• No results found

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

N/A
N/A
Info
Downloaden
Protected

Academic year: 2021

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

Copied!
19
0
0

Bezig met laden.... (Bekijk nu de volledige tekst)

Download het nu ( 19 pagina )

Hele tekst

(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)  Chapter4 LackofimmuneresponsestoMycobacterium tuberculosisDosRregulonproteinsfollowing MycobacteriumbovisBCGvaccination.         . ƒ›‘—‰‹ǡͳ‡‹‡‡ ‡Ž—ǡͳ–‡˜‡ Ǥ‹–Šǡʹƒ†ƒǤ–‡™ƒ”–ǡ͵‡‹‡‡ Ǥ ”‹‰‰‡ǡͳ‡‡•ǤǤǤ ”ƒ‡ǡͳƒ”Ž‡‡ ǤǤ‡”†—›ǡͳ”‹•–ƒǤ˜ƒ‡‹Œ‰ƒƒ”†‡ǡͳƒ”–‹

(3) Ǥ‘•—‹Žǡ͵ ƒœ‡ŽǤ‘ ”‡ŽŽǡʹ”‹• —›‰‡ǡͶ‘ ǤǤ––‡Š‘ˆˆǡͳƒ†‹ Š°ŽǤŽ‡‹ͳ  ͳ‡’ƒ”–‡–‘ˆ

(4) —‘Š‡ƒ–‘Ž‘‰›ƬŽ‘‘†”ƒ•ˆ—•‹‘ƒ†‡’ƒ”–‡–‘ˆ

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

(6) ˆ‡ –‹‘—•ƒ† ”‘’‹ ƒŽ‹•‡ƒ•‡•ǡ‘†‘ Š‘‘Ž‘ˆ ›‰‹‡‡Ƭ”‘’‹ ƒŽ‡†‹ ‹‡ǡ‡’’‡Ž–”‡‡–ǡ‘†‘ǡ ‹–‡†‹‰†‘Ǣ͵‡’ƒ”–‡–‘ˆ‹ ”‘„‹‘Ž‘‰›ǡ‹˜‡”•‹–›‘ˆ‘Ž‘”ƒ†‘ ‡ƒŽ–Š ‹‡ ‡•‡–”‡ǡ ǢͶƒ„‘”ƒ–‘”›‘ˆ› ‘„ƒ –‡”‹ƒŽ

(7) —‘Ž‘‰›ǡ

(8) Ǧƒ•–‡—”

(9) •–‹–—–‡ǡͳͳͺͲ”—••‡Ž•ǡ ‡Ž‰‹—  InfectImmun.2007Jul;75(7):35233530.. .

(10) Chapter4. Abstract    ‹• ™‹†‡Ž› —•‡† ƒ• ƒ ˜ƒ ‹‡ ƒ‰ƒ‹•– –—„‡” —Ž‘•‹• ȋȌ †‡•’‹–‡ ‹–• ˜ƒ”‹ƒ„Ž‡ ’”‘–‡ –‹˜‡ ‡ˆˆ‹ ƒ ›Ǥ ‡Žƒ–‹˜‡Ž› Ž‹––Ž‡ ‹• ‘™ ƒ„‘—– –Š‡ ‹—‡ ”‡•’‘•‡ ’”‘ˆ‹Ž‡• ˆ‘ŽŽ‘™‹‰   ˜ƒ ‹ƒ–‹‘ ‹ ”‡Žƒ–‹‘ –‘ ’”‘–‡ –‹‘ ƒ‰ƒ‹•– Ǥ ‡”‡ ™‡ –‡•–‡† ™Š‡–Š‡”   ˜ƒ ‹ƒ–‹‘ ”‡•—Ž–• ‹ ‹—‡ ”‡•’‘•‡• –‘ ‘• ȋ˜͵ͳ͵͵ Ȍ ”‡‰—Ž‘ ‡ ‘†‡† ’”‘–‡‹•Ǥ Š‡•‡ •‘Ǧ ƒŽŽ‡†  Žƒ–‡ › ƒ–‹‰‡• ƒ”‡ –ƒ”‰‡–‡† „› –Š‡ ‹—‡ •›•–‡ †—”‹‰ ’‡”•‹•–‡– Mycobacterium tuberculosis ‹ˆ‡ –‹‘ ƒ† Šƒ˜‡ „‡‡ ƒ••‘ ‹ƒ–‡†™‹–Š‹—‹–›ƒ‰ƒ‹•–Žƒ–‡–M.tuberculosis‹ˆ‡ –‹‘Ǥ InsilicoƒƒŽ›•‹•‘ˆ–Š‡‘•”‡‰—Ž‘‹ ƒ†M.tuberculosis•Š‘™‡†ƒ–Ž‡ƒ•–ͻ͹Ψ Š‘‘Ž‘‰› ‹ ƒ‹‘ ƒ ‹† •‡“—‡ ‡ǡ ™‹–Š Ͷͳ ‘—– ‘ˆ Ͷͺ ‰‡‡• „‡‹‰ ‹†‡–‹ ƒŽǤ ”ƒ• ”‹’–‹‘ƒŽ ’”‘ˆ‹Ž‹‰ ‘ˆ ͳͶ †‹ˆˆ‡”‡–   •–”ƒ‹•ǡ —†‡” Š›’‘š‹ƒ ƒ† ‹–”‹  ‘š‹†‡ ‡š’‘•—”‡ in vitro, ”‡˜‡ƒŽ‡† ƒ ˆ— –‹‘ƒŽ ‘• ”‡‰—Ž‘ •‹‹Žƒ” –‘ –Šƒ– ‘„•‡”˜‡† ‹ M. tuberculosisǤ ‡š–ǡ ™‡ ƒ••‡••‡† Š—ƒ ‹—‡ ”‡•’‘•‡• –‘ ƒ •‡”‹‡• ‘ˆ ‹—‘Ǧ†‘‹ƒ–  Žƒ–‡ ›ƒ–‹‰‡•ƒ†ˆ‘—†–Šƒ– ˜ƒ ‹ƒ–‹‘ˆƒ‹Ž•–‘‹†— ‡•‹‰‹ˆ‹ ƒ–”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡•Ǥ ‹‹Žƒ” ”‡•—Ž–• ™‡”‡ ˆ‘—† ‹   ˜ƒ ‹ƒ–‡† Ȁ  ‹ ‡Ǥ

(11)  ‘–”ƒ•–ǡ ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ‘„•‡”˜‡† ‹ ‹†‹˜‹†—ƒŽ• ™‹–Š •—•’‡ –‡† ‡š’‘•—”‡–‘ȋƒ•‹†‹ ƒ–‡†„›’‘•‹–‹˜‡

(12) J”‡•’‘•‡•–‘•’‡ ‹ˆ‹ ƒ–‹‰‡•Ǧ ͸ ƒ†  ǦͳͲȌǡ ƒ† ‹ ‹ ‡ ˜ƒ ‹ƒ–‡† ™‹–Š ’Žƒ•‹†  ‡ ‘†‹‰ •‡Ž‡ –‡† Žƒ–‡ › ƒ–‹‰‡•Ǥ ‹ ‡‹—‡”‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡•Šƒ˜‡„‡‡ƒ••‘ ‹ƒ–‡†™‹–Š ‘–”‘Ž‘ˆ Žƒ–‡– M. tuberculosis ‹ˆ‡ –‹‘ǡ ‘—” ˆ‹†‹‰• •—’’‘”– –Š‡ †‡˜‡Ž‘’‡– ‘ˆ ˜ƒ ‹ƒ–‹‘ •–”ƒ–‡‰‹‡• ‹ ‘”’‘”ƒ–‹‰ ‘• ”‡‰—Ž‘ ƒ–‹‰‡• –‘ ‘’Ž‡‡– ƒ† ‹’”‘˜‡ –Š‡ —””‡– ˜ƒ ‹‡Ǥ. ͺ͸.

(13) ImmunitytoTBlatencyantigensafterBCGvaccination. Introduction —„‡” —Ž‘•‹•ȋȌ ”‡ƒ‹•ƒƒŒ‘”‰Ž‘„ƒŽŠ‡ƒŽ–Š–Š”‡ƒ–Ǥƒ Š›‡ƒ”ƒ„‘—–‡‹‰Š–‹ŽŽ‹‘ ‡™ ƒ•‡•‘ —”ƒ†–™‘‹ŽŽ‹‘’‡‘’Ž‡†‹‡ˆ”‘Ǥ

(14) –‹•‡•–‹ƒ–‡†–Šƒ–‘‡–Š‹”† ‘ˆ–Š‡™‘”Ž†’‘’—Žƒ–‹‘‹•Žƒ–‡–Ž›‹ˆ‡ –‡†™‹–ŠMycobacteriumtuberculosisǤ ”‘–Š‹• ˜ƒ•–Žƒ–‡–”‡•‡”˜‘‹”ƒ„‘—–ͳͲΨ‘ˆ‹ˆ‡ –‡†’‡‘’Ž‡ƒ”‡‡š’‡ –‡†–‘†‡˜‡Ž‘’‘˜‡”– †‹•‡ƒ•‡†—”‹‰–Š‡‹”Ž‹ˆ‡–‹‡Ǥ ‘™‡˜‡”ǡ™‹–Š–Š‡‡š’ƒ†‹‰

