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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)  Chapter6 Cross-reactive immunity to Mycobacterium tuberculosis DosR regulon encoded antigens in individuals infected with environmental, non-tuberculous mycobacteria              ƒ›‘—‰‹ͳǡǤǤǤ‡††›ʹǡƒ†”ƒǤ”‡†ͳǡ‡‹‡‡ Ǥ ”‹‰‰‡ͳǡ‡‡•ǤǤǤ ”ƒ‡ͳǡ”‹•–ƒǤ˜ƒ‡‹Œ‰ƒƒ”†‡ͳǡƒ”Ž‡‡ ǤǤ‡”†—›ͳǡ ƒ”›Ǥ Š‘‘Ž‹͵ǡ‹ Š‡ŽǤ Ž‡‹ͳǡ‘ ǤǤ––‡Š‘ˆˆͳ . ‡’ƒ”–‡–

(3) ˆ‡ –‹‘—•‹•‡ƒ•‡•ǡ‡‹†‡‹˜‡”•‹–›‡†‹ ƒŽ‡–”‡ǡŠ‡‡–Š‡”Žƒ†•ͳǢ ‡’ƒ”–‡–‘ˆ‹‘ Š‡‹•–”›ʹƒ†‡’ƒ”–‡–‘ˆ‡†‹ ‹‡ǡ‹˜‹•‹‘‘ˆ

(4) ˆ‡ –‹‘—•‹•‡ƒ•‡•ƒ†. ‡‘‰”ƒ’Š‹ ‡†‹ ‹‡͵ǡ–ƒˆ‘”†‹˜‡”•‹–› Š‘‘Ž‘ˆ‡†‹ ‹‡ǡƒŽ‘Ž–‘ǡǡ  InfectImmun.2009Nov:77(11):50715079.

(5) Chapter6. Abstract Mycobacterium tuberculosis ȋM. tuberculosisȌ ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ƒ”‡ Š‹‰ŠŽ›‹—‘‰‡‹ ‹M.tuberculosisǦ‹ˆ‡ –‡†Š—ƒ•ƒ†ƒ••‘ ‹ƒ–‡†™‹–ŠŽƒ–‡– ‹ˆ‡ –‹‘Ǥ‡Šƒ˜‡‹˜‡•–‹‰ƒ–‡†–Š‡Š›’‘–Š‡•‹•–Šƒ–‹ˆ‡ –‹‘™‹–Š‘”‡š’‘•—”‡–‘‘Ǧ –—„‡” —Ž‘—• › ‘„ƒ –‡”‹ƒ ȋȌ ƒ ‹†— ‡ ”‘••Ǧ”‡ƒ –‹˜‡ ‹—‹–› –‘ M. tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡••‹ ‡”‡•’‘•‹˜‡‡••Šƒ•„‡‡‘„•‡”˜‡† ‹‘ǦM.tuberculosis‡š’‘•‡†„—–”‡•’‘•‹˜‡‹†‹˜‹†—ƒŽ•Ǥ M.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•’‡ ‹ˆ‹ Ǧ ‡ŽŽ”‡•’‘•‡•™‡”‡•–—†‹‡† ‹  ‘ˆ  ‹ˆ‡ –‡†Ȁ‡š’‘•‡† ‹†‹˜‹†—ƒŽ•Ǥ  ™ƒ• —•‡† –‘ †‡–‡”‹‡ –Š‡ ’”‡•‡ ‡ ‘ˆ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ’”‘–‡‹ ‘”–Š‘Ž‘‰• ƒ‘‰ ‡˜‹”‘‡–ƒŽ› ‘„ƒ –‡”‹ƒƒ†‘Ǧ› ‘„ƒ –‡”‹ƒǤ ‹‰‹ˆ‹ ƒ–

(6) J ’”‘†— –‹‘ ™ƒ• ‘„•‡”˜‡† ‹  ˆ”‘  ‹ˆ‡ –‡†Ȁ‡š’‘•‡† ‹†‹˜‹†—ƒŽ• ‹ ”‡•’‘•‡ –‘ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡•Ǥ  ‘•Ǧ ”‡‰—Ž‘ ‡ ‘†‡† ’”‘–‡‹ ‘”–Š‘Ž‘‰• ™‡”‡ ’”‘‹‡–Ž› ’”‡•‡– ‹ –—„‡” —Ž‘—•Ǧ ƒ† ‡˜‹”‘‡–ƒŽ › ‘„ƒ –‡”‹ƒǡ ƒ† •—”’”‹•‹‰Ž› ƒŽ•‘ ‹ ‘Ǧ› ‘„ƒ –‡”‹ƒǤ Š‡ —„‹“—‹–‘—•’”‡•‡ ‡‘ˆ–Š‡Š‹‰ŠŽ› ‘•‡”˜‡†‘•ƒ•–‡””‡‰—Žƒ–‘”Ǧ’”‘–‡‹˜͵ͳ͵͵  •—‰‰‡•–•–Šƒ––Š‹•‹•ƒ‰‡‡”ƒŽƒ†ƒ’–‹˜‡„ƒ –‡”‹ƒŽ”‡•’‘•‡Ǧ”‡‰—Žƒ–‘”Ǥ ‡”‡’‘”–ƒˆ‹”•–•‡”‹‡•‘ˆM.tuberculosisƒ–‹‰‡•–‘™Š‹ Š ”‘••Ǧ”‡ƒ –‹˜‡‹—‹–› ‹•‹†— ‡†„›‹ˆ‡ –‹‘Ȁ‡š’‘•—”‡ǤŠ‡Š‹‰Š ‘•‡”˜ƒ–‹‘‘ˆM.tuberculosis‘•Ǧ ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ‘•– Ž‹‡Ž› ‡ƒ„Ž‡• –Š‡ –‘ ‹†— ‡ ”‘•• ”‡ƒ –‹˜‡ Ǧ ‡ŽŽ ”‡•’‘•‡•Ǥ. ͳʹͲ.

(7) NTMinducedresponsestoM.tuberculosisDosRantigens. Introduction ‡ƒ”Ž›ǡ–—„‡” —Ž‘•‹•ȋȌ Žƒ‹•ͳǤ͹‹ŽŽ‹‘Ž‹˜‡•Ǥ

(8) –•‰Ž‘„ƒŽ‹ ‹†‡ ‡‡š ‡‡†•ͻ‹ŽŽ‹‘ ‡™ ƒ•‡•Ǥ‘”„‹†‹–›ƒ†‘”–ƒŽ‹–›ƒ”‡Ž‹‡Ž›–‘‹ ”‡ƒ•‡ˆ—”–Š‡”ƒ•ƒ”‡•—Ž–‘ˆ ”‡ƒ –‹˜ƒ–‹‘ ‹

(9) ǦͳȀMycobacterium tuberculosis ȋM. tuberculosisȌ ‘Ǧ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ•ǡ ƒ• ™‡ŽŽ ƒ• –Š‡ ”‹•‹‰ ˆ”‡“—‡ ‹‡• ‘ˆ —Ž–‹Ǧ†”—‰ ”‡•‹•–ƒ– ȋȌ ƒ† ‡š–‡•‹˜‡Ž› †”—‰ ”‡•‹•–ƒ– ȋȌ M. tuberculosis •–”ƒ‹• ȋͶͳȌǤ

(10) – ‹• ‡•–‹ƒ–‡† –Šƒ– ʹ „‹ŽŽ‹‘ ’‡‘’Ž‡ ƒ””› ƒ Žƒ–‡–  ‹ˆ‡ –‹‘ ȋ

(11) ȌǤ Š‹• ˜ƒ•– ”‡•‡”˜‘‹” ˆ‘”• ƒ ƒŒ‘” •‘—” ‡‘ˆ‡™ ƒ•‡•ǣ‘‡‘—–‘ˆ‡˜‡”›–‡M.tuberculosis‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•™‹ŽŽ †‡˜‡Ž‘’ƒ –‹˜‡†‹•‡ƒ•‡ƒ–‘‡’‘‹–‹–Š‡‹”Ž‹ˆ‡–‹‡ǡ™Š‹Ž‡–Š‡”‡ƒ‹†‡”‹•ƒ„Ž‡–‘ ‘–ƒ‹–Š‡„ƒ ‹ŽŽ‹™‹–Š‘—–ƒ› Ž‹‹ ƒŽ•›’–‘•Ǥ

(12)  ƒ •‡”‹‡• ‘ˆ ”‡ ‡– M. tuberculosis ƒ–‹‰‡ †‹• ‘˜‡”› •–—†‹‡•ǡ ƒ‹‹‰ ƒ– ‹†‡–‹ˆ›‹‰ ‡™M.tuberculosis„‹‘ƒ”‡”ƒ†˜ƒ ‹‡ƒ–‹‰‡•ǡ™‡ˆ‘—†–Šƒ–‰‡‡•ˆ”‘–Š‡M. tuberculosis ‘• ȋ˜͵ͳ͵͵ Ȍ ”‡‰—Ž‘ ‡ ‘†‡ ƒ–‹‰‡• –Šƒ– ƒ ‹†— ‡ •’‡ ‹ˆ‹  Ǧ ‡ŽŽ ‹—‹–›‹M.tuberculosis‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•ȋʹͲǡ͵ʹȌǤ—„‡” Ž‡„ƒ ‹ŽŽ‹‡š’”‡••–Š‡ ‘• ”‡‰—Ž‘ —†‡” in vitro ‘†‹–‹‘• ‘ˆ Š›’‘š‹ƒǡ Ž‘™ †‘•‡ ‹–”‹  ‘š‹†‡ ȋͶͲȌ ƒ† ƒ”„‘ ‘‘š‹†‡ǡ ȋͳͻǡ ͵͹Ȍ ‘†‹–‹‘• –Š‘—‰Š– –‘ „‡ ‡ ‘—–‡”‡† „› ’‡”•‹•–‹‰ ‹–”ƒ ‡ŽŽ—Žƒ” „ƒ ‹ŽŽ‹ ‹ –Š‡ ‹—‘Ǧ ‘’‡–‡– Š‘•–Ǥ –—†‹‡• Šƒ˜‡ ƒŽ•‘ ”‡’‘”–‡† —’Ǧ ”‡‰—Žƒ–‡† ‡š’”‡••‹‘ ‘ˆ ‘• ”‡‰—Ž‘ ‰‡‡• ‹ ‹ˆ‡ –‡† —”‹‡ ƒ ”‘’Šƒ‰‡• ƒ† ‹ˆ‡ –‡† —”‹‡ Ž—‰ –‹••—‡• ȋͳͻǡ ͵ͷǦ͵͹ȌǤ

(13) ’‘”–ƒ–Ž›ǡ ‹—‹–› –‘ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ‹‰Š– ‘–”‹„—–‡ –‘ –Š‡ ‘–”‘Ž ‘ˆ ’‡”•‹•–‡– M. tuberculosis ‹ˆ‡ –‹‘ •‹ ‡ •‡˜‡”ƒŽ ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ™‡”‡ ’”‡ˆ‡”‡–‹ƒŽŽ› ”‡ ‘‰‹œ‡† „› •—„Œ‡ –• ™‹–Š 

(14)  ȋʹͲǡ ͵ʹȌǤ ‹ƒŽŽ›ǡ ™‡ ƒŽ•‘ ˆ‘—† –Šƒ–   ˜ƒ ‹ƒ–‹‘ †‘‡• ‘– ‹†— ‡ ‹—‡ ”‡•’‘•‡•–‘ M.tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡•ǡ ™Š‹ Š ‹‰Š– ’ƒ”–Ž› —†‡”Ž‹‡ ‹–• ‹‡ˆˆ‹ ƒ › ƒ‰ƒ‹•– Žƒ–‡ M. tuberculosis‹ˆ‡ –‹‘ȋͳ͸ǡʹͳȌǤ —”‹‰ –Š‡•‡ •–—†‹‡•ǡ ™‡ —‡š’‡ –‡†Ž› ‘„•‡”˜‡† –Šƒ– •‘‡ M. tuberculosis ‘•Ǧ ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ™‡”‡ ƒŽ•‘ ”‡ ‘‰‹œ‡† „› Š‡ƒŽ–Š› ‘–”‘Ž• ȋ Ȍ ™Š‘ Šƒ† ƒ ’‘•‹–‹˜‡‹˜‹–”‘

(15) J”‡•’‘•‡–‘’—”‹ˆ‹‡†’”‘–‡‹†‡”‹˜ƒ–‹˜‡ȋȌ‘”M.tuberculosis Ž›•ƒ–‡Ǥ ‘™‡˜‡”ǡ ‘‡ ‘ˆ –Š‡•‡ –—„‡” —Ž‹ •‹ –‡•– ȋȌ ‡‰ƒ–‹˜‡  Šƒ† Šƒ† ƒ› ‘™ ‡š’‘•—”‡ –‘ ‘” ‹ˆ‡ –‹‘ ™‹–Š M. tuberculosisǡ ‘” Šƒ† ”‡ ‡‹˜‡†   ȋʹͲȌǤ  ‡ –Š‡”‡ˆ‘”‡ Š›’‘–Š‡•‹œ‡† –Šƒ– –Š‡•‡ ”‡•’‘•‡• ‘—Ž† „‡ †—‡ –‘ ‡š’‘•—”‡ –‘ ‡˜‹”‘‡–ƒŽǡ‘Ǧ–—„‡” —Ž‘—•› ‘„ƒ –‡”‹ƒȋȌǤ  ‘’”‹•‡ ƒŽŽ › ‘„ƒ –‡”‹ƒŽ •’‡ ‹‡• –Šƒ– ƒ”‡ ‘– ‹ Ž—†‡† ™‹–Š‹ –Š‡ M. tuberculosis ‘’Ž‡š ȋM. tuberculosisǡ M. bovisǡ M. bovis  ǡ Mycobacterium africanumǡ Mycobacterium microtiǡ ƒ† Mycobacterium canettiȌ ‘” Mycobacterium leprae ȋͺǡ ʹͺȌǤ  ƒ”‡ ˆƒ —Ž–ƒ–‹˜‡ ‹–”ƒ ‡ŽŽ—Žƒ” „ƒ –‡”‹ƒ ™‹–Š •’‡ ‹ˆ‹  ‹ Š‡• ‹ –Š‡ ‡˜‹”‘‡–ǡƒ”‡—„‹“—‹–‘—•Ž›’”‡•‡–ƒ†‘’’‘”–—‹•–‹ Ǥ‹ƒ‰‘•‹•ƒ†–”‡ƒ–‡–‘ˆ Ž—‰ ‹ˆ‡ –‹‘• ƒ—•‡† „›  ‹˜‘Ž˜‡• ƒ”‡ˆ—Ž ‡˜ƒŽ—ƒ–‹‘ ‘ˆ –Š‡ ‹ˆ‡ –‹‘ •‹ ‡ ‘ ”‡ˆ‡”‡ ‡ •–ƒ†ƒ”† ‘” ’ƒ”ƒ‡–‡” ‡š‹•–• „› ™Š‹ Š –Š‡ †‹ˆˆ‡”‡–  ƒ „‡ Šƒ”ƒ –‡”‹œ‡† ȋͷȌǤ

(16) – Šƒ• Ž‘‰ „‡‡ •—•’‡ –‡† –Šƒ– ‡š’‘•—”‡ –‘  ƒ •Šƒ’‡ Š‘•– ‹—‹–›Ǥ ‘” ‡šƒ’Ž‡ǡ ‡‘ƒ–ƒŽ   ˜ƒ ‹ƒ–‹‘ ”‡•—Ž–• ‹ •‹‰‹ˆ‹ ƒ– ’”‘–‡ –‹‘ ƒ‰ƒ‹•–’‡†‹ƒ–”‹ ǡ„—–‰‡‡”ƒŽŽ›ˆƒ‹Ž•–‘’”‘–‡ –ƒ†‡“—ƒ–‡Ž›ƒ‰ƒ‹•–’—Ž‘ƒ”›‹ ƒ†—Ž–•Ǣ–Š‹•Žƒ––‡”ˆƒ‹Ž—”‡Šƒ•„‡‡ƒ––”‹„—–‡†‹’ƒ”––‘–Š‡‹—‘‘†—Žƒ–‘”›‡ˆˆ‡ –•. ͳʹͳ.

