‡–Š‡ƒ–‹‰‡™‹–Šƒ

(70) Ǧɀ”‡•’‘•‡ƒ„‘˜‡–Š‡†‡–‡ –‹‘Ž‡˜‡Ž‘ˆ–Š‡ƒ••ƒ›Ǥ ‡†‹ƒ

(71) ǦJ ’”‘†— –‹‘ ƒ‘‰ ”‡•’‘†‡”• ‹ –Š‡ ‰”‘—’ ‘ˆ Ϊ ‹†‹˜‹†—ƒŽ• ‹ ”‡•’‘•‡ –‘ ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͹  ƒ† ˜ʹ͸ʹͺ ™ƒ• ͷ͸Ͷǡ ͵ͺʹǡ ͳͻͷ ƒ† ͳ͸Ͳ ’‰ȀŽǡ ”‡•’‡ –‹˜‡Ž›ǡ ™Š‹Ž‡ ‹ –Š‡ ‰”‘—’ ‘ˆ  ’ƒ–‹‡–• Ž‘™‡”

(72) ǦJ ”‡•’‘•‡• ™‡”‡ ˆ‘—†ǡ ™‹–Š ‡†‹ƒ• ‘ˆ ͳ͸Ͳǡ ͳ͵͹ǡ ͳͻͶ ƒ† ͹ͻ ’‰ȀŽǡ ”‡•’‡ –‹˜‡Ž› ȋ ‹‰—”‡ ͵ȌǤ Š‹• †‹ˆˆ‡”‡ ‡ ™ƒ• •–ƒ–‹•–‹ ƒŽŽ› •‹‰‹ˆ‹ ƒ– ˆ‘” ˜ͳ͹͵͵  ȋPαͲǤͲͲͺȌǤ

(73)  ‘”†‡” –‘ ‘’ƒ”‡ ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ™‹–Š ”‡•’‘•‡• –‘ ƒ M. tuberculosisǦ•’‡ ‹ˆ‹  ƒ–‹‰‡ 3. 3. CFP-10 -. Rv3134c. MTB lysate -. Rv3133c. Rv3131. Rv3132c. Rv3129. Rv3130c. Rv3127. Rv2628. Rv3126c. Rv2627c. Rv2626c. Rv2623. Rv2624c. Rv2032. Rv2031c. Rv2030c. Rv2029c. Rv1996. Rv2007c. Rv1738. Rv1813c. Rv1733c. Rv0569. Rv0572c. 2. Rv0079. IFN-J (pg/ml). 2. Ͷͻ.

(74) Chapter2. ‘—–•‹†‡–Š‡‘•”‡‰—Ž‘ǡ‘ˆ–Š‡•ƒ‡‹†‹˜‹†—ƒŽ•™‡”‡ƒŽ•‘•–‹—Žƒ–‡†™‹–Šƒ ’‡’–‹†‡ ’‘‘Ž ‘ˆ  ǦͳͲǡ ƒ ƒ–‹‰‡ –Šƒ– ‹• •‡ ”‡–‡† „› –—„‡” Ž‡ „ƒ ‹ŽŽ‹ †—”‹‰ ƒ –‹˜‡ ”‡’Ž‹ ƒ–‹‘Ǥ

(75)  ‘–”ƒ•––‘Žƒ–‡ ›ƒ–‹‰‡•ǡ ǦͳͲ‹†— ‡†•‹‰‹ˆ‹ ƒ–Ž›•–”‘‰‡”

(76) Ǧ J ”‡•’‘•‡• ƒ‘‰  ’ƒ–‹‡–• ƒ• ‘’ƒ”‡† –‘ Ϊ ‹†‹˜‹†—ƒŽ•ǡ ™‹–Š ƒ ‡†‹ƒ ƒ‘‰”‡•’‘†‡”•‘ˆʹͶʹƒ†ͷͻ’‰ȀŽǡ”‡•’‡ –‹˜‡Ž›ȋPαͲǤͲͶʹȌȋ ‹‰—”‡͵ȌǤ   CFP-10 Rv1733c Rv2627c Rv2628  Rv2029c * **  10   10   10   TB TST TB TST TB TST TB TST TB TST  Figure3.IFNresponseprofilestothefourbestrecognizedM.tuberculosislatencyantigensandthe M.tuberculosisspecificsecretedantigenCFP10.IFNproductionbyPBMCfromTBpatients(TB)andTST positive individuals (TST) in response to Rv1733c, Rv2029c, Rv2627c Rv2628 and CFP10 (peptide pool) is shown.HorizontallinesindicatethemedianIFNJproductionamongpersonswhoareabletorespondtothe antigen.ResponseswerecomparedusingaMannWhitneyUtest;*,P<.05;**P<.01  ‘ ƒƒŽ›œ‡ –Š‹• †‹ˆˆ‡”‡ ‡ ‹ ƒ–‹‰‡ ”‡ ‘‰‹–‹‘ ’ƒ––‡” „‡–™‡‡  ’ƒ–‹‡–• ƒ† Žƒ–‡–Ž› ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ• ˆ—”–Š‡”ǡ ™‡ ‘’ƒ”‡† –Š‡ •–”‡‰–Š ‘ˆ –Š‡ ‹—‡ ”‡•’‘•‡ –‘ –Š‡ Ͷ „‡•– ”‡ ‘‰‹œ‡† Žƒ–‡ › ƒ–‹‰‡• ˜‡”•—•  ǦͳͲ ™‹–Š‹ ‡ƒ Š ‹†‹˜‹†—ƒŽǡ—•‹‰–Š‡‹Ž ‘š‘•‹‰‡†”ƒ–‡•–Ǥ

(77) Ϊ‹†‹˜‹†—ƒŽ•

(78) ǦJ”‡•’‘•‡•–‘ ˜ͳ͹͵͵ ǡ˜ʹͲʹͻ ǡ˜ʹ͸ʹ͹ ƒ†˜ʹ͸ʹͺ™‡”‡Š‹‰Š‡”–Šƒ–‘ ǦͳͲȋPδͲǤͲͳǡPδͲǤͲͳǡ PδͲǤͲͳƒ†PαͲǤͲ͹ǡ”‡•’‡ –‹˜‡Ž›ȌǤŠ‡‘’’‘•‹–‡ƒ–‹‰‡”‡ ‘‰‹–‹‘’”‘ˆ‹Ž‡™ƒ•ˆ‘—† ˆ‘”’ƒ–‹‡–•ǡ‹””‡•’‡ –‹˜‡‘ˆ™Š‡–Š‡”–Š‡›Šƒ†ƒ –‹˜‡‘” —”‡††‹•‡ƒ•‡ǣ–Š‡”‡™ƒ•ƒ •–”‘‰‡”

(79) ǦJ ”‡•’‘•‡–‘ ǦͳͲ –Šƒ–‘ ˜ͳ͹͵͵ ǡ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͹  ƒ† ˜ʹ͸ʹͺ ȋPαͲǤͳͻǡ PαͲǤͲͳǡ PαͲǤͲͶ ƒ† PδͲǤͲͳǡ ”‡•’‡ –‹˜‡Ž›ȌǤ —„•‡“—‡–Ž›ǡ ˆ‘” ‡ƒ Š ‹†‹˜‹†—ƒŽ –Š‡