(15) ǦͳȀ

(16) ’ƒ†‡‹ –Š‹• —„‡”‹•‡š’‡ –‡†–‘•‘ƒ”‹–Š‡‡š–ˆ‡™†‡ ƒ†‡•ȋͳͳǡͶʹȌǤ Š‡ —””‡–˜ƒ ‹‡‹•–Š‡Ž‹˜‡ƒ––‡—ƒ–‡†„ƒ –‡”‹—Mycobacteriumbovisƒ ‹ŽŽ—• ƒŽ‡––‡Ǧ —±”‹ȋ ȌǤ ‹•‘™–‘’”‘–‡ –ƒ‰ƒ‹•–•‡˜‡”‡ˆ‘”•‘ˆ‹›‘—‰ Š‹Ž†”‡ƒ†ƒ‰ƒ‹•–Ž‡’”‘•›Ǥ ‘™‡˜‡”ǡ‹–†‘‡•‘–‡ˆˆ‹ ‹‡–Ž›ƒ† ‘•‹•–‡–Ž›’”‘–‡ – ƒ‰ƒ‹•– ’—Ž‘ƒ”›  ‹ ƒ†—Ž–•ǡ –Š‡ ‘•– ’”‡˜ƒŽ‡– ƒ† ‘–ƒ‰‹‘—• ˆ‘” ‘ˆ Ǣ ‡‹–Š‡”†‘‡• ‘ˆˆ‡”’”‘–‡ –‹‘ˆ”‘”‡ƒ –‹˜ƒ–‹‘‘ˆŽƒ–‡–‹ˆ‡ –‹‘ǤŠ‹•’ƒ”–Ž› ‡š’Žƒ‹•™Š› Šƒ•Ž‹––Ž‡‹’ƒ –‘–Š‡‰Ž‘„ƒŽ‡’‹†‡‹ †‡•’‹–‡‹–•™‹†‡•’”‡ƒ† —•‡ƒ•ƒ’”‘’Š›Žƒ –‹ ˜ƒ ‹‡ȋͶ͵ȌǤ˜‡”–Š‡›‡ƒ”•ƒ›Š›’‘–Š‡•‡•Šƒ˜‡„‡‡’—– ˆ‘”™ƒ”†–‘‡š’Žƒ‹–Š‡ƒ’’ƒ”‡–˜ƒ”‹ƒ„‹Ž‹–›‹’”‘–‡ –‹˜‡‡ˆˆ‹ ƒ ›‘ˆ ǡ™Š‹ Š˜ƒ”‹‡• ˆ”‘ Ͳ –‘ ͺͲΨ ȋͳ͸ȌǤ š’Žƒƒ–‹‘• ˆ‘” –Š‹• ‹ ‘•‹•–‡ › ‹ Ž—†‡ †‹ˆˆ‡”‡ ‡• ‹ –”‹ƒŽ ‡–Š‘†‘Ž‘‰›ǡ ’‘’—Žƒ–‹‘ Š‘•– ‰‡‡–‹ •ǡ —•‡ ‘ˆ †‹ˆˆ‡”‡–   ˜ƒ ‹‡ •–”ƒ‹• ȋʹȌ ƒ† Š‡–‡”‘‰‡‡‘—• ‹—‹–› –‘ ƒ ˜ƒ”‹‡–› ‘ˆ ‡˜‹”‘‡–ƒŽ › ‘„ƒ –‡”‹ƒ –Šƒ– ƒ› ‹–‡”ˆ‡”‡™‹–Šǡ‘”ƒ•–Š‡’”‘–‡ –‹‘’”‘˜‹†‡†„› ȋ͹ǡʹ͸ȌǤ

(17) —‡ ”‡•’‘•‡ ’”‘ˆ‹Ž‡• ˆ‘ŽŽ‘™‹‰   ˜ƒ ‹ƒ–‹‘ ‘’”‹•‡ ›”‹ƒ† ‡ˆˆ‡ –‘” ‡ Šƒ‹••ǡ —Ž–‹’Ž‡ Ǧ ‡ŽŽ •—„•‡–• ƒ† ƒ› –ƒ”‰‡–‡† ƒ–‹‰‡•Ǥ   ‹• ƒ’ƒ„Ž‡ ‘ˆ ‹†— ‹‰ Šͳ ”‡•’‘•‡• ȋ͵ͺȌǡ ™Š‹ Š ƒ”‡ ”‹–‹ ƒŽ ‹ › ‘„ƒ –‡”‹ƒŽ ‹ˆ‡ –‹‘• ȋͳ͹ȌǤ

(18)  ƒ††‹–‹‘ǡ   ‹• ƒŽ•‘ ƒ’ƒ„Ž‡ ‘ˆ ‹†— ‹‰ „‘–Š ͶΪ ƒ† ͺΪ  ‡ŽŽ ”‡•’‘•‡• –‘ ƒ–‹‰‡• •Šƒ”‡† ™‹–Š M. tuberculosi•ǡ •— Š ƒ• •‡ ”‡–‡† ƒ–‹‰‡• ‘ˆ –Š‡ › ‘Ž›Ž –”ƒ•ˆ‡”ƒ•‡ˆƒ‹Ž›ȋ‰ͺͷȌȋͳͻǡʹͲǡ͵͵Ȍƒ†‘Ǧ†‡Ž‡–‡†‡„‡”•‘ˆ–Š‡Ǧ͸ˆƒ‹Ž› ȋe.g.ͳͲǤͶȌȋ͵ʹȌǡ„—–ƒŽ•‘Š‡ƒ–•Š‘ ’”‘–‡‹•Ž‹‡ •’͸ͷƒ† •’͹ͲȋͳͷȌǤ ‘™‡˜‡”ǡ ‹– ‹• •–‹ŽŽ ‘– ‘’Ž‡–‡Ž› ‘™ Š‘™ –Š‡•‡ ƒ† ‘–Š‡” ƒ–‹‰‡Ǧ•’‡ ‹ˆ‹  ‹—‡ ”‡•’‘•‡• ‘–”‹„—–‡–‘’”‘–‡ –‹‘ƒ‰ƒ‹•–Ǥ ‡ ‡–Ž› ™‡ •–—†‹‡† Š—ƒ Ǧ ‡ŽŽ ”‡•’‘•‡• –‘ ‘• ȋ˜͵ͳ͵͵ Ȍ ”‡‰—Ž‘ ‡ ‘†‡† ƒ–‹‰‡• ȋ”‡ˆ‡””‡† –‘ ƒ•  Žƒ–‡ › ƒ–‹‰‡•Ȍ ‘ˆ M. tuberculosis ȋʹͶȌǤ ‡ ‘„•‡”˜‡† ’”‡ˆ‡”‡–‹ƒŽ”‡ ‘‰‹–‹‘‘ˆŽƒ–‡ ›ƒ–‹‰‡•„›ƒ–‘—š•‹–‡•–’‘•‹–‹˜‡‹†‹˜‹†—ƒŽ• ™‹–Š Žƒ–‡–  ‘’ƒ”‡† –‘ ’ƒ–‹‡–• ™‹–Š  †‹•‡ƒ•‡ǡ •—‰‰‡•–‹‰ –Šƒ– –Š‡•‡ ‹—‡ ”‡•’‘•‡• ƒ”‡ ƒ••‘ ‹ƒ–‡† ™‹–Š Žƒ–‡–  †‹•‡ƒ•‡ ȋͳͶǡʹͶȌǤ Š‡ ‘• ”‡‰—Ž‘ ‹• ‡š’”‡••‡†„›–—„‡” Ž‡„ƒ ‹ŽŽ‹—†‡”invitro ‘†‹–‹‘•‘ˆŠ›’‘š‹ƒƒ†Ž‘™†‘•‡‹–”‹  ‘š‹†‡ ‡š’‘•—”‡ ȋͶͲȌǡ ƒ† ‹

(19) JǦƒ –‹˜ƒ–‡† ƒ ”‘’Šƒ‰‡• ȋ͵ͲȌǤ Š‡•‡ ‘†‹–‹‘• ƒ”‡ –Š‘—‰Š– –‘ ‹‹  –Š‡ ‡˜‹”‘‡– ‡ ‘—–‡”‡† „› –—„‡” Ž‡ „ƒ ‹ŽŽ‹ in vivo ™Š‡ ’‡”•‹•–‹‰‹‹—‘Ǧ ‘’‡–‡–Š‘•–•ȋ͵ͳȌǤ ‡ ‘ˆ –Š‡ ‘•– ƒ„—†ƒ–Ž› ’”‘†— ‡† ’”‘–‡‹• †—”‹‰ Š›’‘š‹ƒ ‹• –Š‡ ͳ͸Ǧƒ DǦ ”›•–ƒŽŽ‹Š‘‘Ž‘‰ •’ȋ˜ʹͲ͵ͳ ȌȋͳʹȌǤ •’‹•’ƒ”–‘ˆ–Š‡‘•”‡‰—Žƒ–‡†‰‡‡•ƒ† ‹• –ƒ”‰‡–‡† „› „‘–Š ͶΪ  ‡ŽŽ• ȋͻǡͶͳȌ ƒ† ͺΪ  ‡ŽŽ• ȋͳͲȌǤ

(20) –‡”‡•–‹‰Ž›ǡ ‹ˆƒ–• ˜ƒ ‹ƒ–‡† ™‹–Š   †‘ ‘– ‘—– ‹—‡ ”‡•’‘•‡• –‘ •’ǡ ™Š‡”‡ƒ• –Š‡› ƒ”‡ ƒ’ƒ„Ž‡ ‘ˆ ‰‡‡”ƒ–‹‰ ‹—‡ ”‡•’‘•‡• –‘ ‘–Š‡”  ƒ–‹‰‡• ȋ͵ͻȌǤ Š‡ ƒ„•‡ ‡ ‘ˆ ‹—‡”‡•’‘•‡•–‘–Š‹•’ƒ”–‹ —Žƒ”Žƒ–‡ ›ƒ–‹‰‡Ž‡†—•–‘–Š‡ˆ‘”—Žƒ–‹‘‘ˆ‘—” Š›’‘–Š‡•‹•Ǥ

(21) –Š‹••–—†›™‡–‡•–‡†–Š‡Š›’‘–Š‡•‹•–Šƒ– ˜ƒ ‹ƒ–‹‘‹Š—ƒ•ƒ†. ͺ͹.