(17) Chapter6. ‘ˆ‡š’‘•—”‡Ȁ‹ˆ‡ –‹‘ȋʹǡ͹ǡͳͲǡʹ͸ȌǡƒŽ–Š‘—‰Š–Š‡‹‡–‹ •‘ˆ–Š‡Žƒ––‡”ƒ•™‡ŽŽƒ• –Š‡—†‡”Ž›‹‰‡ Šƒ‹••‹˜‘Ž˜‡†”‡ƒ‹—†‡ˆ‹‡†Ǥ ‡”‡ǡ ™‡ Šƒ˜‡ ‹˜‡•–‹‰ƒ–‡† ™Š‡–Š‡” ‹ˆ‡ –‹‘ ™‹–Š ‘” ‡š’‘•—”‡ –‘  ƒ ‹†— ‡ ”‘••Ǧ”‡ƒ –‹˜‡ ‹—‹–› –‘ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡•Ǥ ‡ ƒŽ•‘ •–—†‹‡†–Š‡’”‡•‡ ‡‘ˆM.tuberculosis‘•”‡‰—Ž‘’”‘–‡‹‘”–Š‘Ž‘‰•ƒ†Š‘‘Ž‘‰• ƒ‘‰› ‘„ƒ –‡”‹ƒƒ†•‡˜‡”ƒŽ‘Ǧ› ‘„ƒ –‡”‹ƒŽ•’‡ ‹‡•Ǥ . MaterialsandMethod Studysubjects ‡ Š—†”‡† ƒ† –Š‹”–›Ǧ•‡˜‡ —– Š •—„Œ‡ –• ™‡”‡ ‹ Ž—†‡† ‹ –Š‹• •–—†›ǣ ͺͲ „Ž‘‘† „ƒ†‘‘”•Ǣ͵͵Š‡ƒŽ–Š›ǡM.tuberculosis—‡š’‘•‡†ǡ ‘Ǧ˜ƒ ‹ƒ–‡†‹†‹˜‹†—ƒŽ•Ǣ ͳʹ  ‹ˆ‡ –‡† •—„Œ‡ –•Ǣ ƒ† ͳʹ  ‡š’‘•‡† •—„Œ‡ –•Ǥ —ŽŽ Šƒ”ƒ –‡”‹•–‹ • ‘ˆ –Š‡ Žƒ––‡” –™‘ ‰”‘—’• Šƒ˜‡ „‡‡ †‡• ”‹„‡† ‹ †‡–ƒ‹Ž ‡Ž•‡™Š‡”‡ ȋͶȌǤ

(18)  „”‹‡ˆǡ ™‡ ‹ Ž—†‡† ’ƒ–‹‡–•ˆ‘”™Š‘M.marinumȋα͹ȌŠƒ†„‡‡ —Ž–—”‡†ˆ”‘ƒ–›’‹ ƒŽŽ‡•‹‘‘–Š‡ Šƒ† ‘” ˆ‘”‡ƒ”Ǥ ‘ †‹• ”‹‹ƒ–‡ „‡–™‡‡ ‹ˆ‡ –‹‘ ƒ† ‘Ž‘‹œƒ–‹‘ǡ M. kansasii ȋαͷȌ ‹ˆ‡ –‹‘ ™ƒ• †‡ˆ‹‡† „› Šƒ”ƒ –‡”‹•–‹  ”ƒ†‹‘‰”ƒ’Š‹  ƒ„‘”ƒŽ‹–‹‡• ‹ ‘„‹ƒ–‹‘ ™‹–Š ƒ ’‘•‹–‹˜‡ —Ž–—”‡ ˆ”‘ ƒ „”‘ Š‘• ‘’‹  ™ƒ•Š‹‰ ‘” Ž—‰ „‹‘’•› •’‡ ‹‡ ‘” ƒ– Ž‡ƒ•– ʹ ’‘•‹–‹˜‡ •’—–— —Ž–—”‡•ǡ ‹ –Š‡ ƒ„•‡ ‡ ‘ˆ ƒ ƒŽ–‡”ƒ–‹˜‡ †‹ƒ‰‘•‹•Ǥ—””‡–Ž›ǡ‘”‡ˆ‡”‡ ‡•–ƒ†ƒ”†‘”’ƒ”ƒ‡–‡”‡š‹•–•„›™Š‹ Š‡š’‘•—”‡–‘ ‡˜‹”‘‡–ƒŽ› ‘„ƒ –‡”‹ƒ ƒ„‡ Šƒ”ƒ –‡”‹œ‡†‘”“—ƒ–‹ˆ‹‡†Ǥ

(19) †‹˜‹†—ƒŽ•‡š’‘•‡† –‘™‡”‡•‡Ž‡ –‡†„›”‡ƒ•‘‹‰–Šƒ–‡š’‘•—”‡™‘—Ž†„‡‘•–’”‘‘— ‡††—”‹‰ ”‡’‡ƒ–‡†ƒ†‹–‡•‡ ‘–ƒ –™‹–Š–Š‡ƒ–—”ƒŽŠƒ„‹–ƒ–‘ˆ‡˜‹”‘‡–ƒŽ„ƒ –‡”‹ƒǡ†—‡ –‘ ’”‘ˆ‡••‹‘ƒŽ ‘” ”‡ ”‡ƒ–‹‘ƒŽ ƒ –‹˜‹–‹‡•Ǥ ™‡”• ‘ˆ –”‘’‹ ƒŽ ˆ‹•Š –ƒ• ȋαͶȌǡ ˜‡–‡”‹ƒ”‹ƒ• ȋα͵Ȍ ƒ† ’”‘ˆ‡••‹‘ƒŽ ˆŽ‘™‡” ‰”‘™‡”• ȋαͷȌ ™‡”‡ •‡Ž‡ –‡† ƒ• ”‡’”‡•‡–ƒ–‹˜‡‰”‘—’•Ǥ–—†›•—„Œ‡ –•™‡”‡”‡ ”—‹–‡†ƒ––Š‡ƒ†ƒ––Š‡‡‰‹‘ƒŽ ‡ƒŽ–Š ‡”˜‹ ‡ ‹ ‡Ž‡‡ ȋȌǤ Š‡ •–—†› ’”‘–‘ ‘Ž• ȋʹͲ͹Ȁͻͻ ƒ† ͳ͵͸Ȁͻ͹Ȍ ™‡”‡ ƒ’’”‘˜‡†„›–Š‡

(20) •–‹–—–‹‘ƒŽ‡˜‹‡™‘ƒ”†‘ˆ–Š‡Ǥ ŽŽ •–—†› •—„Œ‡ –• ‡š ‡’– „Ž‘‘† „ƒ †‘‘”•ǡ ƒ•™‡”‡† ƒ “—‡•–‹‘ƒ‹”‡ ƒ„‘—–   ˜ƒ ‹ƒ–‹‘ǡ –”ƒ˜‡Ž Š‹•–‘”› ƒ† Š‹•–‘”‹  Ȁ ‘–ƒ –Ǥ ‘‡ ‘ˆ –Š‡ •–—†› •—„Œ‡ –• —•‡†‘”Šƒ†—•‡†‹—‘•—’’”‡••‹˜‡–”‡ƒ–‡–‘”„‡Ž‘‰‡†–‘ƒ”‹•‰”‘—’ˆ‘”

(21)  ‹ˆ‡ –‹‘Ǥ Ž‘‘† ™ƒ• ‘„–ƒ‹‡† „› ˜‡‹’— –—”‡ ƒˆ–‡” ™”‹––‡ ‹ˆ‘”‡† ‘•‡– ™ƒ• ‘„–ƒ‹‡†Ǥ ‡”‹’Š‡”ƒŽ „Ž‘‘† ‘‘— Ž‡ƒ” ‡ŽŽ• ȋȌ ™‡”‡ ‹•‘Žƒ–‡† —•‹‰ ‹ ‘ŽŽ †‡•‹–› ‰”ƒ†‹‡– ‡–”‹ˆ—‰ƒ–‹‘ƒ†•–‘”‡†‹Ž‹“—‹†‹–”‘‰‡—–‹Ž—•‡Ǥ  M.tuberculosisantigens ‡ ‘„‹ƒ–’”‘–‡‹•ȋƒ„Ž‡ͳȌ™‡”‡’”‘†— ‡†ƒ•†‡• ”‹„‡†’”‡˜‹‘—•Ž›ȋͳͷȌǤ”‹‡ˆŽ›ǡ •‡Ž‡ –‡† M. tuberculosis ͵͹˜ ‰‡‡• ™‡”‡ ƒ’Ž‹ˆ‹‡† „›  ˆ”‘ ‰‡‘‹  ͵͹˜ ƒ† Ž‘‡†„› ƒ–‡™ƒ›‡ Š‘Ž‘‰›ȋ

(22) ˜‹–”‘‰‡ǡƒ‹‡‰‘ȌǤ”‘–‡‹•™‡”‡‘˜‡”Ǧ ‡š’”‡••‡† ‹ Escherichia coli •–”ƒ‹ ʹͳȋ͵Ȍ ƒ† ’—”‹ˆ‹‡† ƒ• †‡• ”‹„‡† ȋͳͷȌǤ ‡ ‘„‹ƒ– ’”‘–‡‹• ™‡”‡ •—„Œ‡ –‡† –‘ “—ƒŽ‹–› ƒ••—”ƒ ‡ ƒ† “—ƒŽ‹–› ‘–”‘Ž ȋȀȌ ƒ••ƒ›• ƒ• †‡• ”‹„‡† ‹ ȋʹͳȌ ‹ Ž—†‹‰ –‡•–‹‰ ˆ‘” ”‡•‹†—ƒŽ ‡†‘–‘š‹ Ž‡˜‡Ž•ǡ ƒ„•‡ ‡‘ˆ‘Ǧ•’‡ ‹ˆ‹  ‡ŽŽ•–‹—Žƒ–‹‘‹‘”‡•’‘•‹˜‡†‘‘”•ƒ†ƒ„•‡ ‡ ‘ˆ ‡ŽŽ—Žƒ”–‘š‹ ‹–›ƒ•ƒ••‡••‡†„›Žƒ ‘ˆ‹Š‹„‹–‹‘‘ˆ‹–‘‰‡‹†— ‡†’”‘Ž‹ˆ‡”ƒ–‹‘Ǥ. ͳʹʹ.

(23) NTMinducedresponsestoM.tuberculosisDosRantigens. •”‡ˆ‡”‡ ‡ƒ–‹‰‡•ȋͶͻǢ

(24) ǡ‡ƒ”Ȍƒ†M.tuberculosisǮŠ›’‘š‹ ǯŽ›•ƒ–‡ ȋ͵ͳǡͶ͵ǡͶͶȌ™‡”‡—•‡†ȋ’”‘˜‹†‡†„›”Ǥ‡–‡”†‡”•‡ǡ

(25) ǡ‡ƒ”ȌǤ ›–Š‡–‹  ’‡’–‹†‡• ˆ”‘ Ǧ͸ ƒ†  ǦͳͲ ™‡”‡ ’”‘†— ‡† ƒ• ’”‡˜‹‘—•Ž› †‡• ”‹„‡† ȋͳ͹ȌǤ ‘” „‘–Š ƒ–‹‰‡•ǡ ‹‡ ’‡’–‹†‡• ȋʹͲ ƒƒ ™‹–Š ͳͲ ƒƒ ‘˜‡”Žƒ’Ȍ •’ƒ‹‰ –Š‡ ‘’Ž‡–‡’”‘–‡‹•‡“—‡ ‡™‡”‡•›–Š‡•‹œ‡†Ǥ  Lymphocytestimulationassay ›’Š‘ ›–‡•–‹—Žƒ–‹‘ƒ••ƒ›•™‡”‡’‡”ˆ‘”‡†ƒ•’”‡˜‹‘—•Ž›†‡• ”‹„‡†ȋʹͲȌǤ”‹‡ˆŽ›ǡ ȋͳǤͷέͳͲͷȀ™‡ŽŽȌ™‡”‡ —Ž–—”‡†‹

(26) ȋ ‹„ ‘ǡƒ‹•Ž‡›ǡȌ•—’’Ž‡‡–‡†™‹–Š ͳͲΨ’‘‘Ž‡†Š—ƒ•‡”—ǡͷͲȀŽ’‡‹ ‹ŽŽ‹ƒ†ͷͲP‰ȀŽ•–”‡’–‘› ‹ǡ‹ͻ͸Ǧ™‡ŽŽ ”‘—†Ǧ„‘––‘ ‹ ”‘–‹–‡” ’Žƒ–‡• ȋ— ǡ ‘•‹Ž†‡ǡ ‡ƒ”Ȍ ƒ– ͵͹qǡ ͷΨ ʹǡ ‹ –Š‡ ƒ„•‡ ‡‘”’”‡•‡ ‡‘ˆ•–‹—Žƒ–ȋ‹–”‹’Ž‹ ƒ–‡ȌǤŠ‡ˆ‘ŽŽ‘™‹‰ƒ–‹‰‡ ‘ ‡–”ƒ–‹‘• ™‡”‡—•‡†ǣƒŽŽM.tuberculosis”‡ ‘„‹ƒ–’”‘–‡‹•ƒ–ͲǤ͵͵Pȋƒ˜‡”ƒ‰‡ ‘ ‡–”ƒ–‹‘ ͺρ‰ȀŽǡ”ƒ‰‡ͶǤ͵Ǧͳ͸ǤʹȌǡM.tuberculosisŠ›’‘š‹ Ž›•ƒ–‡ƒ†„‘–Šƒ–ͷP‰ȀŽƒ† ’‡’–‹†‡’‘‘Ž•‘ˆǦ͸ƒ† ǦͳͲƒ–ͳP‰ȀŽˆ‘”‡ƒ Š’‡’–‹†‡ǤŠ›–‘Šƒ‡ƒ‰‰Ž—–‹‹ ȋ Ǣ ‡‡Žǡ ǡ ʹ P‰ȀŽȌ ƒ† ‡†‹— ™‡”‡ —•‡† ƒ• ’‘•‹–‹˜‡ ƒ† ‡‰ƒ–‹˜‡ ‘–”‘Ž ”‡•’‡ –‹˜‡Ž›Ǥ–†ƒ›͸ǡ•—’‡”ƒ–ƒ–•™‡”‡Šƒ”˜‡•–‡†ƒ†•–‘”‡†ƒ–ȂʹͲ‘—–‹Ž—•‡Ǥ  DetectionofIFNJJbyELISA