(80) Ǧɀ”‡•’‘•‡–‘ ǦͳͲ™ƒ••—„–”ƒ –‡†ˆ”‘–Š‡”‡•’‘•‡–‘˜ͳ͹͵͵ •— Š–Šƒ– ƒ ’‘•‹–‹˜‡ ˜ƒŽ—‡ ™‘—Ž† ‹†‹ ƒ–‡ –Šƒ– –Š‡ ”‡•’‘•‡ –‘ ˜ͳ͹͵͵  ‹• •–”‘‰‡” ™Š‹Ž‡ ƒ ‡‰ƒ–‹˜‡˜ƒŽ—‡™‘—Ž†‹†‹ ƒ–‡ƒ•–”‘‰‡””‡•’‘•‡–‘ ǦͳͲǤŠ‡•ƒ‡™ƒ•†‘‡ˆ‘” ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͹  ƒ† ˜ʹ͸ʹͺǤ Š‹• ‘’Ž‡‡–ƒ”› ƒƒŽ›•‹• ”‡˜‡ƒŽ‡† –Šƒ– ‹ Ϊ ‹†‹˜‹†—ƒŽ• –Š‡ ‡ƒ †‹ˆˆ‡”‡ ‡ ‹

(81) Ǧɀ ”‡•’‘•‡ „‡–™‡‡  ǦͳͲ ƒ† ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ˜ʹ͸ʹ͹ ƒ†˜ʹ͸ʹͺ™ƒ•Ͷͷͳǡ͵ͲͺǡͳͺͶƒ†ͶͶ’‰ȀŽ”‡•’‡ –‹˜‡Ž›ǡ™Š‹Ž‡‹  ’ƒ–‹‡–• ‡‰ƒ–‹˜‡ ˜ƒŽ—‡• ™‡”‡ ‘„–ƒ‹‡† ȋǦ͵͹͵ǡ Ǧ͵͸ͷǡ ǦͶͷͺ ƒ† Ǧͷ͵͸ ’‰ȀŽ ”‡•’‡ –‹˜‡Ž›ȋPδͲǤͲͳǡPαͲǤͲͶǡPαͲǤͲͳƒ†PαͲǤͲʹȌǤ  CumulativeIFNyresponsetoantigensofthedormancyregulon •‡ƒ Š‹†‹˜‹†—ƒŽ™ƒ•ˆ‘—†–‘„‡ƒ„Ž‡–‘”‡ ‘‰‹œ‡ƒ†‹ˆˆ‡”‡–•‡–‘ˆŽƒ–‡ ›ƒ–‹‰‡•ǡ ™‡ ƒŽ —Žƒ–‡†–Š‡ ——Žƒ–‹˜‡

(82) ǦJ”‡•’‘•‡–‘ƒŽŽʹͷŽƒ–‡ ›ƒ–‹‰‡•–‘ ƒ’–—”‡–Š‡ ‘˜‡”ƒŽŽ ‹—‡ ”‡•’‘•‡ –‘ –Š‡ –‡•–‡† •‡– ‘ˆ ‘• ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ™‹–Š‹ ‡ƒ Š’‡”•‘ǤŠ‹•ƒƒŽ›•‹••Š‘™‡†–Šƒ–ƒ•‹‰‹ˆ‹ ƒ–Ž›Š‹‰Š‡” ——Žƒ–‹˜‡

(83) ǦJ .

(84) ǦJȋ’‰ȀŽȌ IFN- (pg/ml). 4. 3. 2. ͷͲ.

(85) ImmuneresponsestolatencyantigensofM.tuberculosis .   aM.tuberculosis lysateb25latencyantigens   ȗȗȗ ȗȗȗ ȗȗȗ ȗȗȗ  10    10    10    HC TB TST HC TB TST  Figure4.IFNresponseprofilestoM.tuberculosislysateandthegroupof25latencyantigens.IFN  production by PBMC from uninfected healthy controls (HC), TB patients (TB) and TST positive individuals  (TST)inresponseto(a)M.tuberculosislysateand(b)thecumulativeIFNproductionto25latencyantigens.  TBpatientsduringtreatmentareindicatedwithopencircles(o)andcuredTBpatientswithclosedcircles(x).  TST+personswithrecentexposureareindicatedwithopencircles(o)andTST+withamoreremoteexposure  (x). Horizontal lines indicate the median IFNJ production among responders, and responses were with comparedusingaMannWhitneyUtest;***,P<0.01.   ”‡•’‘•‡–‘–Š‡ƒ–‹‰‡•‡ ‘†‡†„›–Š‡‘•”‡‰—Ž‘™ƒ••‡‡‹–Š‡‰”‘—’‘ˆΪ ‹†‹˜‹†—ƒŽ• ‘’ƒ”‡† –‘  ’ƒ–‹‡–• ȋ‡†‹ƒ

(86) ǦJ ‘ˆ ͳͶͷ͵ ƒ† ʹ͸͵ ’‰ȀŽ ”‡•’‡ –‹˜‡Ž›ǡPαǤͲͲ͵Ȍƒ†–‘ ‘–”‘Ž•ȋ‡†‹ƒ

(87) Ǧɀ‘ˆͶ͵Ͷ’‰ȀŽǡPαǤͲͲ͵Ȍȋ ‹‰—”‡ͶȌǤ

(88)  ‘–”ƒ•–ǡˆ‘”™Š‘Ž‡M.tuberculosisŽ›•ƒ–‡‘•‹‰‹ˆ‹ ƒ–†‹ˆˆ‡”‡ ‡•™‡”‡‘„•‡”˜‡† „‡–™‡‡  ’ƒ–‹‡–• ƒ† Ϊ ‹†‹˜‹†—ƒŽ• „—– –Š‡‹” ”‡•’‘•‡• ™‡”‡ •‹‰‹ˆ‹ ƒ–Ž› Š‹‰Š‡” ™Š‡ ‘’ƒ”‡† –‘ Š‡ƒŽ–Š› ‘–”‘Ž• ȋPδͲǤͲͳȌ ȋ ‹‰—”‡ ͶȌǤ ‹‰—”‡ Ͷ ˜‹•—ƒŽ‹œ‡• ”‡•’‘•‡•‹’ƒ–‹‡–•„‘–Š†—”‹‰ƒ –‹˜‡†‹•‡ƒ•‡ƒ†ˆ‘ŽŽ‘™‹‰ —”‡ǡ„—–•—„‰”‘—’• ™‡”‡ –‘‘ •ƒŽŽ ˆ‘” •‡’ƒ”ƒ–‡ •–ƒ–‹•–‹ ƒŽƒƒŽ›•‹•Ǥ —„‰”‘—’ ƒƒŽ›•‹• ™ƒ• ƒŽ•‘ †‘‡ ˆ‘” –Š‡‰”‘—’‘ˆ ‘˜‡”–‡”•™Š‹ Š™ƒ••’Ž‹–—’‹–‘–Š‘•‡™‹–Š”‡ ‡–‡š’‘•—”‡–‘M. tuberculosisƒ†–Š‘•‡™Š‘Šƒ†„‡‡‡š’‘•‡†‘”‡–Šƒʹ›‡ƒ”•’”‹‘”–‘–Š‡–‹‡‘ˆ „Ž‘‘† •ƒ’Ž‹‰Ǥ —„•‡“—‡–Ž›ǡ ƒ ”‡‰”‡••‹‘ ƒƒŽ›•‹• ™ƒ• †‘‡ ‹ ™Š‹ Š ——Žƒ–‹˜‡