(22) Chapter4. ‹ƒ‘—•‡‘†‡Žˆƒ‹Ž•–‘‹†— ‡‹—‡”‡•’‘•‡•–‘‘–‘Ž› •’„—–‰‡‡”ƒŽŽ›–‘  Žƒ–‡ › ƒ–‹‰‡• –Šƒ– ƒ”‡ –ƒ”‰‡–‡† „› –Š‡ ‹—‡ •›•–‡ †—”‹‰ Žƒ–‡– M. tuberculosis‹ˆ‡ –‹‘Ǥ . MaterialsandMethods InvitroexpressionoftheBCGDosRregulon š’”‡••‹‘‘ˆ–Š‡‘•”‡‰—Ž‘„›M.tuberculosis•–”ƒ‹ ͵͹˜ƒ†ͳͶ†‹ˆˆ‡”‡–  •–”ƒ‹• ȋ‘ƒ—‰Š– ȋ  Ȍǡ ƒ•–‡—” ͳͶͲǡ ™‡†‡ǡ ‘ƒ—‰Š–ǡ ƒ’ƒǡ ƒƒ†ƒǡ ‹‡–ƒǡ ƒ‹•Š 

(23)  ͳ͵͵ͳǡ —••‹ƒǡ ”ƒœ‹Žǡ ‹ ‡ǡ ‘• ‘™ǡ ƒ•–‡—” ͳ͵͵ ƒ† ƒ•–‡—” ͳͳ͹͵ǡ ȋ‹†Ž›’”‘˜‹†‡†„›”Ǥ‰‡Ž‘

(24) œœ‘ǡ‘Ž‘”ƒ†‘–ƒ–‡‹˜‡”•‹–›ǡȌ™ƒ•†‡–‡”‹‡† —•‹‰ •–ƒ†ƒ”† ‡–Š‘†• ‘ˆ ‹ ”‘ƒ””ƒ›  ‡š’”‡••‹‘ ƒƒŽ›•‹• ƒ• ’”‡˜‹‘—•Ž› †‡• ”‹„‡† ȋͶͲȌǤ ”‹‡ˆŽ›ǡ › ‘„ƒ –‡”‹ƒ ™‡”‡ ‰”‘™ ‹ ͹ ͻ ‡†‹— ȋ•—’’Ž‡‡–‡† ™‹–Š „‘˜‹‡ •‡”— ƒŽ„—‹ǡ ƒŽǡ ‰Ž— ‘•‡ǡ ƒ† ‰Ž› ‡”‘ŽȌ ‹ ʹͷͲ Ž ˜‡–‡† –‹••—‡ —Ž–—”‡ˆŽƒ••ƒ†•Šƒ‹‰ͻͲ”’Ǥ–ƒ —Ž–—”‡ͲǤͳͷǡ͵ͲŽ —Ž–—”‡•™‡”‡’Žƒ ‡†‹ ƒ ƒƒ‡”‘„‹  ƒ•ƒ Šƒ„‡” ȋ‡ –‘ǡ ‹ ‹•‘ ƒ† ‘’ƒ›Ȍ ƒ† ‘–‹—‡† –‘ •Šƒ‡Ǥ ‡ˆ‡”‡ ‡ —Ž–—”‡• ™‡”‡ –”‡ƒ–‡† ‹ –Š‡ •ƒ‡ ƒ‡” „—– ‘– ’Žƒ ‡† ‹ –Š‡ ƒƒ‡”‘„‹  Šƒ„‡”Ǥ ˆ–‡” ˆ‘—” Š‘—”•  ™ƒ• ‹•‘Žƒ–‡† ƒ† ‹ ”‘ƒ””ƒ› ƒƒŽ›•‹• ™ƒ• ‘†— –‡†ƒ•’”‡˜‹‘—•Ž›”‡’‘”–‡†ȋͶͲȌ™‹–Š‘Ž‹‰‘— Ž‡‘–‹†‡‹ ”‘ƒ””ƒ›•’”‘˜‹†‡† „›‘Ž‘”ƒ†‘–ƒ–‡‹˜‡”•‹–›–Š”‘—‰Š–Š‡—„‡” —Ž‘•‹•ƒ ‹‡‡•–‹‰ƒ†‡•‡ƒ” Š ƒ–‡”‹ƒŽ• ‘–”ƒ –Ǥ  Studysubjects Crosssectionalstudy(TheNetherlands) ‘’”‹•‹‰Ͷ͵Š‡ƒŽ–Š›ƒ†—Ž–’‡”•‘•ȋͳͲƒŽ‡ǡ ͵͵ˆ‡ƒŽ‡Ȍ™Š‘™‡”‡˜ƒ ‹ƒ–‡†™‹–Š „‡–™‡‡ͳƒ†͵͹›‡ƒ”•„‡ˆ‘”‡–Š‹••–—†› ȋ‡†‹ƒ –‹‡ ƒˆ–‡” ˜ƒ ‹ƒ–‹‘ ʹͷ ›‡ƒ”•ȌǤ Š‡ ƒ‰‡ ƒ– –Š‡ –‹‡ ‘ˆ „Ž‘‘† •ƒ’Ž‹‰ ”ƒ‰‡†ˆ”‘ʹͲǦ͸Ͳ›‡ƒ”•ǤŠ‹”–›Ǧ‡‹‰Š–‹†‹˜‹†—ƒŽ•™‡”‡‘ˆ—– Š‘”‹‰‹Ǣ–Š‡”‡ƒ‹‹‰ ͷ ‹†‹˜‹†—ƒŽ• ™‡”‡ ‘ˆ ‡”ƒǡ ”‹–‹•Šǡ ‡–Š‡”Žƒ†• –‹ŽŽ‡ƒǡ Š‹Ž‹’’‹‡ ƒ† ‘—–Š ‘”‡ƒ †‡• ‡–Ǥ Ž‘‘† •ƒ’Ž‡• ™‡”‡ ‘„–ƒ‹‡† ˆ”‘ ƒŽŽ •–—†› •—„Œ‡ –• ƒˆ–‡” ™”‹––‡ ‹ˆ‘”‡† ‘•‡–™ƒ•‘„–ƒ‹‡†ǡ—•‹‰•–ƒ†ƒ”†˜‡‘—•’— –—”‡ƒ†„Ž‘‘† ‘ŽŽ‡ –‹‘ ‹Š‡’ƒ”‹‹œ‡†–—„‡•Ǥ—„•‡“—‡–Ž›ǡ’‡”‹’Š‡”ƒŽ„Ž‘‘†‘‘— Ž‡ƒ” ‡ŽŽ•ȋȌ™‡”‡ ‹•‘Žƒ–‡† —•‹‰ ƒ ‹ ‘ŽŽ †‡•‹–› ‰”ƒ†‹‡– ƒ† •–‘”‡† ‹ Ž‹“—‹† ‹–”‘‰‡ ƒ• †‡• ”‹„‡† ’”‡˜‹‘—•Ž› ȋʹͶȌǤ Š‡ •–—†› ’”‘–‘ ‘Ž ȋʹͲ͹ȀͻͻȌ ™ƒ• ƒ’’”‘˜‡† „› –Š‡ ‡–Š‹ ƒŽ ”‡˜‹‡™ „‘ƒ”†‘ˆ–Š‡‡‹†‡‹˜‡”•‹–›‡†‹ ƒŽ‡–”‡Ǥ Longitudinal BCG vaccination study (United Kingdom) ‘’”‹•‹‰ ƒ†‘Ž‡• ‡–• ™Š‘ ™‡”‡”‡ ”—‹–‡†–Š”‘—‰Š–Š‡• Š‘‘Ž•ǯ ˜ƒ ‹ƒ–‹‘”‘‰”ƒ‡ȋͶȌǤ‡ƒ”ͺ’—’‹Ž• ȋƒ‰‡ ͳʹǦͳ͵ ›‡ƒ”•Ȍ ™‡”‡ ‹ˆ‘”‡† ˜‡”„ƒŽŽ› ƒ† „› ƒ ‹ˆ‘”ƒ–‹‘ •Š‡‡– ‘ˆ –Š‡ •–—†› ƒ† ”‡ ”—‹–‡– ’”‘ ‡‡†‡† ˆ‘ŽŽ‘™‹‰ ™”‹––‡ ‹ˆ‘”‡† ‘•‡– ˆ”‘ ’ƒ”‡– ‘” ‰—ƒ”†‹ƒ ƒ† ˜‡”„ƒŽ ‘•‡– ˆ”‘ –Š‡ Š‹Ž†Ǥ š Ž—•‹‘ ”‹–‡”‹ƒ ™‡”‡ ‡˜‹†‡ ‡ ‘ˆ ’”‡˜‹‘—• ˜ƒ ‹ƒ–‹‘ȋ • ƒ”‘”˜ƒ ‹ƒ–‹‘”‡ ‘”†•Ȍ‘”•‡”‹‘—•‹ŽŽ‡••Ǥ–Š‹ ƒŽ „ƒ ‰”‘—†•‘ˆ’ƒ”–‹ ‹’ƒ–•™‡”‡ƒ•ˆ‘ŽŽ‘™•ǣŠ‹–‡”‹–‹•Šȋ͵ͲΨȌǡŠ‹–‡

(25) ”‹•Šȋ͵ΨȌǡ Žƒ ƒ”‹„„‡ƒȋʹʹΨȌǡŽƒ ˆ”‹ ƒȋͳ͵ΨȌǡŽƒ ‘–Š‡”ȋ͹ΨȌǡ•‹ƒƒ‹•–ƒȋͳʹΨȌǡ •‹ƒ‘–Š‡”ȋͷΨȌƒ†‹š‡†Ȁ‘–Š‡”ȋͺΨȌǤ. ͺͺ.