(27) J ‘ ‡–”ƒ–‹‘• ™‡”‡ ‡ƒ•—”‡† „› 

(28)  ȋǦ›‡ Šǡ –”‡ Š–ǡ Ȍ ƒ• ’”‡˜‹‘—•Ž› †‡• ”‹„‡†ȋʹͲȌǤŠ‡†‡–‡ –‹‘Ž‹‹–‘ˆ–Š‡ƒ••ƒ›™ƒ•ʹͲ’‰ȀŽǤƒŽ—‡•‘ˆ—•–‹—Žƒ–‡† —Ž–—”‡• ȋ‡†‹ƒ ‘ ‡–”ƒ–‹‘ ʹͲ ’‰ȀŽǡ ”ƒ‰‡ ʹͲǦͳͺͶȌ ™‡”‡ •—„–”ƒ –‡† ˆ”‘ •–‹—Žƒ–‡† —Ž–—”‡• –‘ ‘„–ƒ‹ –Š‡ ƒ–‹‰‡‹  ”‡•’‘•‡•Ǥ ‡•’‘•‡• ™‡”‡ ”‡‰ƒ”†‡† ’‘•‹–‹˜‡‹ˆ–Š‡”‡•’‘•‡™ƒ•tͳͲͲ’‰ȀŽǤ  AssessmentofDosRproteinorthologsinenvironmental(myco)bacteria. ‡‡ Š‘‘Ž‘‰• ƒ”‡ ‰‡‡• ‹ †‹ˆˆ‡”‡– •’‡ ‹‡• –Šƒ– †‡• ‡†‡† ˆ”‘ ƒ ‘‘ ƒ ‡•–”ƒŽ•‡“—‡ ‡Ǥ ‡‡Š‘‘Ž‘‰•ƒ”‡ˆ—”–Š‡”•’‡ ‹ˆ‹‡†ƒ•‘”–Š‘Ž‘‰•™Š‡–Š‡› Šƒ˜‡”‡–ƒ‹‡†–Š‡•ƒ‡ˆ— –‹‘‹–Š‡†‹ˆˆ‡”‡–•’‡ ‹‡•Ǥ ‡”‡ǡ’”‘–‡‹‘”–Š‘Ž‘‰•ˆ‘”M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ™‡”‡ ‹†‡–‹ˆ‹‡† ƒ• ”‡ ‹’”‘ ƒŽ „‡•– ƒ– Š‡•Ǥ”‘–‡‹•‡“—‡ ‡•–Šƒ–™‡”‡•‘—” ‡†ˆ”‘ƒ–‹‘ƒŽ‡–‡”ˆ‘”‹‘–‡ Š‘Ž‘‰›

(29) ˆ‘”ƒ–‹‘ ȋ

(30) Ȍ ƒ† ƒ‘–ƒ–‡† ƒ– —„‡” —Ž‘•‹• ƒ–ƒ„ƒ•‡ ȋ͵ͲȌ ™‡”‡ —•‡† ‹ –Š‹• ƒƒŽ›•‹•Ǥ •‹‰ „ƒ•‹  Ž‘ ƒŽ ƒŽ‹‰‡– •‡ƒ” Š –‘‘Ž ȋȌ ’”‘‰”ƒ ȋͳȌǡ ’”‘–‡‹ •‡“—‡ ‡•ˆ”‘M.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•™‡”‡ ‘’ƒ”‡†™‹–Š ‘–Š‡”ȋ› ‘Ȍ„ƒ –‡”‹ƒŽ•’‡ ‹‡•ƒ†˜‹ ‡Ǧ˜‡”•ƒǤ‡ ‹’”‘ ƒŽ„‡•–ƒ– Š‹‰’ƒ‹”•„‡–™‡‡ M.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ƒ†–Š‘•‡‘ˆ‘–Š‡”•™‡”‡‹†‡–‹ˆ‹‡†ƒ• ‘”–Š‘Ž‘‰ ’ƒ‹”•Ǥ Š‡ –Š‡”‡ ™ƒ• ‘ ”‡ ‹’”‘ ƒŽ „‡•– ƒ– Šǡ ƒ Š‹– –Šƒ– ’”‘†— ‡† –Š‡ Š‹‰Š‡•– ’‡” ‡– •‹‹Žƒ”‹–› • ‘”‡ ™ƒ• –ƒ‡ ƒ• „‡•– Š‘‘Ž‘‰Ǥ  —–Ǧ‘ˆˆ ˜ƒŽ—‡ ‘ˆ ͶͲΨ •‹‹Žƒ”‹–›• ‘”‡™ƒ•—•‡†Ǥ  Statisticalanalysis Š‡‹Ž ‘š‘•‹‰‡†”ƒ–‡•–™ƒ•—•‡†–‘ ‘’ƒ”‡–Š‡”‡•’‘•‡•’‡”ƒ–‹‰‡‹–Š‡ •–—†›’‘’—Žƒ–‹‘–‘–Š‡—•–‹—Žƒ–‡†ȋ‡†‹—Ȍ ‘†‹–‹‘ǤŠ‡‘ˆ‡””‘‹ ‘””‡ –‹‘ ȋ ‘””‡ –‡†PǦ˜ƒŽ—‡αͳǦȋͳǦPȌȌ™ƒ•ƒ’’Ž‹‡†ƒ•’‘•–ǦŠ‘ ƒ†Œ—•–‡–ǤŠ‡”—•ƒŽǦƒŽŽ‹• –‡•– ™ƒ• —•‡† ˆ‘” ‘’ƒ”‹•‘ „‡–™‡‡ ‰”‘—’• ƒ† ˆ‘ŽŽ‘™‡† „› —• ’‘•–ǦŠ‘  –‡•– ™Š‡ ƒ’’”‘’”‹ƒ–‡Ǥ ŽŽ •–ƒ–‹•–‹ ƒŽ ƒƒŽ›•‡• ™‡”‡ ’‡”ˆ‘”‡† ‘ –Š‡ ”ƒ™ †ƒ–ƒ ȋ‹Ǥ‡Ǥ ‘–. ͳʹ͵.

(31) Chapter6. ‘””‡ –‡†ˆ‘”–Š‡‡†‹—˜ƒŽ—‡•ȌǤ–ƒ–‹•–‹ ƒŽƒƒŽ›•‡•™‡”‡’‡”ˆ‘”‡†™‹–ŠͳͶǤͲ ƒ† ”ƒ’Šƒ†”‹•ͶǤͲʹǢPδͲǤͲͷ™ƒ• ‘•‹†‡”‡†–‘„‡•–ƒ–‹•–‹ ƒŽŽ›•‹‰‹ˆ‹ ƒ–Ǥ  . Results SelectionofM.tuberculosisDosRregulonencodedantigens ‹‰Š– ‘ˆ –Š‡ ‘•– ‹–‡”‡•–‹‰ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ™‡”‡ •‡Ž‡ –‡†ˆ‘”ˆ—”–Š‡”‹˜‡•–‹‰ƒ–‹‘ȋƒ„Ž‡ͳȌǤ‡Ž‡ –‹‘™ƒ•„ƒ•‡†‘Ǧ ‡ŽŽ”‡ ‘‰‹–‹‘ ’”‘ˆ‹Ž‡• ‹  ’ƒ–‹‡–•ǡ  ‘˜‡”–‡”• ƒ† Š‡ƒŽ–Š› —Ǧ‹ˆ‡ –‡† ‘–”‘Ž• ȋ Ȍ ‘„•‡”˜‡† ‹ ‘—” ‡ƒ”Ž‹‡” •–—†› ȋʹͲȌǣ ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ ˜ʹͲ͵ʹǡ ˜ʹ͸ʹ͹ ǡ ˜͵ͳʹͻ ”ƒ‡† ƒ‘‰ –Š‡ –‘’ ͳͲ ‘•– ˆ”‡“—‡–Ž› ”‡ ‘‰‹œ‡† ƒ–‹‰‡• ‹ ƒŽŽ –Š”‡‡ ‰”‘—’•Ǥ –‹‰‡• ˜ʹ͸ʹ͸  ƒ† ˜ʹ͸ʹͺ ™‡”‡ •‡Ž‡ –‡† ƒ• –Š‡› ”ƒ‡† ƒ‘‰ –Š‡ –‘’ ͳͲ ƒ–‹‰‡• ‹ ƒ– Ž‡ƒ•– –™‘ •–—†› ‰”‘—’•ǡ ‹ Ž—†‹‰ –Š‡  ‘˜‡”–‡”•Ǥ ˜ʹͲ͵ͳ  ȋͳ͸ Š‡ƒ–Ǧ•Š‘  ’”‘–‡‹ǡ •’ǡ ƒǦ ”›•–ƒŽŽ‹ȌȋͶʹȌ ™ƒ• •‡Ž‡ –‡† •‹ ‡ ‹– Šƒ• „‡‡ ”‡Žƒ–‹˜‡Ž› ™‡ŽŽ •–—†‹‡† ‹ ƒ–‹Ǧ› ‘„ƒ –‡”‹ƒŽ ‹—‹–›Ǥ ŽŽ ƒ–‹‰‡• ™‡”‡ –‡•–‡† ‹ ‡“—‹‘Žƒ” ‘ ‡–”ƒ–‹‘• –‘ ƒŽŽ‘™ ˆ‘” †‹”‡ – ‘’ƒ”‹•‘ ‘ˆ ‹—‘‰‡‹ ‹–› „‡–™‡‡ –Š‡ †‹ˆˆ‡”‡–’”‘–‡‹•ǡ•‹ ‡–Š‡›˜ƒ”‹‡†‹•‹œ‡ȋͳʹǤ͵ǦͶ͸Ǥ͵ƒȌǤ  Table1.SelectedM.tuberculosis DosR antigenstestedinpresentstudy ‘•‰‡‡ ˜ͳ͹͵͵ ˜ʹͲʹͻ ˜ʹͲ͵ͳ ˜ʹͲ͵ʹ ˜ʹ͸ʹ͸ ˜ʹ͸ʹ͹ ˜ʹ͸ʹͺ ˜͵ͳʹͻ a. ‡‡ ‘Ž‡ —Žƒ” a a ƒ‡ ƒ••ȋƒȌ pfkB hspX acg. ʹʹǤͶ ͵ͷǤͶ ͳ͸Ǥ͵ ͵͸Ǥ͸ ͳͷǤͷ Ͷ͸Ǥ͵ ͳ͵Ǥͳ ͳʹǤ͵. a. ”‘†— –. ‘•‡”˜‡†–”ƒ•‡„”ƒ‡’”‘–‡‹ Š‘•’Š‘ˆ”— –‘‹ƒ•‡ˆ ‡ƒ–•Š‘ ’”‘–‡‹ •’ȋƒŽ’ŠƒǦ ”›•–ƒŽŽ‹Ȍ ›’‘–Š‡–‹ ƒŽ’”‘–‡‹ ‰ ‘•‡”˜‡†Š›’‘–Š‡–‹ ƒŽ’”‘–‡‹ ‘•‡”˜‡†Š›’‘–Š‡–‹ ƒŽ’”‘–‡‹ ›’‘–Š‡–‹ ƒŽ’”‘–‡‹ ‘•‡”˜‡†Š›’‘–Š‡–‹ ƒŽ’”‘–‡‹. ‡ˆ‡”‡ ‡ ʹͲǡʹͳǡ͵ʹ ʹͲǡʹͳǡ͵ʹ ͳͳǡͳ͸ǡʹͲǡʹͳǡ͵ʹǡͶʹǦͶͶ ͳͶǡʹͲǡʹͻǡ͵ʹ ͸ǡʹͲǡʹͳǡ͵ͳǡ͵ʹǡ͵͸ ʹͲǡʹͳǡ͵ʹ ʹͲǡʹͳǡ͵ʹ ʹͲ. Annotationsarefromwww.tbdb.organdhttp://genolist.pasteur.fr/TubercuList/.  InvitroPPDresponsesinhealthyindividuals:asurveyamongsthealthyM. tuberculosisunexposeddonors. ‹˜‡ –Š‡ —„‹“—‹–‘—• ƒ–—”‡ ‘ˆ ǡ ‹– ‹• Ž‹‡Ž› –Šƒ– Š—ƒ• ƒ”‡ ‡š’‘•‡† –‘ǡ ƒ† ‹—‘Ž‘‰‹ ƒŽŽ› ’”‹‡† „›  ȋ͵ͻƒȌǤ ‡ –Š‡”‡ˆ‘”‡ ƒ••‡••‡† –Š‡ ‹ ˜‹–”‘ ”‡•’‘•‹˜‡‡•• –‘  ‹ –™‘ †‹ˆˆ‡”‡– ‰”‘—’• ‘ˆ Š‡ƒŽ–Š› ‹†‹˜‹†—ƒŽ• ƒ† ˆ‘” ‘’ƒ”‹•‘ǡ‹‡š’‘•‡†Ȁ‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•Ǥˆ‘–‡ǡ‹•‘–M.tuberculosisǦ •’‡ ‹ˆ‹  •‹ ‡ ‹– ‘–ƒ‹• ƒ› ƒ–‹‰‡• –Šƒ– ƒ”‡ ”‘••Ǧ”‡ƒ –‹˜‡ ™‹–Š ‘–Š‡” › ‘„ƒ –‡”‹ƒǡ‹ Ž—†‹‰ ƒ†Ǥ Š‡ ˆ‹”•– ‰”‘—’ ‘ˆ  ‘’”‹•‡† M. tuberculosis —‹ˆ‡ –‡†Ȁ—‡š’‘•‡†ǡ   —˜ƒ ‹ƒ–‡† ‹†‹˜‹†—ƒŽ• ȋαʹ͹ȌǤ ™‡–› ‹†‹˜‹†—ƒŽ• Šƒ† ƒ ‡‰ƒ–‹˜‡  ȋ–Š‡ ”‡ƒ‹‹‰•‡˜‡™‡”‡‘–Ǧ–‡•–‡†ȌǤ‡ ‘†Ž›ǡƒ‰”‘—’‘ˆŠ‡ƒŽ–Š›—– Š„Ž‘‘†„ƒ †‘‘”•ȋα͸͸Ȍ™ƒ•‹ Ž—†‡†ȋ—‘™Ǧ•–ƒ–—•ȌǤŠ‹•‰”‘—’™ƒ•Ž‡••™‡ŽŽ†‡ˆ‹‡† •‹ ‡ ‘ •’‡ ‹ˆ‹  ‹ˆ‘”ƒ–‹‘ ™ƒ• ƒ˜ƒ‹Žƒ„Ž‡ ‘ ‡”‹‰   ˜ƒ ‹ƒ–‹‘ ƒ†  ‡š’‘•—”‡Ȁ ‘–ƒ –Š‹•–‘”›Ǥ ‘™‡˜‡”ǡ‰‹˜‡–Š‡Ž‘™‹ ‹†‡ ‡‹–Š‡‡–Š‡”Žƒ†•ǡ  . ͳʹͶ.