(89) ǦJ ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ‘’ƒ”‡† „‡–™‡‡ –Š‡ –™‘ ‰”‘—’•ǡ ™Š‹Ž‡ ‘–”‘ŽŽ‹‰ˆ‘”–Š‡‡ˆˆ‡ –‘ˆƒ‰‡ǡ‰‡‡”ƒŽ”‡•’‘•‹˜‡‡••‘ˆǦ ‡ŽŽ•ȋ„›ƒ†Œ—•–‹‰ˆ‘”–Š‡ ”‡•’‘•‡ –‘ M. tuberculosisŽ›•ƒ–‡ ƒ†  Ȍ ƒ† ’‘••‹„Ž‡ ™ƒ‹‰ ‘ˆ ‹—‹–› ȋ„› ƒ†Œ—•–‹‰ ˆ‘” –Š‡ –‹‡ „‡–™‡‡ ‹‹–‹ƒŽ ‹ˆ‡ –‹‘ ™‹–Š M. tuberculosis ƒ† –Š‡ –‹‡ ‘ˆ „Ž‘‘† •ƒ’Ž‹‰ȌǤ Š‹• ƒƒŽ›•‹• •Š‘™‡† –Šƒ–ǡ ƒŽ•‘ ƒˆ–‡” ƒ†Œ—•–‹‰ ˆ‘” ƒŽŽ ‘ˆ –Š‡ ƒ„‘˜‡Ǧ ‡–‹‘‡†˜ƒ”‹ƒ„Ž‡•ǡƒ•‹‰‹ˆ‹ ƒ–Ž›Š‹‰Š‡” ——Žƒ–‹˜‡

(90) ǦJ”‡•’‘•‡–‘–Š‡ƒ–‹‰‡• ‘ˆ–Š‡‘•”‡‰—Ž‘™ƒ•‘„•‡”˜‡†‹Ϊ‹†‹˜‹†—ƒŽ• ‘’ƒ”‡†–‘’ƒ–‹‡–•Ǥ ‹ƒŽŽ›ǡ ”‡•’‘•‡ ’”‘ˆ‹Ž‡• ƒŽ•‘ †‹ˆˆ‡”‡† „‡–™‡‡ –Š‡ –™‘ ‰”‘—’• ‘ˆ M. tuberculosis ‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•™‹–Š”‡‰ƒ”†–‘–Š‡ƒ„•‘Ž—–‡—„‡”‘ˆŽƒ–‡ ›ƒ–‹‰‡•–Šƒ–™‡”‡ ”‡ ‘‰‹œ‡†ǣ Ϊ ’‡”•‘• ”‡ ‘‰‹œ‡† •‹‰‹ˆ‹ ƒ–Ž› ‘”‡ Žƒ–‡ › ƒ–‹‰‡• ȋ‡ƒ ‘ˆ ͷǤͶȌ–Šƒ’ƒ–‹‡–•ȋ‡ƒ‘ˆʹǤͶȌȋPαͲǤͲͶȌǤ  

(91) ǦJȋ’‰ȀŽȌ. 4. 3. 2. ͷͳ.

(92) Chapter2. Discussion Š‡’”‡•‡–•–—†›’”‘˜‹†‡•–Š‡ˆ‹”•–†‡• ”‹’–‹‘‘ˆŠ—ƒǦ ‡ŽŽ”‡•’‘•‡•–‘ƒŽƒ”‰‡ •‡”‹‡•‘ˆ’”‘–‡‹•‡ ‘†‡†„›–Š‡”‡ ‡–Ž›†‡• ”‹„‡††‘”ƒ ›ȋ‘•Ȍ”‡‰—Ž‘‘ˆM. tuberculosis. ŽŽ ʹͷ –‡•–‡† Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ƒ„Ž‡ –‘ ‹†— ‡ Š—ƒ Ǧ ‡ŽŽ ”‡•’‘•‡•ǡ —•‹‰ M. tuberculosisǦ•’‡ ‹ˆ‹  Ǧ ‡ŽŽ Ž‹‡•Ǥ ‹‰Š–‡‡ ‘ˆ –Š‡•‡ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ”‡ ‘‰‹œ‡† „›  ˆ”‘ M. tuberculosis‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ•ǡ ‹†‹”‡ –Ž› ‘ˆ‹”–Šƒ– ‘• ”‡‰—Ž‘ ‡ ‘†‡† ’”‘–‡‹• ƒ”‡ ‡š’”‡••‡† †—”‹‰ ƒ–—”ƒŽ M.tuberculosis‹ˆ‡ –‹‘‹Š—ƒ•Ǥ—””‡•—Ž–•‹†‹ ƒ–‡–ŠƒΪ‹†‹˜‹†—ƒŽ•–‡†–‘ ”‡ ‘‰‹œ‡ ‘”‡ Žƒ–‡ › ƒ–‹‰‡•ǡ ƒ† Šƒ˜‡ ƒ •–”‘‰‡” ——Žƒ–‹˜‡

(93) Ǧɀ ”‡•’‘•‡ ™Š‡ ‘’ƒ”‡†–‘‹†‹˜‹†—ƒŽ•™Š‘†‡˜‡Ž‘’‡†Ǥ

(94)  ‘–”ƒ•–ǡ

(95) Ǧɀ”‡•’‘•‡•–‘ Ǧ ͳͲǡ ƒ M. tuberculosis•’‡ ‹ˆ‹  ƒ–‹‰‡ •‡ ”‡–‡† †—”‹‰ ƒ –‹˜‡ ”‡’Ž‹ ƒ–‹‘ǡ ™‡”‡ •‹‰‹ˆ‹ ƒ–Ž›•–”‘‰‡”‹’ƒ–‹‡–•Ǥ —– ‘ˆ –Š‡ ͳͺ Žƒ–‡ › ƒ–‹‰‡• –Šƒ– ™‡”‡ ”‡ ‘‰‹œ‡† „›  ‘ˆ M. tuberculosis ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ• ‘Ž› •’ Šƒ† „‡‡ ’”‡˜‹‘—•Ž› ‹†‡–‹ˆ‹‡† ƒ• ƒ M. tuberculosis ƒ–‹‰‡ ȏͳ͸ȐǤ ˆ –Š‡•‡ ‡™Ž› ‹†‡–‹ˆ‹‡† ƒ–‹‰‡•ǡ ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͹  ƒ† ˜ʹ͸ʹͺ ™‡”‡ ‘•– ˆ”‡“—‡–Ž› ”‡ ‘‰‹œ‡†ǡ „› ͸ͳΨǡ ͸ͳΨǡ ͷʹΨ ƒ† ͵ͷΨ ‘ˆ Ϊ ‹†‹˜‹†—ƒŽ•ǡ”‡•’‡ –‹˜‡Ž›ǤŠ‡•‡ƒ–‹‰‡•™‡”‡ˆ‘—†–‘‹†— ‡”‡Žƒ–‹˜‡Ž›•–”‘‰

(96) Ǧɀ ”‡•’‘•‡• ™Š‡ ‘’ƒ”‡† –‘ –Š‡ ™‡ŽŽǦ‘™ ‹—‘†‘‹ƒ– •‡ ”‡–‡† ƒ–‹‰‡  ǦͳͲǤ ‘•‹–‹˜‡”‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡•‹’ƒ–‹‡–•™‡”‡‘–‡–‹”‡Ž›—‡š’‡ –‡†ƒ• ‘•– ’ƒ–‹‡–• ‰‘ –Š”‘—‰Š ƒ ’Šƒ•‡ ‘ˆ Žƒ–‡– ‹ˆ‡ –‹‘ „‡ˆ‘”‡ ’”‘‰”‡••‹‘ –‘ƒ –‹˜‡  †‹•‡ƒ•‡ ‘ —”•Ǣ ‡‘”› ‹—‡ ”‡•’‘•‡• ‹†— ‡† †—”‹‰ –Š‹• Žƒ–‡– ’Šƒ•‡ ƒ› ”‡ƒ‹†‡–‡ –ƒ„Ž‡–Š‡”‡ƒˆ–‡”Ǥ