(26) ImmunitytoTBlatencyantigensafterBCGvaccination. –Š‹ ƒŽƒ’’”‘˜ƒŽˆ‘”–Š‹••–—†›™ƒ•‰‹˜‡„›–Š‡‘ ƒŽ‡•‡ƒ” Š–Š‹ •‘‹––‡‡‘ˆ ‡†„”‹†‰‡ ƒ† ƒŽ–Šƒ ‘”‡•– ‡ƒŽ–Š —–Š‘”‹–› ȋƬ Ȍ ƒ† „› –Š‡ –Š‹ • ‘‹––‡‡‘ˆ–Š‡‘†‘ Š‘‘Ž‘ˆ ›‰‹‡‡Ƭ”‘’‹ ƒŽ‡†‹ ‹‡Ǥ ƒ•‡Ž‹‡„Ž‘‘†•ƒ’Ž‡•™‡”‡ ‘ŽŽ‡ –‡†ˆ”‘’ƒ”–‹ ‹’ƒ–•ƒ––Š‡–‹‡‘ˆ–—„‡” —Ž‹•‹ –‡•–‹‰Ǥ‹–‡•–‹‰™ƒ• ƒ””‹‡†‘—–‘–Š‡˜‘Žƒ”•—”ˆƒ ‡‘ˆ–Š‡ˆ‘”‡ƒ”—•‹‰–Š‡ ‡ƒˆ –‡ Š‹“—‡ ™‹–Š –—„‡” —Ž‹ Ǥ  „ƒ•‡Ž‹‡ ‘ˆ ͳͲ Ž ‘ˆ ‹–”ƒ˜‡‘—• „Ž‘‘† ™ƒ• –ƒ‡ ƒ† –”ƒ•ˆ‡””‡† ‹–‘ –—„‡• ‘–ƒ‹‹‰ ͳͲͲ  ‘ˆ ’”‡•‡”˜ƒ–‹˜‡Ǧˆ”‡‡ •‘†‹— Š‡’ƒ”‹ ȋ‘‘’ƒ”‹ǡŠƒ”ƒ ‡—–‹ ƒŽ•–†Ǥ”‡šŠƒǡȌǤŽ‘‘†•ƒ’Ž‡•™‡”‡•‡–—’‹–Š‡ ™Š‘Ž‡„Ž‘‘†ƒ••ƒ›ƒ••‘‘ƒ•’‘••‹„Ž‡‘–Š‡•ƒ‡†ƒ›ƒ•˜‡ƒ’— –—”‡ǤŠ‡ ‡ƒˆ–‡•– ‹†—”ƒ–‹‘ ™ƒ• ‹•’‡ –‡† ƒˆ–‡” ͹ †ƒ›• ƒ† ‰”ƒ†‡† ƒ’’”‘’”‹ƒ–‡Ž› „› ‡š’‡”‹‡ ‡† —”•‡•Ǥ Š‘•‡ †—‡ –‘ ”‡ ‡‹˜‡   ˆ‘ŽŽ‘™‹‰ ƒ ‡‰ƒ–‹˜‡ ‡ƒˆ –‡•– ”‡ ‡‹˜‡†   ‹‡†‹ƒ–‡Ž›ȋαʹʹȌǤ™‘–‘ˆ‘—”™‡‡•ˆ‘ŽŽ‘™‹‰˜ƒ ‹ƒ–‹‘ǡ†‡’‡†‹‰—’‘• Š‘‘Ž ƒ˜ƒ‹Žƒ„‹Ž‹–›ǡ”‡ ”—‹–•™‡”‡”‡˜‹•‹–‡†ˆ‘”ƒˆ‘ŽŽ‘™Ǧ—’ǡͳͲŽ„Ž‘‘†•ƒ’Ž‡Ǥ  M.tuberculosisantigens ‡ ‘„‹ƒ–’”‘–‡‹•™‡”‡’”‘†— ‡†ƒ•’”‡˜‹‘—•Ž›†‡• ”‹„‡†ȋͳͺȌǤ”‹‡ˆŽ›ǡ— Ž‡‘–‹†‡ •‡“—‡ ‡• ‘ˆ •‡Ž‡ –‡† M. tuberculosis ͵͹˜ ‰‡‡• ™‡”‡ ‘„–ƒ‹‡† ˆ”‘ Š––’ǣȀȀ‰‡‘Ž‹•–Ǥ’ƒ•–‡—”Ǥˆ”Ȁ—„‡” —‹•–Ǥ ‡‡• ™‡”‡ ƒ’Ž‹ˆ‹‡† „›  ˆ”‘ ‰‡‘‹   ‘ˆ M. tuberculosis ͵͹˜ ƒ† Ž‘‡† „› ƒ–‡™ƒ› ‡ Š‘Ž‘‰› ȋ

(27) ˜‹–”‘‰‡ǡ ƒ ‹‡‰‘ǡȌ‹’ͳ͹ǡƒ„ƒ –‡”‹ƒŽ‡š’”‡••‹‘˜‡ –‘” ‘–ƒ‹‹‰ƒǦ–‡”‹ƒŽŠ‡šƒǦ Š‹•–‹†‹‡–ƒ‰ˆ‘””ƒ’‹†’—”‹ˆ‹ ƒ–‹‘™‹–Š‹ ‡ŽǦ Š‡Žƒ–‹‰”‡•‹ǤŠ‡’”‘–‡‹•™‡”‡‘˜‡”Ǧ ‡š’”‡••‡† ‹ Escherichia coli ʹͳȋ͵Ȍ ƒ† ’—”‹ˆ‹‡† ƒ• ’”‡˜‹‘—•Ž› †‡• ”‹„‡† ȋͳͺȌǤ ‡“—‡ ‹‰™ƒ•’‡”ˆ‘”‡†–‘ ‘ˆ‹”–Š‡‹†‡–‹–›‘ˆ–Š‡ Ž‘‡†ˆ”ƒ‰‡–•Ǥ‹œ‡ ƒ† ’—”‹–› ™‡”‡ Š‡ ‡† „› ‰‡Ž ‡Ž‡ –”‘’Š‘”‡•‹• ƒ† ‡•–‡” „Ž‘––‹‰ ™‹–Š ƒ–‹Ǧ ‹• ƒ–‹„‘†‹‡• ȋ

(28) ˜‹–”‘‰‡ȌǤ ‡•‹†—ƒŽ ‡†‘–‘š‹ Ž‡˜‡Ž• ™‡”‡ †‡–‡”‹‡† ™‹–Š ƒ ‹—Ž—• ‡„‘ ›–‡ ›•ƒ–‡ ƒ••ƒ› ȋƒ„”‡šȌ ƒ† ™‡”‡ ˆ‘—† –‘ „‡ „‡Ž‘™ ͷͲ

(29) Ȁ‰ ”‡ ‘„‹ƒ–’”‘–‡‹Ǥ”‘–‡‹„ƒ– Š‡•™‡”‡•—„•‡“—‡–Ž›–‡•–‡†ˆ‘”‘Ǧ•’‡ ‹ˆ‹  ‡ŽŽ •–‹—Žƒ–‹‘ƒ†ˆ‘”’‘–‡–‹ƒŽ ‡ŽŽ—Žƒ”–‘š‹ ‹–›‹Ž›’Š‘ ›–‡•–‹—Žƒ–‹‘ƒ••ƒ›•—•‹‰  ‘ˆ M. tuberculosis —‡š’‘•‡†ǡ   —˜ƒ ‹ƒ–‡†ǡ ƒ–‘—š •‹ –‡•– ‡‰ƒ–‹˜‡ Š‡ƒŽ–Š›†‘‘”•Ǥ Mycobacterium tuberculosis Ž›•ƒ–‡ǡ ‰”‘™ —†‡” Ž‘™ ‘š›‰‡ ‘†‹–‹‘• ȋȌǡ ™ƒ• ‘„–ƒ‹‡† ˆ”‘ ‰”‘™‹‰ M. tuberculosis ͵͹˜ ˆ‘” ʹͶ Š‘—”• ‹ –—„‡• ™‹–Š –‹‰Š–Ž› • ”‡™‡† ƒ’• ƒ• ’”‡˜‹‘—•Ž› †‡• ”‹„‡† ȋʹͻȌǤ Š‡ Ž‘™ ‘š›‰‡ †‡”‹˜‡† M. tuberculosis Ž›•ƒ–‡ ™ƒ• ‹†Ž› ’”‘˜‹†‡† „› ” ƒ”‡ ‡Ž†‹‰Š ƒ† ” ‡–‡” †‡”•‡ ȋ–ƒ–‡• ‡”—

(30) •–‹–—–‡ȋ

(31) Ȍǡ‘’‡Šƒ‰‡ǡ‡ƒ”ȌǤ  Invitroproliferationassays Lymphocytestimulationassays(crosssectionalBCGvaccinationstudyȌ™‡”‡’‡”ˆ‘”‡† —•‹‰‹•‘Žƒ–‡†ƒ•’”‡˜‹‘—•Ž›†‡• ”‹„‡†ȋʹͶȌǤ”‹‡ˆŽ›ǡȋͳǤͷέͳͲͷȀ™‡ŽŽȌ™‡”‡ —Ž–—”‡† ‹

(32) • ‘˜‡̵• ‘†‹ˆ‹‡†  ȋ ‹„ ‘ǡ ƒ‹•Ž‡›ǡ Ȍ •—’’Ž‡‡–‡† ™‹–Š ͳͲΨ ’‘‘Ž‡† Š—ƒ •‡”— ƒ† ͶͲ ȀŽ ’‡‹ ‹ŽŽ‹ ƒ† ͶͲ P‰ȀŽ •–”‡’–‘› ‹ǡ ‹ ͻ͸Ǧ™‡ŽŽ ”‘—†Ǧ„‘––‘ ‹ ”‘–‹–‡” ’Žƒ–‡• ȋ— ǡ ‘•‹Ž†‡ǡ ‡ƒ”Ȍ ƒ– ͵͹qǡ ͷΨ ʹǡ ‹ –Š‡ ƒ„•‡ ‡ ‘” ’”‡•‡ ‡ ‘ˆ •–‹—Žƒ–Ǥ –‹‰‡• ™‡”‡ –‡•–‡† ‹ –Š‡ ˆ‘ŽŽ‘™‹‰ ‘ ‡–”ƒ–‹‘•ǣ Žƒ–‡ › ƒ–‹‰‡•ǡ Ǧ͸ǡ  ǦͳͲ ƒ† ‰ͺͷ ƒŽŽ ƒ– ͲǤ͵͵ Pǡ M. tuberculosis Š›’‘š‹  Ž›•ƒ–‡ ƒ† ’—”‹ˆ‹‡† ’”‘–‡‹ †‡”‹˜ƒ–‹˜‡ ȋȌ ‘ˆ M. tuberculosis ȋ„ƒ– Š Ͷͻ 

(33) ǡ ‡ƒ”Ȍ ƒ– ͷ P‰ȀŽ ƒ† ’‘•‹–‹˜‡ ‘–”‘Ž ’Š›–‘Šƒ‡ƒ‰‰Ž—–‹‹. ͺͻ.