(32) NTMinducedresponsestoM.tuberculosisDosRantigens.               Figure1.ResultsofaninvitroPPDsurveyinhealthyindividualsandNTMinfected/exposedindividuals.  Healthy controls were either a group of well defined healthy, M. tuberculosisuninfected, nonBCG vaccinated  individuals (n=27) or a group of random healthy blood bank donors (n=66). IFNJ responses to PPD were  measuredasanindicationofexposuretomycobacteria.Inboththehealthycontrolandthehealthybloodbank  donorgroups,overhalfortheindividuals,56%and68%respectively,responded(IFN J>100pg/ml)toPPD. TheproportionsofPPDrespondersintheNTMinfected(n=12)orexposed(n=12)individualswereboth75%,  andwereslightlyhighercomparedtothehealthycontrolgroups.Horizontalbarsshowmedianvalues.  ƒ†–Š‡Žƒ ‘ˆƒƒ–‹‘ƒŽ ˜ƒ ‹ƒ–‹‘’‘Ž‹ ›ǡ‘‡‘ˆ–Š‡•‡’ƒ”ƒ‡–‡”•™‘—Ž†„‡ ‡š’‡ –‡†–‘„‡‘ˆŠ‹‰Š•‹‰‹ˆ‹ ƒ ‡Š‡”‡Ǥ ‹‰—”‡ͳ•Š‘™•‹˜‹–”‘

(33) J”‡•’‘•‡•–‘‹„‘–Š‰”‘—’•‘ˆŠ‡ƒŽ–Š› ‘–”‘Ž•Ǥ

(34)  „‘–Š ‰”‘—’•ǡ ‘˜‡” ŠƒŽˆ ‘ˆ –Š‡ ‹†‹˜‹†—ƒŽ•ǡ ͷ͸Ψ ƒ† ͸ͺΨ ”‡•’‡ –‹˜‡Ž›ǡ ”‡•’‘†‡† ‹ ˜‹–”‘–‘ȋ

(35) JεͳͲͲ’‰ȀŽȌǤŽ–Š‘—‰Š–Š‡•‡”‡•’‘•‡•ƒ”‡‘•–Ž‹‡Ž›–Š‡”‡•—Ž–‘ˆ ‡š’‘•—”‡–‘ǡ‹–Š‡ ƒ•‡‘ˆ‘Ž†‡”„Ž‘‘†„ƒ†‘‘”•™‡ ƒ‘–ˆ‘”ƒŽŽ›‡š Ž—†‡ƒ ‘–”‹„—–‹‘ ‘ˆ ”‡‘–‡  ‡š’‘•—”‡ ‘”   ˜ƒ ‹ƒ–‹‘Ǥ Š‡ ’”‘’‘”–‹‘• ‘ˆ ‹ ˜‹–”‘ ”‡•’‘†‡”•‹–Š‡‹ˆ‡ –‡†Ȁ‡š’‘•‡†‰”‘—’ȋͳͺȀʹͶ‘ˆ–Š‡•‡‹†‹˜‹†—ƒŽ•Šƒ† „‡‡Ǧ–‡•–‡†Ǣ‘˜‡”ƒŽŽ™‹–Š‡‰ƒ–‹˜‡”‡•—Ž–Ȍ™‡”‡•Ž‹‰Š–Ž›Š‹‰Š‡”ǡ„‘–Š͹ͷΨǤ

(36)  ‰‡‡”ƒŽǡ –Š‡ Š‹‰Š Ž‡˜‡Ž• ‘ˆ ‹ ˜‹–”‘ ”‡•’‘•‹˜‡‡•• –‘  ‹ –Š‡•‡ •‡Ž‡ –‡† •–—†› ‰”‘—’•ƒ›„‡†—‡–‘–Š‡Š‹‰Š‡”•‡•‹–‹˜‹–›‘ˆ‹˜‹–”‘•‹šǦ†ƒ›ƒ••ƒ›• ‘’ƒ”‡†–‘–Š‡ Ǥ  Table2.CharacteristicsofNTMinfectedorexposedstudysubjectsincludedinthisstudy —„Œ‡ –‰”‘—’ M.marinum •‹’ƒ–‹‡–• M.kansasii Ž—‰’ƒ–‹‡–•. ‘‘ˆ •—„Œ‡ –•. ‡šǡ‘Ǥ‘ˆ‡Ȁ ‘Ǥ‘ˆ™‘‡. ‡ƒƒ‰‡ǡ›‡ƒ”• ȋ”ƒ‰‡Ȍ. ͹ ͷ. ͸Ȁͳ ͶȀͳ. ͷͺǤ͵ȋͶ͵ǤͳǦ͹ͶǤͺȌ ͷͶǤ͸ȋͶͲǤͷǦ͹͸ǤͶȌ. ˜ƒ ‹ƒ–‡† š’‘•‡†–‘ a ™‹–Š.  ͳȀ͹ ͲȀͷ. Ͳ Ͳ. Ž‹‹ ƒŽ•›’–‘• –›’‹ ƒŽƒ“—ƒ”‹—‰”ƒ—Ž‘ƒ b ƒ˜‹–ƒ”›’‡—‘‹ƒ. b. ‡†‹ƒ†—”ƒ–‹‘‘ˆ‡š’‘•—”‡ǡ ›‡ƒ”•ȋ”ƒ‰‡Ȍ “—ƒ”‹—‘™‡”• ‡–‡”‹ƒ”‹ƒ• Ž‘™‡”‰”‘™‡”• a b. Ͷ ͵ ͷ. ͵Ȁͳ ͵ȀͲ ͷȀͲ. ͷͶǤͶȋͶͲǤ͸Ǧ͸ʹǤ͵Ȍ ͵ͺǤͻȋ͵ͶǤ͸ǦͶͳǤ͸Ȍ Ͷ͸Ǥ͹ȋʹͺǤ͵Ǧͷ͸ǤͶȌ. ͲȀͶ ͲȀ͵ ͲȀͷ. Ͳ Ͳ Ͳ. ͵ͲǤͷȋͳͲǦͶͲȌ ͳͳȋͺǦ͵ͲȌ ͵ͺȋͳͷǦͶͶȌ. ǡ‡ ‡‹˜‡†ƒ†‹ƒ‰‘•‹•‘ˆƒ –‹˜‡ǡ™ƒ•‡š’‘•‡†–‘ƒ’ƒ–‹‡–™‹–Š’—Ž‘ƒ”›ǡ‘”™ƒ•‹ Ž—†‡†‹ƒ ‘–ƒ –‹˜‡•–‹‰ƒ–‹‘Ǥ ǡŽŽM.marinum ƒ†M.kansasii ‹ˆ‡ –‹‘•™‡”‡ —Ž–—”‡’”‘˜‡Ǥ.  . ͳʹͷ.

(37) Chapter6 A. NTM exposed/infected individuals.                 B PPD negative controls               Figure 2. IFNJ responses to M. tuberculosis antigens in NTM primed individuals and in healthy, PPD  )individuals.ResponsestoM.tuberculosisantigens:Mtblysate,Ag85B,ESAT6,CFP10,anda negative(PPD  seriesofeightDosRregulonencodedantigensweremeasuredinindividualsinfectedwith,orexposedintensely to   environmental mycobacteria (n=2417). Significant IFNJ production was measured in the NTM primed individuals (A). Also responses to different batches of recombinant M. tuberculosis antigens Ag85B, ESAT6,  CFP10 and eight DosRregulon encoded antigens were tested in different PPD individuals (maximally 20  different PPD individuals). No or low (statistically nonsignificant) responses to the various recombinant M. individuals(B).Thepercentageofrespondersisindicatedabove  tuberculosisantigenswereobservedinPPD each  column for each antigen. The Wilcoxon signed rank test was used for comparison of the height of the antigenic response to the negative control (medium) condition in (A). IFNJ responses t100 pg/ml were  consideredpositive.Horizontalbarsrepresentmedianvalues.PHA,phytohaemagglutenin;Mtblysate,lysateof  M.tuberculosisculturedunderlowoxygencondition.***,P<0.0001;**,P<0.01;*,P<0.05;ns,notsignificant.P  <0.05wasconsideredstatisticallysignificant.  InvitroIFNJJresponsestoselectedM.tuberculosisDosRregulonencoded antigensinindividualsinfectedwithorexposedtoenvironmentalmycobacteria ‡ ‡š– •–—†‹‡† ʹͶ •—„Œ‡ –• ™‹–Š ‡‹–Š‡” ’”‘˜‡  ‹ˆ‡ –‹‘ ȋαͳʹȌ ‘” •‹‰‹ˆ‹ ƒ– ‡š’‘•—”‡ –‘  ȋαͳʹȌ ȋƒ„Ž‡ ʹȌǤ –‹‰‡• ™‡”‡ –‡•–‡† ‹ ƒŽŽ ʹͶ •–—†› •—„Œ‡ –• ‡š ‡’– ˆ‘” ‰ͺͷǡ ˜ʹ͸ʹ͸ ǡ ˜ʹͲ͵ʹ ƒ†  ǦͳͲ ȋƒŽŽ ˆ‘—” ‹ αʹ͵Ȍǡ ƒ† ˜͵ͳʹͻ. ͳʹ͸.

(38) NTMinducedresponsestoM.tuberculosisDosRantigens. ȋαͳ͹Ȍǡ†—‡–‘‹•—ˆˆ‹ ‹‡–ƒ˜ƒ‹Žƒ„Ž‡ˆ”‘•‘‡†‘‘”•Ǥ ‘”ˆ‹˜‡‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ƒ •‹‰‹ˆ‹ ƒ– ”‡•’‘•‡ ™ƒ• ˆ‘—† ȋ˜ͳ͹͵͵ ǡ PαͲǤͲͲʹ͸Ǣ ˜ʹͲʹͻ ǡ PαͲǤͲͳͳǢ˜ʹͲ͵ʹǡPαͲǤͲ͵ͶͳǢ˜ʹ͸ʹ͸ ǡPαͲǤͲʹʹ͸ƒ†˜ʹ͸ʹ͹ ǡPαͲǤͲͲʹͷǢ‹Ž ‘š‘ •‹‰‡†”ƒ–‡•–Ȍǡ ‹‰—”‡ʹǤŠ‡‘ˆ‡””‘‹ ‘””‡ –‹‘™ƒ•’‡”ˆ‘”‡†ˆ‘ŽŽ‘™‹‰–Š‡ ‹Ž ‘š‘ •‹‰‡† ”ƒ –‡•–Ǥ Š‡ ‘ˆ‡””‘‹ ‘””‡ –‹‘ ‹• ”‡‰ƒ”†‡† ƒ• ‘•‡”˜ƒ–‹˜‡Ǣ ‘„‹‡†™‹–Š–Š‡•ƒŽŽ•–—†›’‘’—Žƒ–‹‘‹–ƒ›”‡•—Ž–‹ƒ—†‡”‡•–‹ƒ–‹‘‘ˆ–Š‡ •‹‰‹ˆ‹ ƒ ‡‘ˆ–Š‡”‡•—Ž–•Ǥ‡˜‡”–Š‡Ž‡••ǡˆ‘ŽŽ‘™‹‰–Š‹• ‘””‡ –‹‘–Š‡”‡•’‘•‡•–‘–™‘ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ”‡ƒ‹‡† •‹‰‹ˆ‹ ƒ–ǣ ˜ͳ͹͵͵  ȋPα ͲǤͲ͵͵Ȍƒ†˜ʹ͸ʹ͹ ȋPαͲǤͲ͵ʹȌǤ Š‡ Š‹‰Š‡•– ˆ”‡“—‡ › ‘ˆ ”‡•’‘†‡”• ™ƒ• †‡–‡ –‡† ˆ‘ŽŽ‘™‹‰ •–‹—Žƒ–‹‘ ™‹–Š ˜ͳ͹͵͵  ȋͶʹΨ ”‡•’‘•‡Ȍǡ ™Š‹Ž‡ ‘Ž› ͺΨ ”‡•’‘†‡† –‘ ˜ʹͲ͵ͳ  ȋ ‘ˆ‹”‹‰ ‘—” ’”‡˜‹‘—•‘„•‡”˜ƒ–‹‘•ȋʹͲȌȌǤ  •‹‰‹ˆ‹ ƒ– ’”‘’‘”–‹‘ ‘ˆ –Š‡ †‘‘”• ”‡•’‘†‡† –‘ ‘–”‘Ž ƒ–‹‰‡• ‰ͺͷ ȋͶ͵ΨȌǡ Ǧ͸ȋʹͷΨȌƒ† ǦͳͲȋ͵ͷΨȌǤŽŽ”‡•’‘•‡•–‘Ǧ͸ƒ† ǦͳͲ™‡”‡ ‘ˆ‹‡† –‘ –Š‡ ‹†‹˜‹†—ƒŽ• ™Š‘ ƒŽ•‘ ”‡•’‘†‡†–‘  ‘”M. tuberculosis Ž›•ƒ–‡Ǥ • ‡š’‡ –‡†ǡ ƒ› •—„Œ‡ –• ”‡•’‘†‡† –‘  ƒ† M. tuberculosis Ž›•ƒ–‡ǡ ͹ͷΨ ƒ† ͸͵Ψǡ ”‡•’‡ –‹˜‡Ž›Ǥ

(39) ’‘”–ƒ–Ž›ǡ–Š‡”‡•’‘•‡•ƒ†–Š‡’”‘’‘”–‹‘‘ˆ”‡•’‘†‡”•–‘M.tuberculosis‘•Ǧ ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ™‡”‡ Ž‘™ ȋ‘Ǧ•‹‰‹ˆ‹ ƒ–Ȍ ‘” ƒ„•‡– ‹ Š‡ƒŽ–Š› Ǧ ‡‰ƒ–‹˜‡and‹˜‹–”‘‡‰ƒ–‹˜‡‹†‹˜‹†—ƒŽ•ȋ ‹‰—”‡ʹȌƒ†M.tuberculosisŽ›•ƒ–‡ ‘Ǧ”‡•’‘•‹˜‡ ‹†‹˜‹†—ƒŽ• ȋʹͲȌ •Š‘™‹‰ –Šƒ– ”‡•’‘•‡• –‘ M. tuberculosis ‘•Ǧ ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ƒ”‡ ƒ••‘ ‹ƒ–‡† ™‹–Š › ‘„ƒ –‡”‹— ”‡•’‘•‹˜‡‡•• ƒ† ‡š’‘•—”‡Ǥ ƒ‡ –‘‰‡–Š‡”ǡ ‘—” ”‡•—Ž–• •Š‘™ –Šƒ– ‹†‹˜‹†—ƒŽ• ‹ˆ‡ –‡† ™‹–Šǡ ‘” ‡š’‘•‡† –‘ ‡˜‹”‘‡–ƒŽ › ‘„ƒ –‡”‹ƒǡ Šƒ˜‡ Š‹‰Š ƒ† •‹‰‹ˆ‹ ƒ–

(40) J ”‡•’‘•‡• –‘ ‹†‹˜‹†—ƒŽ ƒ–‹‰‡•‘ˆ–Š‡M.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ǤŠ‡ƒŒ‘”‹–›‘ˆ–Š‡•‡ ‹†‹˜‹†—ƒŽ•”‡•’‘†‡†–‘–Š‡ ‘’Ž‡š› ‘„ƒ –‡”‹ƒŽƒ–‹‰‡•ƒ†M.tuberculosis Š›’‘š‹  Ž›•ƒ–‡ ‹ –Š‡ ƒ„•‡ ‡ ‘ˆƒ›†‡–‡ –ƒ„Ž‡ M. tuberculosis ‡š’‘•—”‡ǡ ‘’ƒ–‹„Ž‡ ™‹–Š‹ˆ‡ –‹‘Ȁ‡š’‘•—”‡Ǥ  IFNJJresponsestoM.tuberculosisDosRregulonencodedantigensinindividual groupswithspecificNTMinfectionorexposure

(41)  –Š‡ ’”‡˜‹‘—• •‡ –‹‘ǡ ƒŽŽ  ‹ˆ‡ –‡†Ȁ‡š’‘•‡† ‹†‹˜‹†—ƒŽ• ™‡”‡ ƒƒŽ›œ‡† ƒ• ƒ •‹‰Ž‡ ‰”‘—’Ǥ ‡”‡ǡ ƒŽ–Š‘—‰Š —„‡”• ƒ”‡ ”‡Žƒ–‹˜‡Ž› •ƒŽŽǡ ”‡•—Ž–• ƒ”‡ ƒƒŽ›œ‡† ’‡” •—„‰”‘—’ǣ ‹‰—”‡ ͵ •Š‘™•

(42) J ”‡•’‘•‡• –‘ ǡ ‰ͺͷǡ Ǧ͸ǡ  ǦͳͲ ƒ† –‘ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͸  ƒ† ˜ʹ͸ʹ͹ ‹M.marinum’ƒ–‹‡–•ȋα͹ȌǡM.kansasii’ƒ–‹‡–•ȋαͷȌƒ†‡š’‘•‡† ‹†‹˜‹†—ƒŽ•ȋαͳʹȌǤ  —„‡” ‘ˆ ‹†‹˜‹†—ƒŽ• ”‡•’‘†‡†–‘ Ǧ͸ ƒ†  ǦͳͲ ƒŽ–Š‘—‰Š–Š‡•‡ ”‡•’‘•‡• ™‡”‡ Ž‘™ ‹ M. kansasii ‹ˆ‡ –‡† ‹†‹˜‹†—ƒŽ•Ǥ ‡•’‘•‡• –‘  ǦͳͲ ™‡”‡ •‹‰‹ˆ‹ ƒ–Ž› Š‹‰Š‡”‹–Š‡M.marinum‹ˆ‡ –‡†‰”‘—’ȋPδͲǤͲͷȌǡ‹Ž‹‡™‹–Š‘—”’”‡˜‹‘—•™‘”ȋͶȌǤ ˜‡”ƒŽŽǡ”‡•’‘•‡•–‘M.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ƒ”‡ˆ‘—†‹ƒŽŽ †‹ˆˆ‡”‡– •—„‰”‘—’•Ǥ ƒ”–‹ —Žƒ”Ž› –‘ ˜ʹͲʹͻ  ƒ† ˜ʹ͸ʹ͸  Š‹‰Š‡” ”‡•’‘•‡• ™‡”‡ ˆ‘—†‹‡š’‘•‡†”ƒ–Š‡”–Šƒ‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•. . ͳʹ͹.