(97) ƒ††‹–‹‘ǡ†—”‹‰†‹•‡ƒ•‡ƒ–Ž‡ƒ•–’ƒ”–‘ˆ–Š‡„ƒ ‹ŽŽ‹ ƒ”‡‡š’‡ –‡†–‘‡ ‘—–‡”Š›’‘š‹  ‘†‹–‹‘•‘”–‘„‡‡š’‘•‡†–‘‹–”‹ ‘š‹†‡™Š‹ Š Ž‡ƒ†•–‘—’”‡‰—Žƒ–‹‘‘ˆ–Š‡†‘”ƒ ›”‡‰—Ž‘ǡƒ••—‰‰‡•–‡†„›–Š‡ˆ‹†‹‰‘ˆ˜ƒ”‹ƒ„Ž‡ Ž‡˜‡Ž• ‘ˆ •’ –”ƒ• ”‹’–• ‹ †‹ˆˆ‡”‡– ”‡‰‹‘• ‘ˆ –Š‡ Ž—‰• ‘ˆ ’ƒ–‹‡–• ™‹–Š Š”‘‹ ǡ ƒ –‹˜‡  ȏʹʹǡʹ͵ȐǤ —”–Š‡”‘”‡ǡ ƒ• ”‡ ‡–Ž› Šƒ• „‡‡ ‘„•‡”˜‡† ˆ‘” „ƒ ‹ŽŽ‹ †—”‹‰ ƒ‡”ƒ–‡† •–ƒ–‹‘ƒ”› ’Šƒ•‡ ‹ ˜‹–”‘ǡ ‹– ‹• ’‘••‹„Ž‡ –Šƒ– ‹  ’ƒ–‹‡–• ‡š’”‡••‹‘ ‘ˆ –Š‡ ‘• ‹• ’ƒ”–‹ƒŽ ‘” ƒŽ–‡”‡†ǡ ”‡•—Ž–‹‰ ‹ ƒ ‘”‡ Ž‹‹–‡† ”‡•’‘•‡ –‘ Žƒ–‡ › ƒ–‹‰‡• ȏʹͻȐǤ ‡ Š›’‘–Š‡•‹œ‡ –Šƒ– ‹—‡ ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ƒ› ‘–”‹„—–‡ –‘ –Š‡ ‘–”‘Ž‘ˆ’‡”•‹•–‡–M.tuberculosis‹ˆ‡ –‹‘ƒ†–Šƒ– Šƒ‰‡•‹’”‘–‡‹‡š’”‡••‹‘ ’”‘ˆ‹Ž‡ †—”‹‰ Žƒ–‡ › ”‡•—Ž– ‹ ƒ ƒŽ–‡”‡† ”‡’‡”–‘‹”‡ ‘ˆ M. tuberculosis ƒ–‹‰‡• ƒ˜ƒ‹Žƒ„Ž‡ˆ‘”Ǧ ‡ŽŽ”‡ ‘‰‹–‹‘ǤŠ‹• ‘—Ž†–Š‡„‡”‡ˆŽ‡ –‡†‹†‹ˆˆ‡”‡ ‡•‹ƒ–‹‰‡ ”‡ ‘‰‹–‹‘ ’ƒ––‡”• ‘ˆ ”‡•’‘†‹‰ Ǧ ‡ŽŽ•Ǥ Š‡ ‘„•‡”˜ƒ–‹‘ –Šƒ– ‹ Ϊ ‹†‹˜‹†—ƒŽ•

(98) ǦJ ”‡•’‘•‡• –‘ –Š‡ Ͷ ‘•– ˆ”‡“—‡–Ž› ”‡ ‘‰‹œ‡† Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ •‹‰‹ˆ‹ ƒ–Ž›Š‹‰Š‡”–Šƒ–‘ ǦͳͲǡ™Š‹Ž‡–Š‡‘’’‘•‹–‡ƒ–‹‰‡”‡ ‘‰‹–‹‘’”‘ˆ‹Ž‡™ƒ• ˆ‘—† ˆ‘”  ’ƒ–‹‡–•ǡ ‹• ‘•‹•–‡– ™‹–Š –Š‹• Š›’‘–Š‡•‹•Ǥ —”–Š‡”‘”‡ǡ Žƒ–‡–Ž› ‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•”‡ ‘‰‹œ‡†•‹‰‹ˆ‹ ƒ–Ž›‘”‡Žƒ–‡ ›ƒ–‹‰‡•ƒ†Šƒ†ƒ•–”‘‰‡”

(99) ǦJ’”‘†— –‹‘‹”‡•’‘•‡–‘–Š‡‰”‘—’‘ˆŽƒ–‡ ›ƒ–‹‰‡•™Š‡ ‘’ƒ”‡†–‘ ’ƒ–‹‡–•Ǥ ‘™‡˜‡”ǡ ‘—” •–—†› ™ƒ• ‘– †‡•‹‰‡† –‘ •’‡ ‹ˆ‹ ƒŽŽ› †‡‘•–”ƒ–‡ ƒ ƒ—•ƒŽ ”‡Žƒ–‹‘•Š‹’ „‡–™‡‡ –Š‡ ‘„•‡”˜‡† ‹—‡ ”‡•’‘•‡• ƒ† ’”‘–‡ –‹‘ ƒ‰ƒ‹•–  †‹•‡ƒ•‡ǡƒ•–Š‹•™‘—Ž†”‡“—‹”‡–Š‡ˆ‘ŽŽ‘™Ǧ—’‘ˆ—–”‡ƒ–‡†Žƒ–‡–Ž›‹ˆ‡ –‡†’‡”•‘•ƒ† †‡–ƒ‹Ž‡†ƒƒŽ›•‹•‘ˆ–Š‡‹‡–‹ •‘ˆ”‡•’‘•‡•‹–Š‘•‡™Š‘™‹ŽŽ’”‘‰”‡••–‘ƒ –‹˜‡. ͷʹ.

(100) ImmuneresponsestolatencyantigensofM.tuberculosis . ˜‡”•—• –Š‘•‡ ™Š‘ ™‹ŽŽ ”‡ƒ‹ Š‡ƒŽ–Š›Ǥ Š‡ ‘„•‡”˜‡† ƒ••‘ ‹ƒ–‹‘ „‡–™‡‡