(34) Chapter4. ȋ Ȍ ȋ‡‡Žǡ Ȍ ƒ– ʹ P‰ȀŽǤ ‘–ƒŽ ˜‘Ž—‡ ™ƒ• ʹͲͲ PŽȀ™‡ŽŽǤ ŽŽ •–‹—Žƒ–‹‘• ™‡”‡ ’‡”ˆ‘”‡†‹–”‹’Ž‹ ƒ–‡Ǥ–†ƒ›͸ǡ•—’‡”ƒ–ƒ–•™‡”‡Šƒ”˜‡•–‡†ȋ͹ͷPŽȀ™‡ŽŽǡ’‘‘Ž‡†’‡” –”‹’Ž‹ ƒ–‡Ȍƒ†•–‘”‡†ƒ–ƒš‹ƒŽŽ›ȂʹͲ‘—–‹Ž—•‡‹

(35) J†‡–‡ –‹‘ƒ••ƒ›Ǥ Dilutedwholebloodassay(longitudinalBCGvaccinationstudy),™ƒ•—•‡†ƒ•’”‡˜‹‘—•Ž› †‡• ”‹„‡†ȋ͵ȌǤ

(36) •—ƒ”›,™Š‘Ž‡„Ž‘‘†™ƒ•†‹Ž—–‡†ͳ‹ͷ™‹–Š•‡”—Ǧˆ”‡‡‡†‹— ȋ

(37) ͳ͸ͶͲ•—’’Ž‡‡–‡†™‹–ŠʹǦ Ž—–ƒ‹‡ǡ

(38) ˜‹–”‘‰‡Ȍƒ†ͳͲͲPŽ™ƒ•’Žƒ–‡† ‹ͻ͸Ǧ™‡ŽŽǡ”‘—†Ǧ„‘––‘‡†–‹••—‡ —Ž–—”‡’Žƒ–‡•ȋ— ǡ‘•‹Ž†‡ǡ‡ƒ”ȌǤ–‹‰‡ ™ƒ• ƒŽ•‘ ƒ††‡† ‹ ͳͲͲ PŽ –‘ ‰‹˜‡ ƒ ˆ‹ƒŽ ™Š‘Ž‡ „Ž‘‘† †‹Ž—–‹‘ ‘ˆ ͳǣͳͲ ƒ† —Ž–—”‡ ˜‘Ž—‡ ‘ˆ ʹͲͲ PŽǤ ‡†‹— ƒ†   ȋͷ P‰ȀŽǢ ‡‡Žǡ Ȍ ‘–ƒ‹‹‰ ™‡ŽŽ• ™‡”‡ ‹ Ž—†‡†ƒ•‡‰ƒ–‹˜‡ƒ†’‘•‹–‹˜‡ ‘–”‘Ž•”‡•’‡ –‹˜‡Ž›ǡ‹’ƒ”ƒŽŽ‡Ž™‹–ŠM.tuberculosis ƒ–‹‰‡•ƒ–ͷP‰ȀŽǣ’—”‹ˆ‹‡†’”‘–‡‹†‡”‹˜ƒ–‹˜‡ȋȌ‘ˆM.tuberculosisȋ„ƒ– ŠͶͻǡ Ž‘– ʹͳͲǢ 

(39) ǡ ‡ƒ”Ȍǡ ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ ˜ʹ͸ʹ͵ǡ ˜ʹ͸ʹ͹ ǡ ˜ʹ͸ʹͺǡ ‰ͺͷ ƒ† ͸Ȁ ͳͲ ˆ—•‹‘ ’”‘–‡‹Ǥ ‡ŽŽ —Ž–—”‡• ™‡”‡ ‹ —„ƒ–‡† ‘ –Š‡ †ƒ› ‘ˆ „Ž‘‘† ‘ŽŽ‡ –‹‘ƒ–͵͹Ǐ™‹–ŠͷΨʹǤ—’‡”ƒ–ƒ–•™‡”‡Šƒ”˜‡•–‡†‘†ƒ›͸ƒ†•–‘”‡†ƒ– ƒš‹ƒŽŽ›ǦʹͲǏ’”‹‘”–‘

(40) Ǥ  DetectionofIFNJJbyELISA Crosssectional study:

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

(42) ȋǦ›‡ Šǡ–”‡ Š–ǡŠ‡‡–Š‡”Žƒ†•ȌǤŠ‡†‡–‡ –‹‘Ž‹‹–‘ˆ–Š‡ƒ••ƒ›™ƒ•ʹͲ ’‰ȀŽǤ 

(43)  •ƒ’Ž‡• ™‡”‡ –‡•–‡† ‹ †—’Ž‹ ƒ–‡Ǥ Š‡ ‡ƒ ˜ƒŽ—‡ ‘ˆ —•–‹—Žƒ–‡† —Ž–—”‡• ™ƒ• •—„–”ƒ –‡† ˆ”‘ –Š‡ ‡ƒ ˜ƒŽ—‡ ‘ˆ –Š‡ •–‹—Žƒ–‡† —Ž–—”‡•Ǥ  ’‘•‹–‹˜‡

(44) J ”‡•’‘•‡ ™ƒ• ’”‡†‡ˆ‹‡† ƒ• tͳͲͲ’‰Ȁ ȋʹͶȌ ‹ –Š‡ ”‘••Ǧ•‡ –‹‘ƒŽ •–—†› ȋŠ‡ ‡–Š‡”Žƒ†•ȌǤ ‘•‹–‹˜‡ in vitro ”‡•’‘•‡• ‘ˆ –Š‡ •–—†› •—„Œ‡ –• –‘ –Š‡  •’‡ ‹ˆ‹  ƒ–‹‰‡• Ǧ͸ ƒ†Ȁ‘”  ǦͳͲ ™‡”‡ —•‡† ƒ• ƒ ƒ”‡” ˆ‘” ’”‡˜‹‘—•  ‡š’‘•—”‡ ȋʹͳǡ͵͹ȌǤ Longitudinalstudy:“—ƒ–‹–ƒ–‹˜‡

(45) J

(46) •™‡”‡†‘‡‹•‹‰Ž‡™‡ŽŽ•ȋͳͲͲPŽȌ—•‹‰ ‘‡” ‹ƒŽŽ›ƒ˜ƒ‹Žƒ„Ž‡ƒ–‹„‘†›’ƒ‹”•ȋŠƒ”‹‰‡Ȍƒ•’”‡˜‹‘—•Ž›†‡• ”‹„‡†ȋ͵ȌǤ ‡ ‘„‹ƒ–

(47) J  Šƒ”‹‰‡Ȍ ™ƒ• —•‡† ˆ‘” –Š‡ •–ƒ†ƒ”† —”˜‡ ™‹–Š Ž‘™‡•– †‡–‡ –‹‘Ž‹‹–‘ˆ͵ͳ’‰ȀŽǤ‡‰ƒ–‹˜‡ ‘–”‘Žȋ‡†‹—Ȍ˜ƒŽ—‡•™‡”‡•—„–”ƒ –‡†ˆ”‘ ƒŽŽ ”‡•—Ž–•Ǥ  ’‘•‹–‹˜‡

(48) J ”‡•’‘•‡ ™ƒ• ’”‡†‡ˆ‹‡† ƒ• ε͸ʹ ’‰ȀŽ ȋ͵Ȍ ‹ –Š‹• Ž‘‰‹–—†‹ƒŽ•–—†›ȋ‹–‡†‹‰†‘ȌǤ’‘•‹–‹˜‡ ‘–”‘Ž•—’‡”ƒ–ƒ–™ƒ•‹ Ž—†‡†‹ †—’Ž‹ ƒ–‡‘‡ƒ Š

(49) ’Žƒ–‡–‘ ‘–”‘Žˆ‘”‹–‡”’Žƒ–‡ƒ†‹–”ƒ’Žƒ–‡˜ƒ”‹ƒ–‹‘Ǥ  Invivostudies Ȁ ȋ Ǧʹ†Ȍ‹ ‡™‡”‡„”‡†ƒ––Š‡‹ƒŽ ƒ ‹Ž‹–‹‡•‘ˆ–Š‡

(50) Ǧƒ•–‡—”

(51) •–‹–—–‡‘ˆ ”—••‡Ž•ǡ ˆ”‘ „”‡‡†‹‰ ‘—’Ž‡• ‘”‹‰‹ƒŽŽ› ‘„–ƒ‹‡† ˆ”‘ƒ–‹ Ƭ ‹‰ƒ ȋ‹–‡† ‹‰†‘ȌǤ ŽŽ ƒ‹ƒŽ• ™‡”‡ ͺǦͳͲ ™‡‡• ‘Ž† ƒ– –Š‡ •–ƒ”– ‘ˆ –Š‡ ‡š’‡”‹‡–•Ǥ š’‡”‹‡–•™‡”‡’‡”ˆ‘”‡†‹ƒ‰”‡‡‡–™‹–Š–Š‡–Š‹ ƒŽ‘‹––‡‡‘ˆǦ

(52) Ǧ 

(53) ”‡‰—Žƒ–‹‘•ȋ’‡”‹–‘ǤͲ͸ͲʹͲʹǦͲʹȌǤ ƒŽ‡Ȁ ‹ ‡™‡”‡˜ƒ ‹ƒ–‡†™‹–ŠͲǤʹ‰ȋͳͲ͸ Ȍ‘ˆˆ”‡•ŠŽ›’”‡’ƒ”‡†•‘Ž—–‹‘ ‘ˆ M. bovis   ˜ƒ ‹‡ ȋ•–”ƒ‹ ʹȌ ‰”‘™ ƒ• ƒ •—”ˆƒ ‡ ’‡ŽŽ‹ Ž‡ ‘ •›–Š‡–‹  ƒ—–‘ ‡†‹— ˆ‘” ͳͶ †ƒ›• ƒ† Š‘‘‰‡‹œ‡† „› „ƒŽŽ ‹ŽŽ ȋʹʹȌǤ ‹ ‡ ™‡”‡ ‹—‹œ‡† •—„ —–ƒ‡‘—•Ž› ™‹–Š ͲǤʹ ŽǤ ‡ƒŽ‡ Ȁ  ‹ ‡ ™‡”‡ ƒ‡•–Š‡–‹œ‡† ™‹–Š ‡–ƒ‹‡Ȁš›Žƒœ‹‡ ƒ† ‹Œ‡ –‡† ‹–”ƒ—• —Žƒ”Ž› ‹ „‘–Š “—ƒ†”‹ ‡’• —• Ž‡• ™‹–Š ʹ –‹‡• ͷͲ P‰ ‘ˆ ͳ Ǥ•Ǧ– ˜‡ –‘” ‡ ‘†‹‰ ‘‡ ‘ˆ –Š‡ Žƒ–‡ › ƒ–‹‰‡• ˜ͳ͹͵͵ ǡ ˜ͳ͹͵ͺǡ ˜ʹͲʹͻ ǡ •’ ȋ˜ʹͲ͵ͳ Ȍǡ ˜ʹͲ͵ʹǡ ˜ʹ͸ʹ͸ ǡ ˜ʹ͸ʹ͹ ǡ ˜ʹ͸ʹͺ ‘” Ǧ ͻͲ.