(43) Chapter6.  . Figure 3. IFNJ responses to M. tuberculosis antigens PPD, Ag85B, ESAT6, CFP10 and M. tuberculosis DosR regulon encoded antigens Rv1733c, Rv2029c, Rv2626c and Rv2627c in individuals infected with M. marinum (n=7); M. kansasii (n=5); or intensely exposed to environmental mycobacteria (aquarium owners, flower growersandveterinarians,n=12(n=11inthecaseofCFP10,Ag85B,Rv2626c)).Horizontalbarsrepresent median values. As indicated earlier, IFNJ responses t100 pg/ml were considered positive. Statistical analysis wasperformedwiththeKruskalWallistest.IfP<0.05,analysiswascontinuedbyperformingDunn’sposthoc test,*,P<0.05,**,P<0.01.P<0.05wasconsideredstatisticallysignificant..  ThepresenceofM.tuberculosisDosRregulonproteinorthologsin environmental(myco)bacteria ™‡–›Ǧ•‡˜‡ „ƒ –‡”‹ƒŽ ‰‡‘‡• ™‡”‡ ƒƒŽ›œ‡† ˆ‘” –Š‡ ’”‡•‡ ‡ ‘ˆ ‘”–Š‘Ž‘‰• ‘ˆ –Š‡ ͶͺM.tuberculosis ͵͹˜‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ǤŠ‡•‡Ž‡ –‹‘‡ ‘’ƒ••‡† ˆ‘—” M. tuberculosis •–”ƒ‹• ȋͳͷͷͳǡ Ǯǯǡ Ǯ ͳͳǯ ƒ† Ǯ ƒƒ”Ž‡ǯȌǡ –Š”‡‡ –—„‡” —Ž‘—•ǡ ‘ǦM. tuberculosis •–”ƒ‹• ȋM. bovisǡ M. bovis   ƒ† M. lepraeȌǡ ‡‹‰Š–  •–”ƒ‹• ȋ‡Ǥ‰Ǥ M. marinumȌ ƒ† –™‡Ž˜‡ ‘–Š‡” ȋ‡˜‹”‘‡–ƒŽȌ „ƒ –‡”‹ƒ ȋ‡Ǥ‰Ǥ Streptomyces sppȌ ’Š›Ž‘‰‡‡–‹ ƒŽŽ›”‡Žƒ–‡†–‘› ‘„ƒ –‡”‹ƒǤ‡•—Ž–•ƒ”‡•—ƒ”‹œ‡†‹ƒ„Ž‡͵ǤŠ‡ƒ ‘”–Š‘Ž‘‰ ™ƒ• Žƒ ‹‰ –Š‡ „‡•– Š‘‘Ž‘‰ ™ƒ• •‡Ž‡ –‡†Ǥ • ‡š’‡ –‡†ǡ Š‹‰Š †‡‰”‡‡• ‘ˆ •‹‹Žƒ”‹–‹‡• ˆ‘” ƒŽŽ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ •‡“—‡ ‡• ™‡”‡ ˆ‘—† ‹ M. tuberculosis •–”ƒ‹•ǣ ‹†‡–‹–‹‡• ™‡”‡ Ž‘•‡ –‘ ‘” ‡šƒ –Ž› ͳͲͲΨ ƒ† ˆ‡™ ‘•Ǧ”‡‰—Ž‘ ‘”–Š‘Ž‘‰•• ‘”‡†„‡Ž‘™ͻͻΨ•‹‹Žƒ”‹–›Ǥ

(44)  ‘–”ƒ•–ǡM.lepraeŠƒ†‘”–Š‘Ž‘‰•ȀŠ‘‘Ž‘‰• ˆ‘”‘Ž›•‹šM.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ǡ ‘’ƒ–‹„Ž‡™‹–Š‹–•™‡ŽŽǦ ‘™ ‰‡‘‡ †‘™•‹œ‹‰ ȋͻȌǤ ‡˜‡”–Š‡Ž‡••ǡ M. leprae •Šƒ”‡† ƒ Š‹‰Š †‡‰”‡‡ ‘ˆ •‹‹Žƒ”‹–› ˆ‘” ‘–Š‡” ‡••‡–‹ƒŽǡ M. tuberculosis ‘Ǧ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ’”‘–‡‹•ǡ ‹ Ž—†‹‰˜ͲͶͶͲȋ •’͸ͷǢͻ͸Ψ‹†‡–‹–›Ȍƒ†˜͵ͺͲͶȋ‰ͺͷǢͻͲΨ‹†‡–‹–›ȌǤM.bovis ƒ† M. bovis   „‘–Š ‘–ƒ‹ ˜‹”–—ƒŽŽ› ‹†‡–‹ ƒŽ ‘”–Š‘Ž‘‰• ‘ˆ ƒŽŽ Ͷͺ M. tuberculosis ‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ȋ•‹‹Žƒ”‹–‹‡•ˆ”‘ͻͺΨǦͳͲͲΨȌǤ‹š‘Ǧ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡•ǡ ͳͲǤͶ ȋ˜ͲʹͺͺȌǡ •’͸ͷ ȋ˜ͲͶͶͲȌǡ ‰ͺͷ ȋ˜ͳͺͺ͸ Ȍǡ ͳͲǤ͵ ȋ˜͵Ͳͳͻ Ȍǡ ‰ͺͷ ȋ˜͵ͺͲͶ Ȍ ƒ† Ǧ͸ ȋ˜͵ͺ͹ͷȌǡ ™‡”‡. ͳʹͺ.

(45) NTMinducedresponsestoM.tuberculosisDosRantigens Table3(part1).AnalysisoforthologsorhomologsofMycobacteriumtuberculosis H37Rv DosRencodedantigensintuberculousmycobacteriaandM.leprae. ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͻͺ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͸ʹȗ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ. yc ob. ˜ͲͲ͹ͻ ˜ͲͲͺͲ ˜ͲͲͺͳ ˜Ͳͷ͸ͻ ˜Ͳͷ͹Ͳ ˜Ͳͷ͹ͳ ˜Ͳͷ͹ʹ ˜Ͳͷ͹͵ ˜Ͳͷ͹Ͷ ˜ͳ͹͵͵ ˜ͳ͹͵Ͷ ˜ͳ͹͵ͷ ˜ͳ͹͵͸ ˜ͳ͹͵͹ ˜ͳ͹͵ͺ ˜ͳͺͳʹ ˜ͳͺͳ͵ ˜ͳͻͻ͸ ˜ͳͻͻ͹ ˜ͳͻͻͺ ˜ʹͲͲ͵ ˜ʹͲͲͶ ˜ʹͲͲͷ ˜ʹͲͲ͸ ˜ʹͲͲ͹ ˜ʹͲʹͺ ˜ʹͲʹͻ ˜ʹͲ͵Ͳ ˜ʹͲ͵ͳ ˜ʹͲ͵ʹ ˜ʹ͸ʹ͵ ˜ʹ͸ʹͶ ˜ʹ͸ʹͷ ˜ʹ͸ʹ͸ ˜ʹ͸ʹ͹ ˜ʹ͸ʹͺ ˜ʹ͸ʹͻ ˜ʹ͸͵Ͳ ˜ʹ͸͵ͳ ˜͵ͳʹ͸ ˜͵ͳʹ͹ ˜͵ͳʹͺ ˜͵ͳʹͻ ˜͵ͳ͵Ͳ ˜͵ͳ͵ͳ ˜͵ͳ͵ʹ ˜͵ͳ͵͵ ˜͵ͳ͵Ͷ . M. H37RvDosRantigens. M. yc ob. ac te ri u m tu be ac rc te ul ri u M os yc m is ob tu C be ac D rc C te 15 u r M iu lo 51 yc m si s ob tu st be ac r ai rc te n ul ri u M "C os yc m " is ob tu F1 be ac 1 r te cu ri u M lo yc m si s ob bo (H ac vi aa s te AF rle ri u m 21 m ) 22 bo /9 M vi s 7 yc BC ob G ac st te r. ri u Pa m st le eu pr ae r1 17 TN 3P 2. Ψ‹‹Žƒ”‹–›–‘ ͵͹˜ƒ–‹‰‡a —„‡” —Ž‘—•› ‘„ƒ –‡”‹ƒ. ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͻͺ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͷ͹ȗ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ. ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ. ͳͲͲ ͳͲͲ ͳͲͲ ͹ͳȗ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͻ͹ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ. ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͻͻ ͻͻ ͻͺ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͻͺ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ. ͳͲͲ ͻͺ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͻͻ ͳͲͲ ͻͻ ͻͻ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ. ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ. ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ. ͳͲͲ ͳͲͲ ͳͲͲ ͻͲȗ ͳͲͲ ͳͲͲ. ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ. ͳͲͲ ͳͲͲ ͻͻ ͳͲͲ ͳͲͲ. Ͷ͸ȗ. Ͷ͵ȗ Ͷ͸ȗ. Ͷͺȗ. ͸͸ȗ. ͶͶ. ͵͹˜‘Ǧ‘•ƒ–‹‰‡• ˜ͲʹͺͺȋesxH ȀͳͲǤͶȌ ˜ͲͶͶͲȋgroEL2 Ȁ •’͸ͷǤʹȌ ˜ͳͺͺ͸ ȋfbpB/ ‰ͺͷȌ ˜͵Ͳͳͻ ȋesxR ȀͳͲǤ͵Ȍ ˜͵ͺͲͶ ȋfbpA Ȁ‰ͺͷȌ ˜͵ͺ͹ͷȋesxA Ȁ‡•ƒ–Ǧ͸Ȍ. ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ ͳͲͲ. ͺͷ ͻ͸ ͺͺ ͺʹ ͺͻ ͸ͷ. a. ”–Š‘Ž‘‰•ƒ†Š‘‘Ž‘‰•ȋ‹†‹ ƒ–‡†™‹–ŠȗȌƒ”‡‡š’”‡••‡†„›’‡” ‡–•‹‹Žƒ”‹–›Ǥ —–‘ˆˆ˜ƒŽ—‡• ‘”‡‘ˆͶͲΨ™ƒ•—•‡†Ǥ. ‡‡‹†‡–‹–‹‡•‘ˆ ‘””‡•’‘†‹‰‘”–Š‘Ž‘‰•‘”Š‘‘Ž‘‰•‹–Š‡ƒ••‡••‡†„ƒ –‡”‹ƒŽ•’‡ ‹‡•ƒ”‡†‡• ”‹„‡†‹–Š‡ —’’Ž‡‡–ƒŽƒ–‡”‹ƒŽ. ͳʹͻ.

(46) Chapter6 Table3(part2).AnalysisoforthologsorhomologsofMycobacteriumtuberculosis H37RvDosR encodedantigensinNTM.. H37RvDosRantigens ˜ͲͲ͹ͻ ˜ͲͲͺͲ ˜ͲͲͺͳ ˜Ͳͷ͸ͻ ˜Ͳͷ͹Ͳ ˜Ͳͷ͹ͳ ˜Ͳͷ͹ʹ ˜Ͳͷ͹͵ ˜Ͳͷ͹Ͷ ˜ͳ͹͵͵ ˜ͳ͹͵Ͷ ˜ͳ͹͵ͷ ˜ͳ͹͵͸ ˜ͳ͹͵͹ ˜ͳ͹͵ͺ ˜ͳͺͳʹ ˜ͳͺͳ͵ ˜ͳͻͻ͸ ˜ͳͻͻ͹ ˜ͳͻͻͺ ˜ʹͲͲ͵ ˜ʹͲͲͶ ˜ʹͲͲͷ ˜ʹͲͲ͸ ˜ʹͲͲ͹ ˜ʹͲʹͺ ˜ʹͲʹͻ ˜ʹͲ͵Ͳ ˜ʹͲ͵ͳ ˜ʹͲ͵ʹ ˜ʹ͸ʹ͵ ˜ʹ͸ʹͶ ˜ʹ͸ʹͷ ˜ʹ͸ʹ͸ ˜ʹ͸ʹ͹ ˜ʹ͸ʹͺ ˜ʹ͸ʹͻ ˜ʹ͸͵Ͳ ˜ʹ͸͵ͳ ˜͵ͳʹ͸ ˜͵ͳʹ͹ ˜͵ͳʹͺ ˜͵ͳʹͻ ˜͵ͳ͵Ͳ ˜͵ͳ͵ͳ ˜͵ͳ͵ʹ ˜͵ͳ͵͵ ˜͵ͳ͵Ͷ . M yc ob ac te r iu M yc m ob sp ac .K te M r M S iu yc m ob av ac iu m te r iu 10 M yc m 4 ob m ar ac i n te um r iu M yc m M ul st oba ce r. c ra K1 ter ns 0 ium Ag M yc av y9 ob iu 9 m ac su te r iu bs M yc m p. ob sp pa ac .M ra te tu C riu be M S yc m rc ul ob sm os ac e is gm te r iu a tis m va st r nb .M aa C 2 le ni 15 iP 5 YR -1. Ψ‹‹Žƒ”‹–›–‘ ͵͹˜ƒ–‹‰‡a ‘–—„‡” —Ž‘—•› ‘„ƒ –‡”‹ƒȋȌ. ͷͶ ͷ͹ ͸ͻ ͺͺ ͺ͹ ͸ʹȗ. ͹͵ ͷͷȗ ͺ͹. ͹ͳ ͷͷȗ. ͹ͺ Ͷʹȗ ͸Ͳȗ. Ͷͳȗ ͹ͺ. Ͷͳȗ ͹͹. ͷͷȗ. ͷ͵ȗ. ͷ͸ȗ. ͷ͵. ͷ͸. ͷʹ. ͺ͹ ͺͺ. Ͷͳȗ. Ͷ͸. Ͷʹ. Ͷͳȗ ͹ͷȗ ͺ͵ ͸͸ ͹͹ ͺ͸ Ͷͻ. ͺʹ Ͷͻ ͸͵ ͹Ͳȗ ͹ʹ ͺͺ ͸Ͳ ͹Ͷ ͺ͹ ͹͸ ͹͵ ͹ͳ ͸ͺ. ͺͲ. ͹ʹȗ Ͷͻȗ. ͹ͻ ͸ͷȗ ͺ͵ Ͷʹ ͹͵ȗ ͷͻȗ ͸͸ ͷ͹. Ͷʹȗ ͸Ͳȗ. ͷͶ ͷ͹ ͸ͻ ͺ͹ ͺ͹ ͸ʹȗ. ͷͳ ͷ͸ ͸͸ ͹ͳȗ Ͷʹȗ ͸ͷȗ. ͷ͵ȗ. ͷͷȗ. ͷ͸ȗ. ͺͺ ͺʹ ͺͶ ͷͶȗ. ͷ͵. ͷͺ. Ͷͻ. ͺ͹ ͺͺ. ͺ͹ ͺͺ. ͹ͷȗ ͶͲȗ ͹͵ȗ ͺ͵ ͸͸ȗ ͹͸ ͺ͸ Ͷͻ. Ͷʹ. Ͷ͸. ͶͶ. ͺͻ ͻͲ ͹͸ Ͷ͸. ͸͸ȗ Ͷͻȗ. ͸͹ȗ ͺʹ Ͷͻ. ͸ͷȗ ͸ʹ Ͷͻ. ͸͵ȗ ͸ʹ ͷͲ. Ͷͺ ͺͲ ͸͸ȗ ͺ͵ ͷͻȗ. ͸͵ ͹Ͳȗ ͹ʹ ͺͺ ͸Ͳ ͹Ͷ ͺ͹ ͸Ͷȗ ͹͵ ͹ͳ ͸ͺ. ͸ͺ ͸ͷȗ ͹͵ ͺͲ ͸ͳ ͹͹ ͹ͷȗ ͹ͺ ͹ͷ ͸ͺȗ ͸Ͳ. ͺͲ. Ͷ͸ȗ. ͸͹ ͸͹ȗ ͹Ͷ ͺ͵ ͸ͳ ͹͹ ͺͷ ͺͳ ͹ʹ ͹Ͳ ͸ͳ ͸ͻ ͺͶ ͹ͻ ͸ͻ ͸ͷ. ͹ͷ ͺ͹ ͹ͳ ͺͷ ͷ͹ȗ ͹ͻ ͺͻ ͺ͸ ͸ͺȗ ͺ͸ ͺͶ ͺ͸ ͸Ͳ ͺͶ. ͸͹ȗ ͺ͸ ͷͷȗ ͺ͸ ͸Ͳ ͶͶȗ. ͺͳ. ͺͳ. Ͷ͹ ͹Ͳ ͸͸. ͺ͹ ͸ͻȗ ͹ͻ ͷ͹ȗ ͷͺȗ. ͷ͵ ͷʹȗ ͸ͺ. ͹͵ȗ ͷͻȗ ͸͸ ͹ͳȗ ͷͺȗ. ͸͸. Ͷ͹ ͹Ͳ ͸͸. ͸͸. ͷʹȗ. ͺͳ. ͺͳ. ͸ͷȗ. ͸͸. ͸͸. ͹͵ ͹ͳ ͹͸ ͹ͺ ͻʹ ͷͷȗ. ͺͲ ͸ͷȗ ͹ͷ ͸͹ȗ ͻͶ ͸͸. ͺͲ ͹ͺ ͺ͵ ͺͻ ͻͷ ͹ͻ. ͺͲ ͹ͻ ͺʹ ͺͻ ͻͷ ͹ͺ. ͺͲ ͸ͷȗ ͹͸ ͸͵ ͻͶ ͸͸. ͹͵ ͹ͳ ͹͸ ͹͹ ͻʹ ͷͻȗ. ͹͸ ͹ͳ ͹͹ ͺͲȗ ͻͶ ͷͶȗ. ͸͸ȗ ͷͲȗ ͸͸ ͸ͻ ͹͹ ͹͹ȗ ͻͶ ͷͷȗ. ͺ͸ ͻͷ ͺͲ ͺ͸ȗ ͺͲ ͹Ͷ. ͺͻȗ ͻ͸ ͻʹ ͻͳ ͺͻ. ͻ͵ȗ ͻ͸ ͻͶ ͻͶ ͻͲ ͻ͸. ͻʹȗ ͻ͸ ͻͶ ͻ͵ ͻͲ. ͺͻȗ ͻ͸ ͻʹ ͻͳ ͺͻ. ͺ͸ ͻͷ ͺͲ ͺ͸ȗ ͺͲ ͹Ͷ. ͺͷ ͻͷ ͺʹ ͺͷȗ ͺͲ ͺͲ. ͺͷ ͻͷ ͺ͵ ͺͳȗ ͺ͵ȗ ͷͺ. ͸͸. ͵͹˜‘Ǧ‘•ƒ–‹‰‡• ˜ͲʹͺͺȋesxH ȀͳͲǤͶȌ ˜ͲͶͶͲȋgroEL2 Ȁ •’͸ͷǤʹȌ ˜ͳͺͺ͸ ȋfbpB/ ‰ͺͷȌ ˜͵Ͳͳͻ ȋesxR ȀͳͲǤ͵Ȍ ˜͵ͺͲͶ ȋfbpA Ȁ‰ͺͷȌ ˜͵ͺ͹ͷȋesxA Ȁ‡•ƒ–Ǧ͸Ȍ a. ”–Š‘Ž‘‰•ƒ†Š‘‘Ž‘‰•ȋ‹†‹ ƒ–‡†™‹–ŠȗȌƒ”‡‡š’”‡••‡†„›’‡” ‡–•‹‹Žƒ”‹–›Ǥ —–‘ˆˆ˜ƒŽ—‡• ‘”‡‘ˆͶͲΨ™ƒ•—•‡†Ǥ. ‡‡‹†‡–‹–‹‡•‘ˆ ‘””‡•’‘†‹‰‘”–Š‘Ž‘‰•‘”Š‘‘Ž‘‰•‹–Š‡ƒ••‡••‡†„ƒ –‡”‹ƒŽ•’‡ ‹‡•ƒ”‡†‡• ”‹„‡†‹–Š‡ —’’Ž‡‡–ƒŽƒ–‡”‹ƒŽ. ͳ͵Ͳ.