(101) ǦJ ”‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡•ƒ†ƒ–—”ƒŽ’”‘–‡ –‹‘‡‡†•–‘„‡ˆ—”–Š‡”‹˜‡•–‹‰ƒ–‡†ǡ „—– ™‡ ™‘—Ž† Ž‹‡ –‘ •—‰‰‡•– –Šƒ– –Š‡•‡ ƒ–‹‰‡• ƒ› „‡ ‹–‡”‡•–‹‰ ƒ†‹†ƒ–‡• ˆ‘” ‡˜ƒŽ—ƒ–‹‘‹’‘•–Ǧ‡š’‘•—”‡˜ƒ ‹ƒ–‹‘‘†‡Ž•Ǥ —‡š’‡ –‡†ˆ‹†‹‰‘ˆ–Š‡•–—†›™ƒ•–Š‡”‡ ‘‰‹–‹‘‘ˆŽƒ–‡ ›ƒ–‹‰‡•„›•‘‡‘ˆ –Š‡—‹ˆ‡ –‡† ‘–”‘Ž•Ǥ‘‡‘ˆ–Š‡ ‘–”‘Ž•™‡”‡ ˜ƒ ‹ƒ–‡†ǡŠƒ†ƒ›‹†‡–‹ˆ‹‡† ”‹• ‘ˆ ‡š’‘•—”‡ –‘  ‘” ”‡•’‘†‡† ‹ ˜‹–”‘ –‘ –Š‡ M. tuberculosis•’‡ ‹ˆ‹  ƒ–‹‰‡• Ǧ͸‘” ǦͳͲǤ ‘™‡˜‡”ǡ‘”‡–ŠƒŠƒŽˆ‘ˆ–Š‡ ‘–”‘Ž•”‡ ‘‰‹œ‡†M.tuberculosis Ž›•ƒ–‡ǡ ™Š‹ Š ‹• ‘•– Ž‹‡Ž› ‡š’Žƒ‹‡† „› ‡š’‘•—”‡ –‘ › ‘„ƒ –‡”‹ƒ ‘–Š‡” –Šƒ M. tuberculosis. ‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ‡ƒ”Ž› ‡š Ž—•‹˜‡Ž› •‡‡ ‹ –Š‹• •—„‰”‘—’‘ˆ ‘–”‘Ž•ǡ™Š‡”‡ƒ•˜‹”–—ƒŽŽ›‘”‡•’‘•‡•™‡”‡•‡‡‹–Š‡› ‘„ƒ –‡”‹— ‘Ǧ”‡•’‘•‹˜‡‰”‘—’ǡ•—‰‰‡•–‹‰–Šƒ–”‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡• ‘—Ž†”‡•—Ž–ˆ”‘ ”‘••Ǧ”‡ƒ –‹˜‹–› –‘ ‘Ǧ–—„‡” —Ž‘—• › ‘„ƒ –‡”‹ƒǤ

(102) – ‹• ‹–‡”‡•–‹‰ –‘ ‘–‡ –Šƒ– ‘–Š‡” › ‘„ƒ –‡”‹ƒǡŽ‹‡M.bovisƒ† ǡM.microtiƒ†M.smegmatisŠƒ˜‡ƒ˜‡”›•‹‹Žƒ” †‘”ƒ ›”‡‰—Ž‘ȏ͵Ͳǡ͵ͳȐǤ‘”‡‘˜‡”ǡ–Š‡”‡ƒ›„‡Š‘‘Ž‘‰—‡•‹‘–Š‡”„ƒ –‡”‹ƒ–Šƒ › ‘„ƒ –‡”‹ƒ ƒ—•‹‰ ”‘••Ǧ”‡ƒ –‹˜‹–›Ǥ ˆ ‘–‡ǡ ˜ͳ͹͵͵  ‡ ‘†‡• ƒ ’‘••‹„Ž‡ –”ƒ•‡„”ƒ‡ ’”‘–‡‹ǡ ™Š‹ Š „‡ƒ”• Š‘‘Ž‘‰› ™‹–Š ƒ Š›’‘–Š‡–‹ ƒŽ ’”‘–‡‹ ‘ˆ Streptomyces coelicolor; ƒ† ˜ʹͲʹͻ ǡ ™Š‹ Š ‹• ƒ ’”‡†‹ –‡† ’Š‘•’Š‘ˆ”— –‘‹ƒ•‡ ‹˜‘Ž˜‡†‹‰Ž› ‘Ž›•‹•ǡ‹•‡š’‡ –‡†–‘Šƒ˜‡Š‘‘Ž‘‰—‡•‹‘–Š‡”ȋ› ‘Ȍ„ƒ –‡”‹ƒǤ

(103) –‹• ‘–‘™™Š‡–Š‡”–Š‡‘„•‡”˜‡† ”‘••Ǧ”‡ƒ –‹˜‡‹—‡”‡•’‘•‡–‘Žƒ–‡ ›ƒ–‹‰‡• ƒ‘‰ M. tuberculosis ƒÃ˜‡ ’‡”•‘• ‘–”‹„—–‡• –‘ –Š‡ ƒ–—”ƒŽ ’”‘–‡ –‹‘ –Šƒ– †‡˜‡Ž‘’•‹ͻͲΨ‘ˆ‹†‹˜‹†—ƒŽ•™Š‘ƒ”‡‹ˆ‡ –‡†™‹–ŠM.tuberculosisƒ†”‡ƒ‹ˆ”‡‡ ‘ˆ†‹•‡ƒ•‡Ǣ„—––Š‹•‹•ƒ›„‡ƒ‹’‘”–ƒ––‘’‹ ˆ‘”ˆ—”–Š‡”•–—†‹‡•ȏͷǡ͵ʹȐǤ

(104)  ‘—” •–—†› ™‡ –‡•–‡† ’”‘–‡‹• ‹ ‡“—‹‘Žƒ” ‘ ‡–”ƒ–‹‘•ǡ –‘ ƒŽŽ‘™ ˆ‘” †‹”‡ – ‘’ƒ”‹•‘‘ˆŠ—ƒǦ ‡ŽŽ”‡•’‘•‡•–‘†‹ˆˆ‡”‡–ƒ–‹‰‡•‹ Ž—†‹‰–Š‡’”‡˜‹‘—•Ž› †‡ˆ‹‡†ƒ–‹‰‡ •’ƒ†‡™Ž›‹†‡–‹ˆ‹‡†Žƒ–‡ ›ƒ–‹‰‡•ǤŠ‡”‡•—Ž–•‹†‹ ƒ–‡†–Šƒ– •‡˜‡”ƒŽ‘ˆ–Š‡Žƒ––‡”‹†— ‡†Š‹‰Š‡””‡•’‘•‡•‹ƒŽƒ”‰‡”’”‘’‘”–‹‘‘ˆ•—„Œ‡ –•–Šƒ •’†‹†Ǥ‡‘„•‡”˜‡†–Šƒ– •’ǡƒ––Š‡ ‘ ‡–”ƒ–‹‘–‡•–‡†ǡ™ƒ•”‡ ‘‰‹œ‡†„›‘Ž› ʹͲΨ ‘ˆ  ’ƒ–‹‡–• ™Š‡”‡ƒ• ‹ Ϊ ’‡”•‘•

(105) Ǧɀ ”‡•’‘•‡• ™‡”‡ ˜‡”› ‹ˆ”‡“—‡– ƒ† ‘ˆ ƒ Ž‘™ Ž‡˜‡ŽǤ ˆ ‘–‡ Š‘™‡˜‡”ǡ •‡˜‡”ƒŽ Ǧ ‡ŽŽ Ž‹‡• •–”‘‰Ž› ”‡ ‘‰‹œ‡† –Š‡ ‹†‡–‹ ƒŽ’”‘–‡‹„ƒ– Š‘ˆ •’ǤŠ‡ƒ’’ƒ”‡–†‹• ”‡’ƒ ›™‹–Š ƒ’”‡˜‹‘—••–—†‹‡ǡ‹ ™Š‹ Š ”‡ ‘‰‹–‹‘‘ˆ •’„› Ǧ ‡ŽŽ• ‘ˆΪ ‹†‹˜‹†—ƒŽ• ™ƒ•†‡‘•–”ƒ–‡† ȏͳ͸ǡʹͺȐǡ ƒ›„‡”‡Žƒ–‡†–‘†‹ˆˆ‡”‡ ‡•‹”‡ƒ†‘—–‡–Š‘†‘Ž‘‰›ƒ†–‘ƒ–‹‰‡ ‘ ‡–”ƒ–‹‘• –‡•–‡†ǡ•‹ ‡”‡Žƒ–‹˜‡Ž›Ž‘™ ‘ ‡–”ƒ–‹‘•‘ˆƒ–‹‰‡•™‡”‡—•‡†Ǥ ‹ƒŽŽ›ǡƒ†‹ˆˆ‡”‡ ‡ ‹•–—†›’‘’—Žƒ–‹‘• ‘—Ž†„‡ƒƒ††‹–‹‘ƒŽˆƒ –‘”ǡƒ•‹—‡”‡•’‘•‡•–‘ •’ƒ› Šƒ˜‡™ƒ‡†‹ˆ–Š‡‹ˆ‡ –‹‘™‹–ŠM.tuberculosis™ƒ•”‡‘–‡ǤŠ‡‘„•‡”˜‡†”‡•’‘•‡• –‘ •’™‡”‡ƒŽŽ‹”‡ ‡– ‘˜‡”–‡”•ǡ•—’’‘”–‹‰–Š‡Žƒ––‡”Š›’‘–Š‡•‹•Ǥ