(54) ImmunitytoTBlatencyantigensafterBCGvaccination. ͸Ȁ ͳͲ ˆ—•‹‘ ’”‘–‡‹ ȋʹͳȌ ‘” ‰ͺͷ ȋͳ͵ǡʹͺȌǤ ‹ ‡ ™‡”‡ ˜ƒ ‹ƒ–‡† –Š”‡‡ –‹‡• ƒ– –Š”‡‡Ǧ™‡‡‹–‡”˜ƒŽ•ƒ†‹—‡”‡•’‘•‡•™‡”‡ƒƒŽ›œ‡†ˆ‘—”™‡‡•ƒˆ–‡”–Š‡–Š‹”† ‹—‹œƒ–‹‘Ǥ   ˜ƒ ‹ƒ–‡† ‹ ‡ ™‡”‡ •ƒ ”‹ˆ‹ ‡† ƒ– ͳ ‘” ͵ ‘–Š• ƒˆ–‡” ˜ƒ ‹ƒ–‹‘ ƒ† •’Ž‡‡• ™‡”‡ ”‡‘˜‡† ƒ•‡’–‹ ƒŽŽ› ƒ† Š‘‘‰‡‹œ‡† —•‹‰ ƒ Ž‘‘•‡Ž› ˆ‹––‹‰ ‘— ‡ Š‘‘‰‡‹œ‡”ǤŽƒ•‹†˜ƒ ‹ƒ–‡†‹ ‡™‡”‡•ƒ ”‹ˆ‹ ‡†ˆ‘—”™‡‡•ƒˆ–‡”–Š‡–Š‹”†  ‹—‹œƒ–‹‘Ǥ ’Ž‡‘ ›–‡• ȋͶέͳͲ͸ ‡ŽŽ•ȀŽȌ ˆ”‘ –Š”‡‡ ‹ ‡ ’‡” ‰”‘—’ ™‡”‡ –‡•–‡†ƒ•ƒ’‘‘Žȋ‘–Šͳƒˆ–‡” Ȍ‘”‹†‹˜‹†—ƒŽŽ›ȋ͵ǦͶ‹ ‡ǡ‘–Š͵ƒˆ–‡” ‘” ƒˆ–‡”Žƒ•–˜ƒ ‹ƒ–‹‘Ȍˆ‘” ›–‘‹‡”‡•’‘•‡–‘’—”‹ˆ‹‡†”‡ ‘„‹ƒ–Š‹•Ǧ–ƒ‰‰‡† Žƒ–‡ ›ƒ–‹‰‡•ǡ‰ͺͷ‘”Ǧ͸Ǧ ǦͳͲȋƒŽŽͷP‰ȀŽȌǤ‘‘Ž‡†•—’‡”ƒ–ƒ–•ˆ”‘ƒ– Ž‡ƒ•– –Š”‡‡ ™‡ŽŽ• ™‡”‡ Šƒ”˜‡•–‡† ƒˆ–‡” ͹ʹŠ ™Š‡ ’‡ƒ

(55) J ˜ƒŽ—‡• ƒ „‡ ‡ƒ•—”‡† ƒ† •–‘”‡† ƒ– ǦʹͲι —–‹Ž ƒ••ƒ›‡†Ǥ

(56) J ƒ –‹˜‹–› ™ƒ• “—ƒ–‹ˆ‹‡† „› •ƒ†™‹ Š 

(57)  —•‹‰ ‘ƒ–‹‰ ƒ–‹„‘†› ͶǦ͸ʹ ƒ† „‹‘–‹›Žƒ–‡† †‡–‡ –‹‘ ƒ–‹„‘†›  ͳǤʹ ȋ„‘–Š Šƒ”‹‰‡ȌǤ ••ƒ› •‡•‹–‹˜‹–› ™ƒ• ͷ ’‰ȀŽǤ ƒ’Ž‡• ™‡”‡ –‡•–‡† —†‹Ž—–‡†ǡ ƒ† ƒ– ͳǣͳͲ‘”ͳǣͳͲͲ†‹Ž—–‹‘Ǥ›–‘‹‡ ‘–‡–™ƒ• ƒŽ —Žƒ–‡†ˆ‘”–Š‡†‹Ž—–‹‘™‹–Š˜ƒŽ—‡ ‹–Š‡Ž‹‡ƒ”’ƒ”–‘ˆ–Š‡•–ƒ†ƒ”† —”˜‡Ǥ  Statisticalanalysis ‘” ‘’ƒ”‹•‘ ‘ˆ ’”‘’‘”–‹‘ ‘ˆ ”‡•’‘†‡”• „‡–™‡‡ –‡•– ‰”‘—’• ‹ –Š‡ ”‘••Ǧ •‡ –‹‘ƒŽ •–—†› –Š‡ Š‹ “—ƒ”‡ ‡•– ȋFʹ ‡•–Ȍ ˆ‘” ‹†‡’‡†‡– •ƒ’Ž‡• ™ƒ• —•‡†Ǥ ‘™‡˜‡”ǡ ‹•Š‡”ǯ•‡šƒ ––‡•–ˆ‘”‹†‡’‡†‡–•ƒ’Ž‡•™ƒ•ƒ’’Ž‹‡†‹ˆ‡š’‡ –‡†˜ƒŽ—‡• ™‡”‡ Ž‘™‡” ‘” ‡“—ƒŽ –‘ ͷ ȋE dͷȌǤ ‘’ƒ”‹•‘ ‘ˆ ’”‘’‘”–‹‘ ‘ˆ ”‡•’‘†‡”• ‹ –Š‡ Ž‘‰‹–—†‹ƒŽ •–—†› ™ƒ• ’‡”ˆ‘”‡† „›  ‡ƒ”̵• –‡•– ˆ‘” ’ƒ‹”‡† •ƒ’Ž‡•Ǥ ‘” ƒŽŽ ƒ••ƒ›• P δ ͲǤͲͷ ™ƒ• ‘•‹†‡”‡† •–ƒ–‹•–‹ ƒŽŽ› •‹‰‹ˆ‹ ƒ–Ǥ ‘” •–ƒ–‹•–‹ ƒŽ ƒƒŽ›•‹•  ͳͳǤͲˆ‘”‹†‘™•™ƒ•—•‡†Ǥ . Results InsilicosequenceanalysisandinvitroexpressionoftheDosRregulonofBCG. Š‡‘•”‡‰—Ž‘‘ˆM.tuberculosis‹•‡š’”‡••‡†invitro—†‡” ‘†‹–‹‘•‘ˆŠ›’‘š‹ƒ ƒ† Ž‘™Ǧ†‘•‡ ‹–”‹  ‘š‹†‡ •–‹—Žƒ–‹‘ ȋͶͲȌǤ ‘ ‡˜ƒŽ—ƒ–‡ ™Š‡–Š‡”   ‹• •‹‹Žƒ”Ž› ƒ’ƒ„Ž‡‘ˆ‡š’”‡••‹‰–Š‡‘•”‡‰—Ž‘ǡ™‡ˆ‹”•–ƒ••‡••‡†ƒ˜ƒ‹Žƒ„Ž‡‰‡‘‡•‡“—‡ ‡• ‘ˆM.tuberculosisǡM.bovisƒ† ˆ‘”–Š‡Ž‡˜‡Ž‘ˆ ‘•‡”˜ƒ–‹‘ƒ†–Š‡’‡”ˆ‘”‡†in vitro–”ƒ• ”‹’–‹‘’”‘ˆ‹Ž‹‰‘ˆ‘•”‡‰—Ž‘‡ ‘†‡†‰‡‡•Ǥ  •‡ƒ” Š‡• ȋŠ––’ǣȀȀ „‹ǤŽǤ‹ŠǤ‰‘˜ȀȀȌ ‘ˆ ‘• ‡ ‘†‡† •‡“—‡ ‡• •Š‘™‡† –Šƒ– ƒŽŽ Ͷͺ ‘• ”‡‰—Ž‘ ‡ ‘†‡† ‰‡‡• ™‡”‡ Š‹‰ŠŽ› ‘•‡”˜‡† „‡–™‡‡ M. tuberculosis ͵͹˜ ƒ† ͳͷͷͳ •–”ƒ‹•ǡ M. bovis  ʹͳʹʹȀͻ͹ ƒ†   ƒ•–‡—” ͳͳ͹͵ʹǤ ‘‘Ž‘‰›‘ˆƒ‹‘ƒ ‹†•‡“—‡ ‡•™ƒ•ƒ–Ž‡ƒ•–ͻ͹Ψǡ™‹–ŠͺͷΨȋͶͳ‘ˆ–Š‡ͶͺȌ ‰‡‡•„‡‹‰‹†‡–‹ ƒŽȋdatanotshownȌǤ —„•‡“—‡–Ž›ǡ™‡ƒ••‡••‡†‡š’”‡••‹‘’”‘ˆ‹Ž‡•‘ˆͳͶ†‹ˆˆ‡”‡– ˜ƒ ‹‡•–”ƒ‹• ƒ† M. tuberculosis ͵͹˜ —†‡” in vitro ‘†‹–‹‘• ‘ˆ Š›’‘š‹ƒ ƒ† ‹–”‹  ‘š‹†‡ •–‹—Žƒ–‹‘Ǥ‡•—Ž–••Š‘™‡†–Šƒ–ƒŽŽ–‡•–‡† •–”ƒ‹•Šƒ˜‡ƒˆ— –‹‘ƒŽ‘•”‡‰—Ž‘ ™‹–Š•‹‹Žƒ”‡š’”‡••‹‘’”‘ˆ‹Ž‡•ƒ• ‘’ƒ”‡†–‘M.tuberculosisȋͶͲȌǤ ‹‰—”‡ͳ•Š‘™• –Š‡’”‘ˆ‹Ž‡•‘ˆ‹‡‘•”‡‰—Žƒ–‡†‰‡‡•‘ˆM.tuberculosis ͵͹˜ƒ†  . ͻͳ.