(47) NTMinducedresponsestoM.tuberculosisDosRantigens Table3(part3).AnalysisoforthologsorhomologsofMycobacteriumtuberculosis H37RvDosRencodedantigensinenvironmentalbacteria. a. ͷʹ. ͷ͹ ͹ͻ. C. om yc e. St re pt. H37RvDosRantigens ˜ͲͲ͹ͻ ˜ͲͲͺͲ ˜ͲͲͺͳ ˜Ͳͷ͸ͻ ˜Ͳͷ͹Ͳ ˜Ͳͷ͹ͳ ˜Ͳͷ͹ʹ ˜Ͳͷ͹͵ ˜Ͳͷ͹Ͷ ˜ͳ͹͵͵ ˜ͳ͹͵Ͷ ˜ͳ͹͵ͷ ˜ͳ͹͵͸ ˜ͳ͹͵͹ ˜ͳ͹͵ͺ ˜ͳͺͳʹ ˜ͳͺͳ͵ ˜ͳͻͻ͸ ˜ͳͻͻ͹ ˜ͳͻͻͺ ˜ʹͲͲ͵ ˜ʹͲͲͶ ˜ʹͲͲͷ ˜ʹͲͲ͸ ˜ʹͲͲ͹ ˜ʹͲʹͺ ˜ʹͲʹͻ ˜ʹͲ͵Ͳ ˜ʹͲ͵ͳ ˜ʹͲ͵ʹ ˜ʹ͸ʹ͵ ˜ʹ͸ʹͶ ˜ʹ͸ʹͷ ˜ʹ͸ʹ͸ ˜ʹ͸ʹ͹ ˜ʹ͸ʹͺ ˜ʹ͸ʹͻ ˜ʹ͸͵Ͳ ˜ʹ͸͵ͳ ˜͵ͳʹ͸ ˜͵ͳʹ͹ ˜͵ͳʹͺ ˜͵ͳʹͻ ˜͵ͳ͵Ͳ ˜͵ͳ͵ͳ ˜͵ͳ͵ʹ ˜͵ͳ͵͵ ˜͵ͳ͵Ͷ . St re pt. om yc e. s. av er m iti lis s or M c yn Aoe eb 46 lic ac ol 80 o t C er rA or iu 3( yn m 2) eb di ph ac th te C er riu or ia yn m e eb ef N f C ac ici TC t en C er or s i 13 um yn YS 12 eb gl 9 31 ut ac am 4 te R riu ho ic u m do m je co AT ik cc ei C us R um C ho 13 sp K do 03 .R 41 ba 2 1 H ct A er 1 N oc sp ar h a di er a oi fa de Pr rc s in op 2. i c io a 4. ni IF 1 ba M ct Ac 1 er 01 id i um 52 ot he D ac rm N ne A us Bi s fid KP ce ob llu A1 ac lo 71 te ly 20 tic riu us 2 m lo 11 ng B um N C C 27 05. Ψ‹‹Žƒ”‹–›–‘ ͵͹˜ƒ–‹‰‡ ˜‹”‘‡–ƒŽ„ƒ –‡”‹ƒȋ‘Ǧ› ‘„ƒ –‡”‹ƒŽȌ. ͷ͸ ͸ͺ ͸͹. ͹ͳ. ͷ͹. ͷ͵ ͸Ͳȗ. ͷ͵. Ͷͳȗ. ͶͲȗ. Ͷͳȗ. Ͷͳȗ. Ͷͳȗ ͸͸. ͷ͸ȗ Ͷͷ Ͷ͵. ͸͵ Ͷʹ Ͷ͸. ͷͷȗ. ͷͶȗ. ͷ͵ȗ. ͷͶȗ. ͷʹȗ ͸͹ ͷͳ. ͷ͹. Ͷͳȗ ͸͵. ͷͶ. ͷͷ ͹ʹ. ͶͲȗ. ͷʹȗ. ͷ͵ȗ. ͷͷȗ Ͷʹ. ͷͷȗ Ͷʹ. ͹ͳ ͶͲȗ. ͸͸ ͶͲȗ. ͺͲ ͷͳ. Ͷͷȗ. Ͷ͵. Ͷ͹ȗ. Ͷ͸ȗ. ͸Ͳ. ͸ͳȗ ͷͳȗ Ͷͺ. ͶͶȗ Ͷͻȗ. Ͷͺȗ. Ͷ͵. ͸Ͷ Ͷ͵ȗ ͷ͵ȗ Ͷͷ. ͹ʹ ͸ʹ. ͹ʹ Ͷͻ. ͹ʹ Ͷͻ. ͹Ͷ ͶͲȗ. Ͷͷ. Ͷͷȗ. Ͷ͸ȗ. Ͷͷȗ. Ͷʹȗ. Ͷͺȗ Ͷͺȗ ͸Ͳ. Ͷͻȗ Ͷͻȗ ͷ͸. ͷʹ ͷʹȗ. ͷ͹ȗ ͷͺ. ͷͷȗ ͷ͹ Ͷʹ. ͷ͹ȗ ͷ͵ȗ. Ͷ͵ȗ ͹͸ ͹ͻ ͸Ͳȗ ͷ͵ ͷͳ. Ͷͳȗ ͷͺ. ͷͳ ͷͲ ͹͸ȗ Ͷʹȗ Ͷͺ ͸Ͳȗ. ͷ͸ ͷͲȗ ͸͵ ͹ͷȗ ͶͲȗ ͷͲ. Ͷ͹ȗ Ͷʹȗ ͶͶ ͹Ͷ. Ͷ͸ȗ Ͷͺȗ ͷͳȗ Ͷͷ ͷ͸. ͶͶ. Ͷͷ. ͷͻȗ ͹ͺȗ ͶͲȗ Ͷͺ. ͷͷȗ Ͷ͵ȗ. ͷͻ ͸ʹ ͺͲȗ Ͷͳȗ ͷͲ. ͷ͸ȗ Ͷ͵ȗ. ͷͺ ͺͲȗ Ͷͳȗ ͷͲ. ͷ͸ȗ Ͷ͵ȗ. ͷͶȗ ͶͶȗ ͹ͺȗ Ͷʹȗ. ͷͺ Ͷ͵ȗ. ͸ͳ ͸ʹ ͹ʹ ͹Ͳ Ͷ͹ȗ ͹ͳ ͸ͳȗ. Ͷ͸. ͸͹ȗ ͷͶ. ͷͻ ͸Ͳȗ Ͷͺȗ. ͷͻ ͷͻȗ Ͷͷȗ. Ͷͺ ͺͷ. ͹͵ȗ. ͷͺȗ ͸ʹ ͶͶȗ ͷͲ Ͷͷ. Ͷͻȗ Ͷ͵ȗ. ͷͲ ͶͶ. Ͷͷ. Ͷ͹. ͶͶȗ ͷͺ. ͷ͹ȗ ͺͲ ͶͲȗ. Ͷ͸ Ͷ͸ȗ ͹ͺȗ Ͷͳȗ ͷͲ. ͹Ͳ. Ͷ͸. Ͷ͸ȗ. ͸͵ ͸ͳ ͹ʹȗ Ͷ͵ȗ ͷͲ ͸Ͳȗ. ͷ͸. ͶͶ. Ͷͷ. ͷ͸. ͷ͸ȗ. ͸ͳ ͷͳ ͹Ͷ ͺ͹ Ͷͷȗ. ͷͳȗ ͸͵ ͹Ͳȗ ͺͷ Ͷ͹ȗ. ͷͺ. ͸͹. Ͷͷȗ Ͷ͹ ͸Ͷȗ ͺͲ ͶͶȗ. Ͷͺȗ ͸Ͳ Ͷͳȗ. ͸ʹ Ͷʹȗ. ͷͺ Ͷʹȗ. Ͷ͹ ͷͺ Ͷʹȗ. ͺͻ Ͷʹȗ. ͺͺ ͷͲȗ. ͺͻ ͷ͵. ͺͻ ͷͳȗ. ͺͻ Ͷ͹ȗ. ͻ͵ ͷͷ. Ͷʹȗ. ͷͳ ͸Ͳȗ. ͷ͵ȗ ͷͷȗ. ͷ͵ ͷͷȗ. ͷ͸ ͷ͸. ͷ͸ȗ. Ͷͻ. Ͷ͵ȗ ͷ͵ȗ ͸ͳ Ͷ͵ȗ. ͹ʹ ͹͹. ͸͵. ͺ͹. ͻͲ. ͺͶ. ͵͹˜‘Ǧ‘•ƒ–‹‰‡• ˜ͲʹͺͺȋesxH ȀͳͲǤͶȌ ˜ͲͶͶͲȋgroEL2 Ȁ •’͸ͷǤʹȌ ˜ͳͺͺ͸ ȋfbpB/ ‰ͺͷȌ ˜͵Ͳͳͻ ȋesxR ȀͳͲǤ͵Ȍ ˜͵ͺͲͶ ȋfbpA Ȁ‰ͺͷȌ ˜͵ͺ͹ͷȋesxA Ȁ‡•ƒ–Ǧ͸Ȍ. ͻͲ. ͹͸. ͻͶ ͷ͵ȗ ͷͲȗ. a. ”–Š‘Ž‘‰•ƒ†Š‘‘Ž‘‰•ȋ‹†‹ ƒ–‡†™‹–ŠȗȌƒ”‡‡š’”‡••‡†„›’‡” ‡–•‹‹Žƒ”‹–›Ǥ —–‘ˆˆ˜ƒŽ—‡• ‘”‡‘ˆͶͲΨ™ƒ•—•‡†Ǥ. ‡‡‹†‡–‹–‹‡•‘ˆ ‘””‡•’‘†‹‰‘”–Š‘Ž‘‰•‘”Š‘‘Ž‘‰•‹–Š‡ƒ••‡••‡†„ƒ –‡”‹ƒŽ•’‡ ‹‡•ƒ”‡†‡• ”‹„‡†‹–Š‡ —’’Ž‡‡–ƒŽƒ–‡”‹ƒŽ. ͳ͵ͳ.