(106)  –Š‹• •–—†›™‡ ˆ‘ —•‡† ‘

(107) ǦJ ”‡•’‘•‡• „› Ǧ ‡ŽŽ Ž‹‡• ƒ† Ǥ Š‡ ‡••‡–‹ƒŽ ”‘Ž‡ ‘ˆ

(108) ǦJ ‹ –Š‡ ’”‘–‡ –‹˜‡ ‹—‹–› –‘ › ‘„ƒ –‡”‹ƒ Šƒ• „‡‡ Ž‡ƒ”Ž› †‡‘•–”ƒ–‡†„›•–—†‹‡•‹‰‡‡Ǧ‘ ‘—–‹ ‡ƒ†„›–Š‡‹ ”‡ƒ•‡†•—• ‡’–‹„‹Ž‹–›–‘ › ‘„ƒ –‡”‹ƒ ‹ ‹†‹˜‹†—ƒŽ• ™‹–Š ‰‡‡–‹  †‡ˆ‡ –• ‹ –Š‡

(109) ǦɀȀ‹–‡”Ž‡—‹ǦͳʹȀʹ͵ ’ƒ–Š™ƒ›ȏ͵͵ǡ͵ͶȐǤ‘‡–Š‡Ž‡••ǡˆ—–—”‡•–—†‹‡•‘Žƒ–‡ ›ƒ–‹‰‡••Š‘—Ž†ƒŽ•‘ƒ††”‡•• ’”‘†— –‹‘‘ˆ‘–Š‡” ›–‘‹‡•–Šƒ

(110) Ǧɀȏ͸ȐǤ

(111) ƒ††‹–‹‘ǡ„‡•‹†‡•Ͷ”‡•’‘•‡•ǡ™‡ ƒ”‡ —””‡–Ž› •–—†›‹‰ ͺ Ǧ ‡ŽŽ• •’‡ ‹ˆ‹  ˆ‘” › ‘„ƒ –‡”‹ƒŽ Žƒ–‡ › ƒ–‹‰‡•ǡ ƒ• •‡˜‡”ƒŽ •–—†‹‡• ‹†‹ ƒ–‡ –Šƒ– ͺ Ǧ ‡ŽŽ• ƒ”‡ ‹’‘”–ƒ– ˆ‘” ‘–”‘ŽŽ‹‰ Žƒ–‡– M. tuberculosis‹ˆ‡ –‹‘ȏ͹ǡ͵ͷȐǤ. ͷ͵.

(112) Chapter2.

(113)  ‘ Ž—•‹‘ǡ–Š‡‘•”‡‰—Ž‘™ƒ•ˆ‘—†–‘‡ ‘†‡ƒŠ‹‰Š—„‡”‘ˆM.tuberculosis ƒ–‹‰‡• ™‹–Š •–”‘‰ Ǧ ‡ŽŽ ƒ†

(114) Ǧɀ ‹†— ‹‰ ƒ’ƒ ‹–›Ǥ  –”‡† ™ƒ• ‘„•‡”˜‡† –‘™ƒ”†• •–”‘‰‡”

(115) Ǧɀ ”‡•’‘•‡• –‘ ƒ Žƒ”‰‡” —„‡” ‘ˆ Žƒ–‡ › ƒ–‹‰‡• ‹ Žƒ–‡–Ž› ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ• ƒ• ‘’ƒ”‡† –‘ ‹†‹˜‹†—ƒŽ• ™Š‘ †‡˜‡Ž‘’‡†  †‹•‡ƒ•‡ǡ ™Š‡”‡ƒ• –Š‡ ‘’’‘•‹–‡ ’”‘ˆ‹Ž‡ ™ƒ• ˆ‘—† ˆ‘”  ǦͳͲǤ Š‡•‡ ˆ‹†‹‰• ƒ”‡ ‘•‹•–‡– ™‹–Š –Š‡ Š›’‘–Š‡•‹• –Šƒ– ‹—‡ ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ƒ› ‘–”‹„—–‡ –‘ ƒ–—”ƒŽ ’”‘–‡ –‹‘ ƒ‰ƒ‹•–  †‹•‡ƒ•‡Ǥ ‘™‡˜‡”ǡ •—„•‡“—‡– ’”‘•’‡ –‹˜‡ •–—†‹‡• ‘ˆ Žƒ”‰‡ ‘Š‘”–• ‘ˆ Žƒ–‡–Ž› ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ• ƒ”‡ ‡‡†‡† –‘ †‡–‡”‹‡ Š‘™ •–”‘‰Ž› Ǧ ‡ŽŽ ”‡•’‘•‡• –‘ –Š‡•‡ ‡™Ž› ‹†‡–‹ˆ‹‡† Žƒ–‡ › ƒ–‹‰‡• ƒ”‡ ƒ••‘ ‹ƒ–‡† ™‹–Š  Žƒ–‡ › ƒ†™‹–Š’”‘–‡ –‹‘ƒ‰ƒ‹•–’”‘‰”‡••‹‘–‘™ƒ”†•ƒ –‹˜‡†‹•‡ƒ•‡Ǥ

(116) ˆ•‘ǡŽƒ–‡ ›ƒ–‹‰‡• ƒ›„‡’”‘‹•‹‰–‘‘Ž•ˆ‘”˜ƒ ‹ƒ–‹‘ƒ‰ƒ‹•–”‡ƒ –‹˜ƒ–‹‘Ǥ . Acknowledgements ‡ Ž‹‡ –‘ –Šƒ ‹  ˜ƒ ‘‘Ž‹‰‡ǡ ƒ–‹‘ƒŽ

(117) •–‹–—–‡ ‘ˆ —„Ž‹  ‡ƒŽ–Š ƒ† ˜‹”‘‡–ǡ ‹Ž–Š‘˜‡ǡ –Š‡ ‡–Š‡”Žƒ†•Ǣ ƒ† 

(118) ǡ 

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(120)  ‘–”ƒ – ˆ‘”  ƒ ‹‡ ‡•–‹‰ ƒ† ‡•‡ƒ” Š ƒ–‡”‹ƒŽ• ȋͳ 

(121) Ǧ͹ͷ͵ʹͲȌ ˆ‘” ‰‡‡”‘—•Ž› ’”‘˜‹†‹‰ ”‡ƒ‰‡–•Ǣ ƒ•‹ƒ Ž‡ ‡••‹‡ ƒ† ‘ ‘Ž–‡”„‡‡ ˆ‘” •–ƒ–‹•–‹ ƒŽ ƒ†˜‹•‡ ƒ† ƒƒ’ ˜ƒ ‹••‡Ž ƒ† ‹‘‡ ‘‘•–‡ˆ‘” ”‹–‹ ƒŽŽ›”‡ƒ†‹‰–Š‡ƒ—• ”‹’–Ǥ Š‹• ”‡•‡ƒ” Š ’”‘Œ‡ – Šƒ• „‡‡ •—’’‘”–‡† ‹ ’ƒ”– „› –Š‡ ‘—†ƒ–‹‘ ‹ ”‘„‹‘Ž‘‰› ‡‹†‡ǡ –Š‡ ‡–Š‡”Žƒ†• ”‰ƒ‹•ƒ–‹‘ ˆ‘”  ‹‡–‹ˆ‹  ‡•‡ƒ” Š ƒ† –Š‡ ‘›ƒŽ ‡–Š‡”Žƒ†• ƒ†‡›‘ˆ”–•ƒ† ‹‡ ‡•Ǥ . ͷͶ.