(58) Chapter4. ͻʹ. Rv2628. Rv2627c. Rv2626c. Rv2623. Rv2032. Rv2031c. Rv2029c. Rv1738. Rv1733c. RNA expression (fold induction).  BCG P1173 MTB H37Rv  150  125  100  75  50   25  0     Figure1.ExpressionofDosRgenes(RNA).RNAtranscriptexpressionprofiles(foldinduction)ofnineDosR encoded genes induced during low oxygen conditions in Mycobacterium tuberculosis H37Rv (n=4) and BCG  Pasteur 1173 (n=4). The RNA expression profiles of both strains are highly similar, except for Rv1738. Data  shownasmean+SD  ƒ•–‡—”•–”ƒ‹ͳͳ͹͵™Š‡‡š’‘•‡†–‘Ž‘™‘š›‰‡Ž‡˜‡Ž•Ǥ‡Ž‡ –‹‘‘ˆ–Š‡•‡‹‡‰‡‡• ™ƒ• „ƒ•‡† ‘ ”‡•—Ž–• ˆ”‘ ‘—” ’”‡˜‹‘—• •–—†› ȋʹͶȌ ƒ† ‘–ƒ‹• –Š‡ ˆ‘—” ‘•– ”‡ ‘‰‹œ‡† Žƒ–‡ › ƒ–‹‰‡• ‹ Š—ƒ•Ǥ Š‡•‡ ‰‡‡• ™‡”‡ ˆ—”–Š‡” ƒƒŽ›œ‡† ‹ –Š‹• •–—†›Ǥ  ImmuneresponsestoDosRregulonencodedantigensinhumanBCGvaccinees. ‡š– ™‡ ƒ††”‡••‡† –Š‡ “—‡•–‹‘ ™Š‡–Š‡”   ˜ƒ ‹ƒ–‹‘ ‹ Š—ƒ „‡‹‰• Ž‡ƒ†• –‘ –Š‡‹†— –‹‘‘ˆ‹—‡”‡•’‘•‡•–‘‘•”‡‰—Ž‘‡ ‘†‡†Žƒ–‡ ›ƒ–‹‰‡•–Šƒ–ƒ”‡ –ƒ”‰‡–‡††—”‹‰ƒ–—”ƒŽM.tuberculosis‹ˆ‡ –‹‘Ǥ

(59) J”‡•’‘•‡•–‘‹—‘Ǧ†‘‹ƒ–Žƒ–‡ ›ƒ–‹‰‡•™‡”‡ƒ••‡••‡†‹ƒŽ‘‰‹–—†‹ƒŽ   ˜ƒ ‹ƒ–‹‘ •–—†› ‹ ›‘—‰ ƒ†‘Ž‡• ‡–• ‹ –Š‡ ‹–‡† ‹‰†‘Ǥ ™‡–›Ǧ–™‘ –—„‡” —Ž‹ •‹ –‡•– ȋȌ ‡‰ƒ–‹˜‡ ƒ†‘Ž‡• ‡–• ™‡”‡ ‹ Ž—†‡† ‹ –Š‡ ˜ƒ ‹ƒ–‹‘ ‰”‘—’Ǣ „Ž‘‘† ™ƒ• –ƒ‡ „‡ˆ‘”‡ ’”‡Ǧ ƒ† ’‘•– ȋʹǦͶ ™‡‡•Ȍ   ˜ƒ ‹ƒ–‹‘Ǥ ‡•—Ž–• •Š‘™‡† –Šƒ– ”‡•’‘•‡• –‘ –Š‡ Žƒ–‡ › ƒ–‹‰‡• ‘ˆ –Š‡ ’ƒ”–‹ ‹’ƒ–• „‡ˆ‘”‡   ˜ƒ ‹ƒ–‹‘ ™‡”‡ ‹‹ƒŽǣ ‡†‹ƒ ”‡•’‘•‡• –‘ –‡•–‡† Žƒ–‡ › ƒ–‹‰‡• ˜ͳ͹͵͵ ǡ ˜ʹͲʹͻ ǡ˜ʹ͸ʹ͵ǡ˜ʹ͸ʹ͹ ƒ†˜ʹ͸ʹͺ™‡”‡„‡Ž‘™–Š‡’”‡†‡ˆ‹‡† —–‘ˆˆŽ‡˜‡Ž‘ˆ͸ʹ ’‰ȀŽ

(60) J ƒ• —•‡† ‹ –Š‹• •–—†› ȋ ‹‰—”‡ ʹȌǤ   ˜ƒ ‹ƒ–‹‘ †‹† ‘– ƒŽ–‡” –Š‡ ”‡•’‘•‡’”‘ˆ‹Ž‡•‘ˆ–Š‡ƒ†‘Ž‡• ‡–•–‘–Š‡Žƒ–‡ ›ƒ–‹‰‡•ǣ’”‘’‘”–‹‘‘ˆ”‡•’‘†‡”• ‹–Š‡’”‡Ǧ˜ƒ ‹ƒ–‹‘‰”‘—’”ƒ‰‡†ˆ”‘ͶǤͷΨ–‘͵͵Ǥ͵Ψ ‘’ƒ”‡†–‘ͲΨ–‘͵ͳǤͺΨ ’‘•–Ǧ  ˜ƒ ‹ƒ–‹‘Ǥ –ƒ–‹•–‹ ƒŽ ƒƒŽ›•‹• ‘ˆ –Š‡ ’”‘’‘”–‹‘ ‘ˆ ”‡•’‘†‡”• –‘  Žƒ–‡ › ƒ–‹‰‡• •Š‘™‡† ‘ •‹‰‹ˆ‹ ƒ– †‹ˆˆ‡”‡ ‡ „‡–™‡‡ ’”‡Ǧ ƒ† ’‘•–   ˜ƒ ‹ƒ–‹‘ȋ ‡ƒ”̵•–‡•–ǡPαͲǤͷͲͲ–‘PαͳǤͲͲͲȌǤ ‘ŽŽ‘™‹‰   ˜ƒ ‹ƒ–‹‘ –Š‡”‡ ™ƒ• ƒ •‹‰‹ˆ‹ ƒ– ‹ ”‡ƒ•‡ ‹ –Š‡

(61) J ”‡•’‘•‡ –‘ ˆ”‘Ͷ͸Ψ–‘ͻ͸Ψ”‡•’‘†‡”•ȋPαͲǤͲͲͳȌǤŠ‡”‡™ƒ•‘•‹‰‹ˆ‹ ƒ–†‹ˆˆ‡”‡ ‡ˆ‘” ”‡•’‘•‡•–‘‰ͺͷǡ‘Ž›ƒ–”‡†–‘™ƒ”†•ƒ‹ ”‡ƒ•‡‹”‡•’‘•‡ˆ”‘͸ͶΨ–‘͹͹Ψ ”‡•’‘†‡”• ȋP α ͲǤ͵͹ͷȌǤ Ž–Š‘—‰Š ƒŽŽ ‡Ž‹‰‹„Ž‡ •—„Œ‡ –• ™‡”‡ –‡•–‡† ‡‰ƒ–‹˜‡ ‹ –Š‡ –—„‡” —Ž‹•‹–‡•–ȋ ‡ƒˆ–‡•–Ȍ’”‹‘”–‘ ˜ƒ ‹ƒ–‹‘ǡinvitro•–‹—Žƒ–‹‘™‹–Š ‘” ‰ͺͷ •Š‘™‡† –Šƒ– ƒ ‘•‹†‡”ƒ„Ž‡ ’”‘’‘”–‹‘ ‘ˆ –Š‡ –‡•–‡† ƒ†‘Ž‡• ‡–• ‰ƒ˜‡ ’‘•‹–‹˜‡™Š‘Ž‡„Ž‘‘†ƒ••ƒ›•ȋͶ͸Ψƒ†͸ͶΨ”‡•’‡ –‹˜‡Ž›Ȍǡ™Š‹ Š‹•‘•–Ž‹‡Ž› .

(62) ImmunitytoTBlatencyantigensafterBCGvaccination. IFNJ (pg/ml). pre-BCG vaccination  post-BCG vaccination  B 5 A 5.0 105 105 ** ȗȗ  4 1044 10 4.0   3.0 1033 103  1022 102 2.0  1011 101  1.0  0.0 1000 100  -1.0 -1 -1 -1 10  10 Rv1733c Rv2029c Rv2623 Rv2627c Rv2628 Ag85A E/C FP PHA PPD   Figure 2. IFNJ responses to M. tuberculosis latency antigens in a longitudinal BCG study. Box and  Whisker plot of IFNJ responses to the latency antigens in schoolchildren pre and postBCG vaccination.  Horizontal black line in the box represents the median; lower boundary of the box represents the 25th  percentile and upper boundary the 75th percentile. Whiskers extend from the box to the highest and lowest value with exclusion of the extreme values and the outlier values. Supernatants were taken after 6 days for  measurement of IFNJ production. (A) IFNJ responses of the preBCG vaccinated group to tested latency  antigens.(B)ResponsestoPHAandcontrolantigensPPD,Ag85AandESAT6/CFP10fusionprotein.E/CFP,  ESAT6/CFP10fusionprotein.Vaccinatedadolescents,n=22,exceptforantigenRv1733cintheprevaccinated  group where 12 individuals were tested. An IFNJ response t 62.5 pg/ml was considered positive. The McNemar'stestforpairedsampleswasusedtocomparetheproportionsofresponderspergroup,**P=0.001.   ƒ• ƒ ”‡•—Ž– ‘ˆ ‡š’‘•—”‡ –‘ ”‘••Ǧ”‡ƒ –‹˜‡ ‡˜‹”‘‡–ƒŽ › ‘„ƒ –‡”‹ƒǤ • ‡š’‡ –‡†ǡ ‘‡ ‘ˆ –Š‡ ’ƒ”–‹ ‹’ƒ–• ”‡•’‘†‡† –‘ –Š‡ M. tuberculosis •’‡ ‹ˆ‹  Ǧ͸Ȁ ǦͳͲ ˆ—•‹‘’”‘–‡‹ȋ ‹‰—”‡ʹȌǤŠ—•ǡ–Š‡•‡”‡•—Ž–••Š‘™–Šƒ–‹ƒ†‘Ž‡• ‡–•ˆ‘ŽŽ‘™‹‰  ˜ƒ ‹ƒ–‹‘˜‹”–—ƒŽŽ›‘‹ ”‡ƒ•‡•‹”‡•’‘•‡•–‘M.tuberculosisŽƒ–‡ ›ƒ–‹‰‡•ƒ”‡ ‘„•‡”˜‡†Ǥ ‡š–ǡ ™‡ ƒ””‹‡† ‘—– ƒ ”‘••Ǧ•‡ –‹‘ƒŽ •–—†› ȋŠ‡ ‡–Š‡”Žƒ†•Ȍ ‹ Ž—†‹‰   ˜ƒ ‹ƒ–‡† ƒ†—Ž–• ™‹–Š‘—– ‡š’‘•—”‡ –‘  ȋαʹ͹Ȍ ‘’ƒ”‡† –‘ •—„Œ‡ –• ™‹–Š Ž‹‡Ž› ‡š’‘•—”‡ –‘  ȋαͳ͸ȌǤ ‘” –Š‡ ’—”’‘•‡ ‘ˆ –Š‹• •–—†›ǡ ‹†‹˜‹†—ƒŽ• ™‹–Š ƒ