(48) Chapter6. ‹ Ž—†‡† ƒ• ”‡ˆ‡”‡ ‡ ‰‡‡•Ǥ Š‡•‡ ‰‡‡• Šƒ† ‘”–Š‘Ž‘‰• ‹ ƒŽŽ •‡˜‡ –—„‡” —Ž‘—• › ‘„ƒ –‡”‹ƒŽ •–”ƒ‹•ǡ ™‹–Š ˜‡”› Š‹‰Š •‹‹Žƒ”‹–› –‘ ‘’Ž‡–‡ ‹†‡–‹–›Ǥ ͳͲǤ͵ ƒ† Ǧ͸ˆ‘”‡†–Š‡‡š ‡’–‹‘ǣˆ‘”ͳͲǤ͵‘‘”–Š‘Ž‘‰™ƒ•ˆ‘—†‹M.lepraeǡƒ†ƒ• ‡š’‡ –‡†ǡ‘Ǧ͸‘”–Š‘Ž‘‰™ƒ•’”‡•‡–‹M.bovis Ǥ ‘”–›Ǧ‘‡‘—–‘ˆͶͺM.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ƒ’’‡ƒ”‡†–‘Šƒ˜‡ ‘”–Š‘Ž‘‰• ȋ‘” Š‘‘Ž‘‰•Ȍ ‹ –Š‡  •’‡ ‹‡• ƒƒŽ›œ‡†Ǥ Š‡ —„‡” ‘ˆ ‘• ”‡‰—Ž‘ ‘”–Š‘Ž‘‰•ȀŠ‘‘Ž‘‰• ‹ –Š‡ ‡‹‰Š–  •’‡ ‹‡• ˜ƒ”‹‡† ˆ”‘ –Š‡ ’”‡•‡ ‡ ‘ˆ ʹ͹ ‘”–Š‘Ž‘‰•ȀŠ‘‘Ž‘‰• ‹ M. avium –‘ ͵ͻ ‹ Mycobacterium vanbaaleniiǤ

(49) –‡”‡•–‹‰Ž›ǡ ƒŽ‘•– ŠƒŽˆ ‘ˆ –Š‡ ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ™‡”‡ ’”‡•‡– ‹ ƒŽŽ ‡‹‰Š–  •’‡ ‹‡•Ǥ”–Š‘Ž‘‰•‘ˆƒŽŽˆ‹˜‡”‡ˆ‡”‡ ‡‰‡‡•™‡”‡ˆ‘—†‹–Š‡Ǥ —””‡–Ž›ǡ –Š‡ ‰‡‘‡ •‡“—‡ ‡ ‘ˆ M. kansasii ‹• ‹ ‘’Ž‡–‡ ƒ† –Š‡”‡ˆ‘”‡ ™ƒ• ‘– ‹ Ž—†‡†‹ƒ„Ž‡͵Ǥ ‘™‡˜‡”ǡ— Ž‡‘–‹†‡•‡ƒ” Š‡•™‹–Š–Š‡ƒ˜ƒ‹Žƒ„Ž‡•‡“—‡ ‡• ˆ”‘ 

(50)  ”‡•—Ž–‡† ‹ –Š‡ ‹†‡–‹ˆ‹ ƒ–‹‘ ‘ˆ ͳ͵ M. tuberculosis ‘• ƒ–‹‰‡ Š‘‘Ž‘‰•Ȁ‘”–Š‘Ž‘‰• ȋ•‹‹Žƒ”‹–‹‡• ͹͵ΨǦͺͶΨȌ ‹ M. kansasiiǡ ‹ Ž—†‹‰ ˜ʹ͸ʹ͹  ȋͺͲΨ •‹‹Žƒ”‹–›Ȍ™Š‹ Š™ƒ•–‡•–‡†‹–Š‹••–—†›Ǥ ƒ”‹ƒ„Ž‡—„‡”•‘ˆM.tuberculosis‘•”‡‰—Ž‘‘”–Š‘Ž‘‰•ƒ†Š‘‘Ž‘‰•™‡”‡ƒŽ•‘ ˆ‘—† ‹ ‘Ǧ› ‘„ƒ –‡”‹ƒŽ •’‡ ‹‡• •— Š ƒ• Streptomyces coelicolor ȋ’”‡•‡– ‹ •‘‹ŽȌ ƒ† Bifidobacterium longum ȋƒ ‰ƒ•–”‘‹–‡•–‹ƒŽ ‘‡•ƒŽȌǤ Š‡ ƒ••‡••‹‰ –Š‡ „ƒ –‡”‹ƒŽ •’‡ ‹‡• ™‹–Š ”‡‰ƒ”† –‘ –Š‡ ƒ˜‡”ƒ‰‡ —„‡” ‘ˆ ‘”–Š‘Ž‘‰• ’‡” •‹‰Ž‡ ‘•Ǧ ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡ǡ  Šƒ† •‹‰‹ˆ‹ ƒ–Ž› Š‹‰Š‡” —„‡”• ‘ˆ ‘• ”‡‰—Ž‘ ‡ ‘†‡†’”‘–‡‹‘”–Š‘Ž‘‰•ȋƒ˜‡”ƒ‰‡‘ˆ͵Ǥͺ‘”–Š‘Ž‘‰•’‡”•‹‰Ž‡‘•”‡‰—Ž‘‡ ‘†‡† ƒ–‹‰‡ ƒ‘‰ ‡‹‰Š– ‡šƒ‹‡† Ȍ ™Š‡ ‘’ƒ”‡† –‘ –Š‡ ‘Ǧ› ‘„ƒ –‡”‹ƒŽ •’‡ ‹‡•ȋƒ˜‡”ƒ‰‡‘ˆʹǤͷ‘”–Š‘Ž‘‰•’‡”•‹‰Ž‡‘•”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡ƒ‘‰ͳʹ ‡šƒ‹‡†‘Ǧ› ‘„ƒ –‡”‹ƒȌǤ

(51)  ‘–”ƒ•–ǡ ‘•– ”‡ˆ‡”‡ ‡ ƒ–‹‰‡• Šƒ† ˆ‡™ ‘” ‘ ‘”–Š‘Ž‘‰• ‹ ‡˜‹”‘‡–ƒŽ ‘Ǧ › ‘„ƒ –‡”‹ƒŽ •’‡ ‹‡•ǡ ™‹–Š –Š‡ ƒ–‹ ‹’ƒ–‡† ‡š ‡’–‹‘ ‘ˆ –Š‡ Š‹‰ŠŽ› ‘•‡”˜‡† ‰‡‡ hsp65ȋ˜ͲͶͶͲȌǤ  ‹–‡”‡•–‹‰ ‘„•‡”˜ƒ–‹‘ ‘ ‡”‡† –Š‡ M. tuberculosis ‘• •‡“—‡ ‡ ȋ˜͵ͳ͵͵ Ȍ ‹–•‡Žˆǣ ‘”–Š‘Ž‘‰• ‘ˆ –Š‹• ’”‘–‡‹ ™‡”‡ ˆ‘—† ‹ ƒŽ‘•– ƒŽŽ •’‡ ‹‡• ƒ••‡••‡†ǡ M. leprae ˆ‘”‹‰–Š‡‡š ‡’–‹‘Ǥ“—ƒŽŽ›‹–‡”‡•–‹‰‹•–Š‡ˆƒ ––Šƒ––Š‡•‡˜͵ͳ͵͵ ‘”–Š‘Ž‘‰•Šƒ† ƒ •–”‹‹‰Ž› Š‹‰Š †‡‰”‡‡ ‘ˆ •‹‹Žƒ”‹–› ƒ‘‰ ƒŽŽ › ‘„ƒ –‡”‹ƒŽ •’‡ ‹‡• ȋˆ”‘ ͻ͵ΨȂ ͳͲͲΨȌǢ ƒ† –‘ ƒ Ž‡••‡” ‡š–‡– ƒŽ•‘ ƒ ‘•‹†‡”ƒ„Ž‡ †‡‰”‡‡ ‘ˆ •‹‹Žƒ”‹–› ‹ ‘”‡ †‹•–ƒ–Ž›”‡Žƒ–‡†ǡ‘Ǧ› ‘„ƒ –‡”‹ƒŽ•’‡ ‹‡•ȋ”ƒ‰‹‰ˆ”‘ͷͲΨǦͺ͹ΨȌǤ ƒ‡ –‘‰‡–Š‡”ǡ ‘—” ”‡•—Ž–• †‡‘•–”ƒ–‡ –Šƒ– M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ’”‘–‡‹•Šƒ˜‡‘”–Š‘Ž‘‰•‹„‘–Š‡˜‹”‘‡–ƒŽ› ‘„ƒ –‡”‹ƒŽƒ†‘Ǧ› ‘„ƒ –‡”‹ƒŽ •’‡ ‹‡•ǡ ™‹–Š ƒ ”‡ƒ”ƒ„Ž› Š‹‰Š †‡‰”‡‡ ‘ˆ •‹‹Žƒ”‹–› ˆ‘” –Š‡ †‘”ƒ › ”‡•’‘•‡ ”‡‰—Žƒ–‘”‰‡‡˜͵ͳ͵͵ Ǥ  . Discussion Š‹••–—†›™ƒ•†‡•‹‰‡†–‘‹˜‡•–‹‰ƒ–‡–Š‡Š›’‘–Š‡•‹•–Šƒ–‹ˆ‡ –‹‘™‹–Š‘”‡š’‘•—”‡ –‘ ƒ‹†— ‡ ”‘••Ǧ”‡ƒ –‹˜‡‹—‡”‡•’‘•‡•–‘ƒ”‡ ‡–Ž›‹†‡–‹ˆ‹‡†•‡–‘ˆM. tuberculosis ƒ–‹‰‡•ǡ ƒ‡Ž› M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡•Ǥ ”‡˜‹‘—•Ž›ǡ™‡”‡’‘”–‡†–Šƒ–M.tuberculosis‹ˆ‡ –‡†‹†‹˜‹†—ƒŽ•ȋƒ –‹˜‡ƒ†Žƒ–‡–Ž›Ȍ. ͳ͵ʹ.

(52) NTMinducedresponsestoM.tuberculosisDosRantigens. ƒ”‡•’‘†–‘M.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ȋͳͳǡʹͲǡ͵ʹȌǡƒ†–Šƒ– ”‡•’‘•‹˜‡‡•• –‘ –Š‡•‡ Žƒ–‡ •–ƒ‰‡ ƒ–‹‰‡• ™ƒ• ƒ••‘ ‹ƒ–‡† ™‹–Š ‘–”‘Ž ‘ˆ Žƒ–‡– M. tuberculosis ‹ˆ‡ –‹‘ ȋʹͲǡ ͵ʹȌǤ ‡š’‡ –‡†Ž›ǡ ™‡ ‘„•‡”˜‡† –Šƒ– ƒ •‹‰‹ˆ‹ ƒ– ’”‘’‘”–‹‘ ‘ˆ Š‡ƒŽ–Š›ǡ M. tuberculosis —‹ˆ‡ –‡†ǡ   —˜ƒ ‹ƒ–‡† ‹†‹˜‹†—ƒŽ• ƒŽ•‘ ”‡•’‘†‡†–‘M.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ǡ‡š––‘M.tuberculosisǦ Ž›•ƒ–‡ ȋʹͲȌ ƒ†  ‹ ˜‹–”‘ ȋʹͳȌǤ ‡ –Š‡”‡ˆ‘”‡ Š›’‘–Š‡•‹œ‡† –Šƒ– –Š‡•‡ ”‡•’‘•‡• ‹‰Š– Šƒ˜‡ ”‡•—Ž–‡† ˆ”‘ ‡š’‘•—”‡ –‘ ǡ ™‹–Š ‘ ‘‹–ƒ– ‹†— –‹‘ ‘ˆ ”‘••Ǧ ”‡ƒ –‹˜‡‹—‡”‡•’‘•‡•–‘M.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•Ǥ ˆ ‘–‡ǡ ˜‡”› ˆ‡™ ‹ ˜‹–”‘  ‘Ǧ”‡•’‘•‹˜‡ ‹†‹˜‹†—ƒŽ• ”‡•’‘†‡† –‘ –Š‡ –‡•–‡† ”‡ ‘„‹ƒ– M. tuberculosis ƒ–‹‰‡• ȋ ‹‰—”‡ ʹȌǤ ‘••‹„Ž‡ ‘–ƒ‹ƒ–‹‘ ‘ˆ –Š‡ ”‡ ‘„‹ƒ–’”‘–‡‹•‹•†‹ˆˆ‹ —Ž––‘‡š Ž—†‡‹–Š‡ƒ„•‡ ‡‘ˆƒ‰‘Ž†•–ƒ†ƒ”† ‘–”‘Žǡ „—–‘—””‹‰‘”‘—•Ȁ’”‘ ‡†—”‡•ƒ†–Š‡•–”‘‰ ‘””‡Žƒ–‹‘„‡–™‡‡”‡•’‘•‡•–‘ M. tuberculosis Ž›•ƒ–‡Ȁ ƒ† –‡•– M. tuberculosis ”‡ ‘„‹ƒ– ƒ–‹‰‡• •–”‡‰–Š‡ –Š‡ ‘ Ž—•‹‘ –Šƒ– ”‡•’‘•‡• ‘„•‡”˜‡† ƒ”‡ ‹†‡‡† –”—Ž› •’‡ ‹ˆ‹ Ǥ ‘”‡‘˜‡”ǡ –Š‡ ’”‡•‡ ‡ ‘ˆ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† Š‘‘Ž‘‰• ‹ ‘Ǧ› ‘„ƒ –‡”‹ƒŽ •’‡ ‹‡• ȋƒ„Ž‡ ͵Ȍ •—‰‰‡•–• –Šƒ– ƒŽ•‘ ‘Ǧ› ‘„ƒ –‡”‹ƒ ‹‰Š– ‡˜‘‡ ”‡•’‘•‡• –‘ M. tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•Ǥ ”‘‡ƒ”Ž›–‘”‡ ‡–’—„Ž‹ ƒ–‹‘•‹–‹•‡˜‹†‡––Šƒ–‡˜‹”‘‡–ƒŽ› ‘„ƒ –‡”‹ƒ•— Š ƒ• M. kansasii, M. smegmatis ƒ† M. avium ƒ”‡ ƒ’ƒ„Ž‡ ‘ˆ ƒ†ƒ’–‹‰ –‘ ‘†‹–‹‘• ‘ˆ •–ƒ”˜ƒ–‹‘ ȋ͵ǡ ʹ͵ǡ ͵ͺȌǤ M. smegmatis ‘– ‘Ž› „‡Šƒ˜‡† •‹‹Žƒ”Ž› –‘ •Ž‘™ ‰”‘™‹‰ M. tuberculosis—†‡”‹˜‹–”‘‘š›‰‡†‡’Ž‡–‹‘ƒ†”‡ƒ –‹˜ƒ–‹‘ ‘†‹–‹‘•ȋͳʹȌ„—–ƒŽ•‘ ‡š’”‡••‡† ‘”–Š‘Ž‘‰• ‘ˆ M. tuberculosis ‘• ƒ–‹‰‡• ˜ʹͲ͵ͳ  ȋDǦ ”›•–ƒŽŽ‹ǡ •’Ȍǡ ˜͵ͳ͵ʹ ǡ ˜͵ͳ͵͵  ȋDosR, devRȌ ƒ† ˜͵ͳ͵Ͷ  ȋʹʹǡ ʹͶȌǤ

(53)  ƒ††‹–‹‘ǡ M. bovis   ƒ†ƒ’–‡†–‘‘š›‰‡•–ƒ”˜ƒ–‹‘‹–Š‡•ƒ‡ˆƒ•Š‹‘ƒ•M.tuberculosis„›—’Ǧ”‡‰—Žƒ–‹‰ ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ˜ʹͲ͵ͳ ǡ ˜͵ͳ͵͵ ǡ ˜ʹ͸ʹ͵ ƒ† ˜ʹ͸ʹ͸  ȋ͸Ȍǡ ƒŽ–Š‘—‰Š‹–™ƒ•”‡ ‡–Ž›•Š‘™–Šƒ–M.bovis ‹•†‡ˆ‡ –‹˜‡‹–Š‡‹†— –‹‘‘ˆ–Š‡M. tuberculosis†‘”ƒ ›‰‡‡•˜ͳ͹͵͸ ƒ†˜ͳ͹͵͹ ȋͳͺȌǤ Š‡‘„•‡”˜‡†