(122) ImmuneresponsestolatencyantigensofM.tuberculosis . References. . ͳǤ. . ʹǤ. . ͵Ǥ. . ͶǤ. . ͷǤ. . ͸Ǥ. . ͹Ǥ. . ͺǤ. . ͻǤ. . ͳͲǤ. . ͳͳǤ. . ͳʹǤ. . ͳ͵Ǥ. . ͳͶǤ. . ͳͷǤ. . ͳ͸Ǥ. . ͳ͹Ǥ. . ͳͺǤ. . ͳͻǤ. . ʹͲǤ. ‘”„‡––ǡǤǤǡƒ––ǡǤ ǤǡƒŽ‡”ǡǤǡƒŠ‡”ǡǤǡ‹ŽŽ‹ƒ•ǡǤ Ǥǡƒ˜‹‰Ž‹‘‡ǡǤǤǡƒ†›‡ǡǤʹͲͲ͵ǤŠ‡ ‰”‘™‹‰„—”†‡‘ˆ–—„‡” —Ž‘•‹•ǣ‰Ž‘„ƒŽ–”‡†•ƒ†‹–‡”ƒ –‹‘•™‹–Š–Š‡

(123) ‡’‹†‡‹ ǤArch.Intern.Med. ͳ͸͵:ͳͲͲͻǦͳͲʹͳǤ ‘”•„—”‰Šǡ Ǥ Ǥǡ ”Ǥ ʹͲͲͶǤ ”‹‘”‹–‹‡• ˆ‘” –Š‡ –”‡ƒ–‡– ‘ˆ Žƒ–‡– –—„‡” —Ž‘•‹• ‹ˆ‡ –‹‘ ‹ –Š‡ ‹–‡† –ƒ–‡•ǤN.Engl.J.Med.͵ͷͲ:ʹͲ͸ͲǦʹͲ͸͹Ǥ ‘›•ƒŽǡǤǡ‹ŽŽ‹‰–‘ǡǤǤǡƒ‹”ǡǤǡ‘•ƒŒŠǡǤǡ•ŽƒǡǤǡ‡‡•ǡ Ǥ Ǥǡˆ‡ǡǤǡ–ƒ˜‡Ž‡›ǡ

(124) Ǥǡ™‡”ǡǤǡƒ† ƒŽ˜ƒ‹ǡǤʹͲͲͷǤˆˆ‡ –‘ˆ ˜ƒ ‹ƒ–‹‘‘”‹•‘ˆMycobacteriumtuberculosis‹ˆ‡ –‹‘‹ Š‹Ž†”‡ ™‹–ŠŠ‘—•‡Š‘Ž†–—„‡” —Ž‘•‹• ‘–ƒ –ǣƒ’”‘•’‡ –‹˜‡ ‘—‹–›Ǧ„ƒ•‡†•–—†›ǤLancet͵͸͸:ͳͶͶ͵ǦͳͶͷͳǤ ‘Ž†‹–œǡ Ǥ Ǥǡ ”‡™‡”ǡ Ǥ Ǥǡ ‡”‡›ǡ Ǥ Ǥǡ ‹Ž•‘ǡ Ǥ Ǥǡ —”†‹ ǡ Ǥǡ ‹‡„‡”‰ǡ Ǥ Ǥǡ ƒ† ‘•–‡ŽŽ‡”ǡ Ǥ ͳͻͻͶǤ ˆˆ‹ ƒ › ‘ˆ   ˜ƒ ‹‡ ‹ –Š‡ ’”‡˜‡–‹‘ ‘ˆ –—„‡” —Ž‘•‹•Ǥ ‡–ƒǦƒƒŽ›•‹• ‘ˆ –Š‡ ’—„Ž‹•Š‡† Ž‹–‡”ƒ–—”‡ǤJAMAʹ͹ͳ:͸ͻͺǦ͹ͲʹǤ ‹‡ǡǤǤͳͻͻͷǤƒ”‹ƒ–‹‘‹’”‘–‡ –‹‘„› ǣ‹’Ž‹ ƒ–‹‘•‘ˆƒ†ˆ‘”Š‡–‡”‘Ž‘‰‘—•‹—‹–›ǤLancet ͵Ͷ͸:ͳ͵͵ͻǦͳ͵ͶͷǤ Šƒǡ Ǥƒ† Ž›ǡ ǤʹͲͲͶǤŠ‡‹—‘Ž‘‰‹ ƒŽƒ•’‡ –•‘ˆŽƒ–‡ ›‹–—„‡” —Ž‘•‹•ǤClin.Immunol.ͳͳͲ:ʹǦ ͳʹǤ ˜ƒ ‹š–‡”‡ǡ Ǥ Ǥǡ ƒ••‹†›ǡ Ǥ Ǥǡ ‡†‡‰ƒƒ”†ǡ Ǥ Ǥǡ ‰‰‡”ǡ Ǥ Ǥǡ ƒ† †‡”•‡ǡ Ǥ ʹͲͲͲǤ ‘–”‘Ž ‘ˆ Žƒ–‡– Mycobacterium tuberculosis ‹ˆ‡ –‹‘ ‹• †‡’‡†‡– ‘ ͺ  ‡ŽŽ•Ǥ Eur.J.Immunol. ͵Ͳ: ͵͸ͺͻǦ ͵͸ͻͺǤ Ž”‹ Š•ǡ Ǥǡ ‘•‹ƒ†‹ǡ Ǥ Ǥǡ ”—•‘˜ǡ Ǥǡ ‘”‰ǡ Ǥǡ ”ƒ†Žǡ Ǥǡ ‹–—Š‹ƒǡ Ǥǡ ‹•Š‡‘ǡ Ǥǡ —•Š‹ƒǡ Ǥǡ ƒ† ƒ—ˆƒǡ Ǥ Ǥ ʹͲͲͶǤ —ƒ –—„‡” —Ž‘—• ‰”ƒ—Ž‘ƒ• ‹†— ‡ ’‡”‹’Š‡”ƒŽ Ž›’Š‘‹† ˆ‘ŽŽ‹ Ž‡ǦŽ‹‡ •–”— –—”‡•–‘‘” Š‡•–”ƒ–‡Ž‘ ƒŽŠ‘•–†‡ˆ‡ ‡‹–Š‡Ž—‰ǤJ.Pathol.ʹͲͶ:ʹͳ͹ǦʹʹͺǤ ’‹‡ƒ† ”‘•‘ͳͻʹ͹Ǥ—„‡” Ž‡„ƒ ‹ŽŽ‹‹Žƒ–‡––—„‡” —Ž‘—•Ž‡•‹‘•ƒ†‹Ž—‰–‹••—‡™‹–Š‘—– –—„‡” —Ž‘—•Ž‡•‹‘•ǤArchPatholLabMedͶ:ͳǦʹͳǤ ‡”ƒ†‡œǦƒ†‘ǡǤǡ ‡›ƒƒ–ŠƒǡǤǡ‡‰‹•–—ǡ Ǥǡ‰—‹Žƒ”ǡǤǡ”‘œ ‘ǡ Ǥǡ ƒ”„‘‡ǡǤǡ‘‘ǡ ǤǤǡƒ† Œ—‡ǡ ǤʹͲͲͲǤ‡”•‹•–‡ ‡‘ˆˆ”‘Mycobacteriumtuberculosis‹•—’‡”ˆ‹ ‹ƒŽŽ›‘”ƒŽŽ—‰–‹••—‡ †—”‹‰Žƒ–‡–‹ˆ‡ –‹‘ǤLancet͵ͷ͸:ʹͳ͵͵Ǧʹͳ͵ͺǤ ‡‹Ž‡”ǡǤǡ Ž”‹ Š•ǡǤǡƒ†‡”ƒǡǤǡ”ƒ†Žǡ Ǥǡ ‘”‰ǡǤǡ”‡ǡ Ǥǡ ‘”ƒ™‹‡–œǡǤǡƒ—ˆƒǡǤ Ǥǡƒ† ‹ Š‡Ž‡ǡǤʹͲͲ͵Ǥ‡ŽŽǦ™ƒŽŽƒŽ–‡”ƒ–‹‘•ƒ•ƒƒ––”‹„—–‡‘ˆMycobacteriumtuberculosis‹Žƒ–‡–‹ˆ‡ –‹‘Ǥ J.Infect.Dis.ͳͺͺ:ͳ͵ʹ͸Ǧͳ͵͵ͳǤ ƒ›‡ǡ Ǥ Ǥ ƒ† ‘Šƒ•‡›ǡ Ǥ Ǥ ʹͲͲͳǤ ‘”‡’Ž‹ ƒ–‹‰ ’‡”•‹•–‡ ‡ ‘ˆ Mycobacterium tuberculosisǤ Annu.Rev.Microbiol.ͷͷ:ͳ͵ͻǦͳ͸͵Ǥ —ˆƒ”‹‡ŽŽ‘ǡ ǤǤǡŠƒǡ Ǥǡƒ† Ž›ǡ ǤǤʹͲͲ͵Ǥƒ–‡––—„‡” —Ž‘•‹•ǣ‡ Šƒ‹••‘ˆŠ‘•–ƒ†„ƒ ‹ŽŽ—•–Šƒ– ‘–”‹„—–‡–‘’‡”•‹•–‡–‹ˆ‡ –‹‘ǤLancetInfect.Dis.͵:ͷ͹ͺǦͷͻͲǤ —ƒǡ Ǥǡ ”ƒ‡ǡ Ǥ Ǥǡ ƒ† ƒ””›ǡ Ǥ Ǥǡ

(125)

(126)

(127)  ͳͻͻ͸Ǥ –ƒ–‹‘ƒ”› ’Šƒ•‡Ǧƒ••‘ ‹ƒ–‡† ’”‘–‡‹ ‡š’”‡••‹‘ ‹ Mycobacterium tuberculosisǣ ˆ— –‹‘ ‘ˆ –Š‡ › ‘„ƒ –‡”‹ƒŽ ƒŽ’ŠƒǦ ”›•–ƒŽŽ‹ Š‘‘Ž‘‰Ǥ J.Bacteriol. ͳ͹ͺ: ͶͶͺͶǦͶͶͻʹǤ ‘•‡”ƒ†•ǡ

(128) ǤǡŽƒ›†‡ǡǤǤǡ”ƒ™ˆ‘”†ǡ Ǥǡƒ‰ƒƒ”†ǡǤǡƒ””›ǡǤǤǡ

(129)

(130)

(131) ǡƒ††‡”•‡ǡǤʹͲͲʹǤ ›’‘š‹  ”‡•’‘•‡ ‘ˆ Mycobacterium tuberculosis •–—†‹‡† „› ‡–ƒ„‘Ž‹  Žƒ„‡Ž‹‰ ƒ† ’”‘–‡‘‡ ƒƒŽ›•‹• ‘ˆ ‡ŽŽ—Žƒ”ƒ†‡š–”ƒ ‡ŽŽ—Žƒ”’”‘–‡‹•ǤJ.Bacteriol.ͳͺͶ:͵ͶͺͷǦ͵ͶͻͳǤ ‹Ž‹•‘ǡǤ Ǥǡ‹Ž‹•‘ǡǤǤǡ‡‡–ǡǤǤǡ ƒ•Ž‘˜ǡǤǡƒ•˜‘Žǡ Ǥǡ‹‰ŠǡǤǡ˜ƒ” ‘˜ƒǡ

(132) Ǥǡƒ†

(133) ˜ƒ›‹ǡ Ǥ ͳͻͻͺǤ —ƒ Ǧ ƒ† Ǧ ‡ŽŽ ”‡ƒ –‹˜‹–› –‘ –Š‡ ͳ͸ƒ ƒŽ’ŠƒǦ ”›•–ƒŽŽ‹ ’”‘–‡‹ ‘ˆ Mycobacterium tuberculosisǤScand.J.Immunol.Ͷͺ:ͶͲ͵ǦͶͲͻǤ Š‡”ƒǡ Ǥ Ǥǡ ‘•—‹Žǡ Ǥǡ  Šƒ’’‹‰‡”ǡ Ǥǡ ‹ƒ‘ǡ Ǥǡ ƒ””‡ŽŽǡ Ǥ

(134) Ǥǡ ƒ†  Š‘‘Ž‹ǡ Ǥ Ǥ ʹͲͲͳǤ ‡‰—Žƒ–‹‘ ‘ˆ –Š‡ Mycobacterium tuberculosis Š›’‘š‹  ”‡•’‘•‡ ‰‡‡ ‡ ‘†‹‰ ƒŽ’Šƒ Ǧ ”›•–ƒŽŽ‹Ǥ Proc.Natl.Acad.Sci.U.S.Aͻͺ:͹ͷ͵ͶǦ͹ͷ͵ͻǤ Ž‘” œ›ǡ Ǥ Ǥǡ  —‡ǡ Ǥ Ǥǡ –ƒ ǡ Ǥ Ǥǡ ƒ—‡”ǡ Ǥ Ǥǡ ƒ†  ‘‘—‰Šǡ Ǥ Ǥ ʹͲͲͳǤ

(135) †‡–‹ˆ‹ ƒ–‹‘ ƒ† Šƒ”ƒ –‡”‹œƒ–‹‘‘ˆ› ‘„ƒ –‡”‹ƒŽ’”‘–‡‹•†‹ˆˆ‡”‡–‹ƒŽŽ›‡š’”‡••‡†—†‡”•–ƒ†‹‰ƒ†•Šƒ‹‰ —Ž–—”‡ ‘†‹–‹‘•ǡ ‹ Ž—†‹‰ ˜ʹ͸ʹ͵ ˆ”‘ ƒ ‘˜‡Ž Žƒ•• ‘ˆ ’—–ƒ–‹˜‡ Ǧ„‹†‹‰ ’”‘–‡‹•Ǥ Infect.Immun. ͸ͻ: ͷ͹͹͹Ǧͷ͹ͺͷǤ ‘•—‹Žǡ Ǥ

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