(54) J”‡•’‘•‡•‘ˆ‹ˆ‡ –‡†Ȁ‡š’‘•‡†‹†‹˜‹†—ƒŽ•–‘M.tuberculosis ƒ–‹‰‡•ǡ ‹ Ž—†‹‰ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡•ǡ •—’’‘”– ‘—” Š›’‘–Š‡•‹•Ǥ Š‡› ƒŽ•‘ ’”‘˜‹†‡ ‹†‹”‡ – ‡˜‹†‡ ‡ –Šƒ–  ‡š’”‡•• ‘• ’”‘–‡‹ ‘”–Š‘Ž‘‰•ȀŠ‘‘Ž‘‰•‹˜‹˜‘ȋ ‹‰—”‡ʹƒ†͵ȌǤ ‡ ‡–Ž›ǡ ƒ —„‡” ‘ˆ › ‘„ƒ –‡”‹ƒŽ ‰‡‘‡• Šƒ• „‡‡ •‡“—‡ ‡†ǡ ‹ Ž—†‹‰  ‰‡‘‡•Ǥ ‡ •›•–‡ƒ–‹ ƒŽŽ› ƒƒŽ›œ‡† –Š‡•‡ ‰‡‘‡• ˆ‘” –Š‡ ’”‡•‡ ‡ ‘ˆ M. tuberculosis ͵͹˜ ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ‘”–Š‘Ž‘‰• ȋ‘” ™Š‡ Žƒ ‹‰ǡ –Š‡ „‡•– ’‘••‹„Ž‡ Š‘‘Ž‘‰Ȍ ȋƒ„Ž‡ ͵ȌǤ ‡•—Ž–• •Š‘™‡† –Šƒ– –Š‡ ƒŒ‘”‹–› ‘ˆ › ‘„ƒ –‡”‹ƒŽ ‰‡‘‡•‹†‡‡†‡ ‘’ƒ••‘”–Š‘Ž‘‰•‘ˆM.tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†‰‡‡•Ǥ • ‡š’‡ –‡†ǡ –Š‡ Š‹‰Š‡•– •‹‹Žƒ”‹–‹‡• ȋƒƒŽ›œ‡† ƒ– –Š‡ ƒ‹‘ ƒ ‹† •‡“—‡ ‡ Ž‡˜‡Ž ‹ ‘”†‡” –‘ ƒ••‡•• ’‘–‡–‹ƒŽ ‹—‘Ž‘‰‹ ƒŽ ”‘••Ǧ”‡ƒ –‹˜‹–›Ȍ ™‡”‡ †‡–‡ –‡† ƒ‘‰ ‡„‡”•‘ˆ–Š‡M.tuberculosis ‘’Ž‡šǤ‘•–”‡Ž‡˜ƒ–ˆ‘”‘—”Š›’‘–Š‡•‹•™ƒ•–Š‡ˆƒ – –Šƒ– ‘”–Š‘Ž‘‰• ‘ˆ Ͷͳ ‘—– ‘ˆ Ͷͺ †‹ˆˆ‡”‡– M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ‰‡‡• ™‡”‡ †‡–‡ –‡† ‹ –Š‡ ‰‡‘‡• ‘ˆ Ǥ ƒ–Š‡” —‡š’‡ –‡†Ž›ǡ •‡˜‡”ƒŽ ‡˜‹”‘‡–ƒŽ nonǦ› ‘„ƒ –‡”‹ƒŽ •’‡ ‹‡• ™‡”‡ ƒŽ•‘ ˆ‘—† –‘ Šƒ˜‡ ƒ’’”‡ ‹ƒ„Ž‡ —„‡”• ‘ˆ M. tuberculosis‘•Ǧ”‡‰—Ž‘‡ ‘†‡†‘”–Š‘Ž‘‰•Ǥˆ‹–‡”‡•–ǡ–Š‡‘•”‡•’‘•‡”‡‰—Žƒ–‘” ‹–•‡Žˆǡ ˜͵ͳ͵͵ ǡ ™ƒ• ˆ‘—† ‹ ƒŽ‘•– ƒŽŽ •’‡ ‹‡• ‡šƒ‹‡† ȋ™‹–Š –Š‡ ‡š ‡’–‹‘ ‘ˆ M. lepraeǡ ™Š‹ Š ‹• ‘–‘”‹‘—• ˆ‘” ‹–• †‘™•‹œ‡† ‰‡‘‡ ȋͻȌȌǤ ˜͵ͳ͵͵  ‡ ‘†‡• ƒ –”ƒ• ”‹’–‹‘ˆƒ –‘”–Šƒ–‡†‹ƒ–‡•–Š‡Š›’‘š‹ ”‡•’‘•‡‘ˆM.tuberculosisȋͳͶǡʹ͹ǡ͵͵ǡ ͳ͵͵.

(55) Chapter6. ͵Ͷǡ ͵ͻȌǤ Š‡ ™‹†‡•’”‡ƒ† ’”‡•‡ ‡ ‘ˆ ˜͵ͳ͵͵  ‘”–Š‘Ž‘‰• ƒ† ‘–Š‡” ‡„‡”• ‘ˆ –Š‡ †‘”ƒ › ”‡‰—Ž‘ •—‰‰‡•– –Šƒ– ƒ†ƒ’–ƒ–‹‘ –‘ Š›’‘š‹ƒ ‹• ƒ Šƒ”ƒ –‡”‹•–‹  •Šƒ”‡† „› „‘–Š ’ƒ–Š‘‰‡‹  ƒ† ‘Ǧ’ƒ–Š‘‰‡‹  › ‘„ƒ –‡”‹ƒǡ ƒ† ‡˜‡ „› •’‡ ‹‡• ‘—–•‹†‡ –Š‡ Mycobacterium‰‡—•Ǥ

(56) –Š‡ —””‡–•–—†›ǡ’ƒ–‹‡–•™‹–Š†‘ —‡–‡†M.kansasiiƒ†M.marinum‹ˆ‡ –‹‘• ™‡”‡ ‹ Ž—†‡†Ǥ ‘–Š › ‘„ƒ –‡”‹ƒ ƒ ƒ—•‡ †‹•‡ƒ•‡ ‹ ‘–Š‡”™‹•‡ Š‡ƒŽ–Š›ǡ ‹—‘ ‘’‡–‡–‹†‹˜‹†—ƒŽ•ǤŽ–Š‘—‰ŠM.avium‹•‘”‡—„‹“—‹–‘—•Ž›’”‡•‡–‹–Š‡ ‡˜‹”‘‡–ǡ ’ƒ–‹‡–• ™‹–Š M. avium ‹ˆ‡ –‹‘ ™‡”‡ ‘– ‹ Ž—†‡† •‹ ‡ M. avium ‹ˆ‡ –‹‘• ƒ”‡ ‘ˆ–‡ ƒ••‘ ‹ƒ–‡† ™‹–Š ’”‡Ǧ‡š‹•–‹‰ †‹•‡ƒ•‡ ‘” ‹—‡ †‡ˆ‹ ‹‡ › ȋͷȌǤ —‡–‘‹–•—„‹“—‹–‘—•ƒ–—”‡ǡ‡š’‘•—”‡–‘M.avium‹‘—”•–—†›‰”‘—’• ƒŠ‘™‡˜‡” ‘–„‡‡š Ž—†‡†Ǥ ƒŽ›•‹•‘ˆ–Š‡”‡•’‘•‡•‹–Š‡M.marinum‘”M.kansasii‹ˆ‡ –‡†’ƒ–‹‡–••Š‘™‡† –Šƒ– –Š‡ ˆ‘”‡” ’ƒ–‹‡–• •‡‡‡† –‘ ”‡•’‘† ‡“—ƒŽŽ› ™‡ŽŽ –‘ ˜ͳ͹͵͵  ƒ† ˜ʹ͸ʹ͹  †‡•’‹–‡–Š‡ˆƒ ––Šƒ–M.marinum‘”–Š‘Ž‘‰•‘ˆ–Š‡•‡–™‘M.tuberculosis‰‡‡•˜ƒ”›‹ –Š‡ †‡‰”‡‡ ‘ˆ •‹‹Žƒ”‹–› ȋͷʹǤ͵Ψ ƒ† ͺͶǤͷΨ ”‡•’‡ –‹˜‡Ž›ȌǤ

(57)  ‘–”ƒ•–ǡ ”‡•’‘•‡• –‘ ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͸  ȋ ‹‰—”‡ ͵Ȍ ƒ† ˜ʹͲ͵ʹ ȋ†ƒ–ƒ ‘– •Š‘™Ȍ ȋʹͻȌ ™‡”‡ ’”ƒ –‹ ƒŽŽ› ƒ„•‡–†‡•’‹–‡–Š‡’”‡•‡ ‡‘ˆ‘”–Š‘Ž‘‰•‘ˆ–Š‡•‡‰‡‡•‹M.marinumǤ ‹‰Š”‡•’‘•‡• –‘ M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͸ ǡ ƒ† ˜ʹ͸ʹ͹  ™‡”‡ ‘„•‡”˜‡† ‹ –Š‘•‡ ™Š‘ ™‡”‡ ‹–‡•‡Ž› ‡š’‘•‡† –‘ ‡˜‹”‘‡–ƒŽ › ‘„ƒ –‡”‹ƒǤ —” •–—†› ‹• ‘– •—ˆˆ‹ ‹‡–Ž› ’‘™‡”‡† –‘ ‡š’Žƒ‹ –Š‡•‡ ’ƒ”–‹ —Žƒ” ‘„•‡”˜ƒ–‹‘•Ǥ‡Ž‹‹–ƒ–‹‘‹•–Šƒ–Ž‡˜‡Ž•‘ˆ‡š’‘•—”‡–‘‹–Š‡Žƒ––‡”‰”‘—’ƒ”‡ —“—ƒ–‹ˆ‹‡†ƒ•‘˜ƒŽ‹†•‡–‘ˆ ”‹–‡”‹ƒ‹•ƒ˜ƒ‹Žƒ„Ž‡ǤŽ–Š‘—‰Š–Š‡•ƒŽŽ—„‡”•ƒ› Šƒ˜‡ ƒ—•‡†•‘‡‘ˆ–Š‡‘„•‡”˜‡††‹ˆˆ‡”‡ ‡•ǡ‹–ƒŽ•‘”‡ƒ‹•’‘••‹„Ž‡–Šƒ–†‹ˆˆ‡”‡– ‹—‡”‡ ‘‰‹–‹‘’”‘ˆ‹Ž‡•ƒ›Šƒ˜‡†‡˜‡Ž‘’‡†•’‡ ‹ˆ‹ ƒŽŽ›ˆ‘ŽŽ‘™‹‰‹ˆ‡ –‹‘ ‘” ‡š’‘•—”‡ǡ †—‡ –‘ ’‘••‹„Ž‡ †‹ˆˆ‡”‡ ‡• ‹ ‡š’”‡••‹‘ ‘ˆ ƒ–‹‰‡•Ǥ ††‹–‹‘ƒŽŽ›ǡ ‹—‘Ǧ‘†—Žƒ–‘”› ‡ˆˆ‡ –• ‘ˆ ”‡’‡ƒ–‡† › ‘„ƒ –‡”‹ƒŽ ‹ˆ‡ –‹‘Ȁ‡š’‘•—”‡ ƒ› Šƒ˜‡ •Šƒ’‡†–Š‡‘„•‡”˜‡†”‡ ‘‰‹–‹‘’”‘ˆ‹Ž‡Ǥ

(58) ƒ› ƒ•‡ǡˆ—”–Š‡”•–—†‹‡•™‹ŽŽ„‡‡‡†‡†–‘ ‘ˆ‹”ƒ†‡š–‡†–Š‡•‡ˆ‹†‹‰•Ǥ

(59)  ‘ Ž—•‹‘ǡ™‡†‘ —‡–Ǧ ‡ŽŽ‹—‹–›ȋ

(60) J”‡•’‘•‡•Ȍ–‘M.tuberculosis‘•Ǧ ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ‹ ‹†‹˜‹†—ƒŽ• ‹ˆ‡ –‡† ™‹–Š ‘” ‡š’‘•‡† –‘ ǡ ‹ –Š‡ ƒ„•‡ ‡‘ˆM.tuberculosis‹ˆ‡ –‹‘ǡM.tuberculosis‡š’‘•—”‡‘” ˜ƒ ‹ƒ–‹‘ǤŠ‡ ”‡•—Ž–• Ž‡† •—’’‘”– –‘ –Š‡ Š›’‘–Š‡•‹• –Šƒ– M. tuberculosis ‘•Ǧ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡ †‹”‡ –‡† ”‡•’‘•‡• ƒ „‡ –Š‡ ”‡•—Ž– ‘ˆ ‡š’‘•—”‡ –‘ ‘” ‹ˆ‡ –‹‘ ™‹–Š ”‘••Ǧ ”‡ƒ –‹‰ Ǥ Š‡ ”‡•—Ž–• ƒ”‡ ‘””‘„‘”ƒ–‡† „› –Š‡ ’”‡•‡ ‡ ‘ˆ ‘”–Š‘Ž‘‰• ‘ˆ ƒ› †‹ˆˆ‡”‡–M.tuberculosis‘•ƒ–‹‰‡•‹‡˜‹”‘‡–ƒŽ› ‘„ƒ –‡”‹ƒƒ•™‡ŽŽƒ•‘Ǧ › ‘„ƒ –‡”‹ƒǤ”‹‘”•–—†‹‡•Šƒ˜‡•—‰‰‡•–‡†•‹‰‹ˆ‹ ƒ–‡ˆˆ‡ –•‘ˆ’”‹‘”•‡•‹–‹œƒ–‹‘„›  ‘   ˜ƒ ‹ƒ–‹‘ ƒ† Š‘•– ‹—‹–› –‘ M. tuberculosisǡ „—– –Š‡ ƒ–‹‰‡• ‹˜‘Ž˜‡† Šƒ˜‡ ‘– „‡‡ ‹†‡–‹ˆ‹‡† ȋͳ͵ǡ ʹͷǡ ʹ͸ȌǤ —” ”‡•—Ž–• ™ƒ””ƒ– ‘”‡ •’‡ ‹ˆ‹  •–—†‹‡•–‘ƒƒŽ›•‡–Š‡ ‘–”‹„—–‹‘ƒ†‹ˆŽ—‡ ‡‘ˆ ”‘••Ǧ”‡ƒ –‹˜‡‹—‹–›ˆ‘ŽŽ‘™‹‰  ‹ˆ‡ –‹‘ ‘ Š‘•– ”‡•’‘•‡• –‘ M. tuberculosisǡ   ƒ† ’‘–‡–‹ƒŽ ‘˜‡Ž  ˜ƒ ‹‡•Ǥ  . ͳ͵Ͷ.

(61) NTMinducedresponsestoM.tuberculosisDosRantigens. Acknowledgements Š‹• ™‘” ™ƒ• •—’’‘”–‡† „› ƒ ‰”ƒ– ˆ”‘ –Š‡ ‘—†ƒ–‹‘ ‹ ”‘„‹‘Ž‘‰› ‡‹†‡ǡ –Š‡ —”‘’‡ƒ ‘‹••‹‘ ™‹–Š‹ –Š‡ ͸–Š ”ƒ‡™‘” ”‘‰”ƒ‡ǡ ‘–”ƒ – ‘Ǥ  ǦǦ ʹͲͲ͵ǦͷͲ͵͵͸͹ ȋŠ‡ –‡š– ”‡’”‡•‡–• –Š‡ ƒ—–Š‘”•ǯ ˜‹‡™• ƒ† †‘‡• ‘– ‡ ‡••ƒ”‹Ž› ”‡’”‡•‡–ƒ’‘•‹–‹‘‘ˆ–Š‡‘‹••‹‘™Š‘™‹ŽŽ‘–„‡Ž‹ƒ„Ž‡ˆ‘”–Š‡—•‡ƒ†‡‘ˆ•— Š ‹ˆ‘”ƒ–‹‘Ȍ ƒ† –Š‡ ‹ŽŽ ƒ† ‡Ž‹†ƒ ƒ–‡• ‘—†ƒ–‹‘ǡ ”ƒ† ŠƒŽŽ‡‰‡• ‹ Ž‘„ƒŽ ‡ƒŽ–Šȋ ͸͓͹Ͷǡ ͳʹ͓ͺʹȌǤ ‡–Šƒ‘”‹‡”‹•ˆ‘”Š‡”‡ˆˆ‘”–•‹‘„–ƒ‹‹‰„Ž‘‘†•ƒ’Ž‡•ˆ‘”–Š‹••–—†›ƒ†™‡ –Šƒ–Š‡‰”‘—’‘ˆ ƒǦ‘—–‡””‹ŒˆŠ‘—–ˆ‘”•›–Š‡•‹•‘ˆǦ͸ƒ† ǦͳͲ’‡’–‹†‡•Ǥ. ͳ͵ͷ.

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