(63) J ”‡•’‘•‡εͳͲͲ’‰ȀŽ–‘M.tuberculosis•’‡ ‹ˆ‹ ƒ–‹‰‡•Ǧ͸ƒ† ǦͳͲȋʹͳǡ͵͹Ȍ ™‡”‡ ‘•‹†‡”‡†’”‡˜‹‘—•Ž›‡š’‘•‡†–‘Ǥ ‹‰—”‡͵•Š‘™•–Š‡‹—‡”‡ ‘‰‹–‹‘’”‘ˆ‹Ž‡•‘ˆ„‘–Š ˜ƒ ‹ƒ–‡†‰”‘—’•–‘–Š‡ Žƒ–‡ ›ƒ–‹‰‡•Ǥ˜‡”ƒŽŽǡ ˜ƒ ‹ƒ–‡†‹†‹˜‹†—ƒŽ•™‹–Š‘—–‡˜‹†‡ ‡‘ˆ‡š’‘•—”‡–‘  •Š‘™‡† •‹‰‹ˆ‹ ƒ–Ž› Ž‘™‡”

(64) J ’”‘†— –‹‘ –‘ –Š‡ Žƒ–‡ › ƒ–‹‰‡• ‘’ƒ”‡† –‘ –Š‡ ‰”‘—’ –Šƒ– Šƒ† ’‘•‹–‹˜‡ ”‡•’‘•‡• –‘ Ǧ͸ ƒ†Ȁ‘”  ǦͳͲǤ Š‡ ‡†‹ƒ

(65) J ”‡•’‘•‡• –‘ ƒŽŽ –‡•–‡† Žƒ–‡ › ƒ–‹‰‡• ‹ –Š‡ —‡š’‘•‡† ‰”‘—’ ™‡”‡ ƒŽŽ „‡Ž‘™ –Š‡ —–Ǧ‘ˆˆŽ‡˜‡Ž‘ˆͳͲͲ’‰ȀŽǡ™Š‡”‡ƒ•–Š‹•™ƒ•–Š‡‘’’‘•‹–‡‹–Š‡‡š’‘•‡†‰”‘—’Ǥ

(66)  –Š‡Žƒ––‡”‰”‘—’‡†‹ƒ

(67) J˜ƒŽ—‡•–‘ƒŽŽ–‡•–‡†Žƒ–‡ ›ƒ–‹‰‡•ǡ‡š ‡’–ˆ‘”’”‘–‡‹ ˜ʹ͸ʹͺǡ ™‡”‡ ƒ„‘˜‡ ͳͲͲ ’‰ȀŽǢ ‹†‹ ƒ–‹‰ –Šƒ– ‘˜‡” ŠƒŽˆ ‘ˆ –Š‡ ‹†‹˜‹†—ƒŽ• •–”‘‰Ž› ”‡ ‘‰‹œ‡†–Š‡ƒ–‹‰‡•ȋ ‹‰—”‡͵ȌǤ    . ͻ͵.

(68) Chapter4. IFNJ (pg/ml). IFNJ (pg/ml).  A 5 10 5 ESAT-6/CFP-10 negative * ** ** * ** **  ESAT-6/CFP-10 positive  1044  1033   1022   1011  1000   -1 10-1  Rv2032 Rv2626c Rv2627c Rv1733c Rv2029c HspX Rv2628   B 1055 ** ** † ** †  1044   1033   1022  1011   1000  -1  10-1 PHA PPD MTB Ag85B ESAT-6 CFP-10  Figure 3. IFNJ responses to M. tuberculosis latency antigens in a crosssectional BCG study. Box and WhiskerplotofIFNJresponsestothelatencyantigensbyBCGvaccinatedindividuals.Horizontalblacklinein theboxrepresentsthemedian;lowerboundaryoftheboxrepresentsthe25thpercentileandupperboundary the75thpercentile.Whiskersextendfromtheboxtothehighestandlowestvaluewithexclusionoftheextreme valuesandtheoutliervalues.Supernatantsweretakenafter6daysformeasurementofIFNJproduction(A) IFNJ responses to the latency antigens of the group that is BCG vaccinated without TB exposure (no IFNJ productiontoESAT6orCFP10)andwithexposuretoTB(positiveIFNJproductiontoESAT6orCFP10).(B) IFNJresponsestocontrolstimuliPHA,PPD,MTB,Ag85B,ESAT6andCFP10. MTB, lysate of M. tuberculosis cultured under low oxygen conditions. BCG vaccinated group without TB exposure,n=23,BCGvaccinatedgroupwithTBexposure,n=16.AnIFNJresponse t100pg/mlwasconsidered positive.F2test,*P<0.05,**P<0.01,†Fishersexacttest.  Š‡’”‘’‘”–‹‘‘ˆ”‡•’‘†‡”•ȋ‹Ǥ‡ǤεͳͲͲ’‰ȀŽ

(69) JȌ’‡”ƒ–‹‰‡™ƒ•ƒ•ˆ‘ŽŽ‘™•ȋ  ˜ƒ ‹ƒ–‡†™‹–Š‘—–‡š’‘•—”‡˜•Ǥ ˜ƒ ‹ƒ–‡†™‹–Š‡š’‘•—”‡Ȍǣ˜ͳ͹͵͵ ͶͶǤͶ Ψ˜•Ǥͻ͵ǤͺΨȋPαͲǤͲͲͳȌǡ˜ʹͲʹͻ ͵͹ǤͲΨ˜•ǤͺͳǤ͵ΨȋPαͲǤͲͲͷȌǡ •’ʹʹǤʹΨ˜•Ǥͷ͸Ǥ͵ ΨȋPαͲǤͲʹͶȌǡ˜ʹͲ͵ʹʹͻǤ͸Ψ˜•Ǥ͸ͺǤͺΨȋPαͲǤͲͳ͵Ȍǡ˜ʹ͸ʹ͸ ʹͲǤͲΨ˜•Ǥ͸ͺǤͺΨȋPα ͲǤͲͲ͵Ȍǡ ˜ʹ͸ʹ͹  ʹͷǤͻ Ψ ˜•Ǥ͹ͷ Ψ ȋP α ͲǤͲͲʹȌ ƒ† ˜ʹ͸ʹͺ ʹͷǤͻ Ψ ˜•Ǥ Ͷ͵Ǥͺ Ψ ȋP α ͲǤʹʹͺȌǤ —”–Š‡”‘”‡ǡ–Š‡Ž‡˜‡Ž•‘ˆ

(70) J’”‘†— –‹‘‹–Š‡ ˜ƒ ‹ƒ–‡†‰”‘—’™‹–Š •—•’‡ –‡†‡š’‘•—”‡™‡”‡•‹‹Žƒ”–‘–Š‘•‡™‡’”‡˜‹‘—•Ž›ˆ‘—†‹ƒ–‘—š’‘•‹–‹˜‡ ‹†‹˜‹†—ƒŽ•ȋʹͶȌǤ

(71) ƒ††‹–‹‘–‘–Š‡”‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡•ǡ‡š’‘•—”‡–‘™ƒ• ƒŽ•‘ ƒ••‘ ‹ƒ–‡† ™‹–Š Š‹‰Š‡”

(72) J ’”‘†— –‹‘ –‘ ‰ͺͷ ȋP α ͲǤͲͲͷȌ ™Š‹ Š ‹• •Šƒ”‡† „‡–™‡‡   ƒ† M. tuberculosis. Š‡ †ƒ–ƒ ƒŽ•‘ •—‰‰‡•– –Šƒ– –Š‡ ”‡•’‘•‡• –‘ › ‘„ƒ –‡”‹ƒŽ ‘’Ž‡šƒ–‹‰‡•Ž‹‡ȋPαͲǤͳ͵ͻȌƒ†M.tuberculosisŽ›•ƒ–‡ȋˆ”‘ ͻͶ.

(73) ImmunitytoTBlatencyantigensafterBCGvaccination. Rv2032. Rv2626c. Rv2627c. Rv2628. HspX. Rv2032. Rv2626c. Rv2627c. Rv2628. ESAT6-CFP10. Rv2029c. HspX. Rv2029c. Rv1733c. Rv1738. ESAT6-CFP10. ESAT6-CFP10. IFNJ (pg/ml). Rv1738. Rv2628. Ag85A. Rv2627c. Rv2628. Rv2627c. Ag85A. Rv2626c Rv2626c. Rv1733c. Rv2032 Rv2032. ESAT6-CFP10. Rv2029c. HspX. Rv2029c. HspX. Rv1733c. Rv1738 Rv1738. Ag85A. Rv1733c. IFNJ (pg/ml). Ag85A. IFNJ (pg/ml). IFNJ (pg/ml). „ƒ –‡”‹ƒ —Ž–—”‡†—†‡”Š›’‘š‹  ‘†‹–‹‘•ȌȋPαͲǤʹ͹ͻȌƒ”‡Š‹‰Š‡”„—–‘•‹‰‹ˆ‹ ƒ– †‹ˆˆ‡”‡ ‡™ƒ•†‡–‡ –‡†ȋ ‹‰—”‡͵ȌǤ ‹‡ƒˆ–‡” ˜ƒ ‹ƒ–‹‘ƒ†‘‡–‘ˆ•ƒ’Ž‹‰˜ƒ”‹‡† ‘•‹†‡”ƒ„Ž›‹‘—”•–—†› ’‘’—Žƒ–‹‘Ǥ ‡ –Š‡”‡ˆ‘”‡ ƒ––‡’–‡† –‘ •‡‡ ƒ ‘””‡Žƒ–‹‘ „‡–™‡‡ –Š‡ Ž‡˜‡Ž ‘ˆ

(74) J ’”‘†— –‹‘ƒ†–‹‡•‹ ‡˜ƒ ‹ƒ–‹‘Ǥ ‘™‡˜‡”ǡ‘–‹‡†‡’‡†‡–ƒ••‘ ‹ƒ–‹‘™ƒ• ‘„•‡”˜‡†ȋ†ƒ–ƒ‘–•Š‘™ȌǤ ƒ‡ –‘‰‡–Š‡”ǡ   ˜ƒ ‹ƒ–‹‘ ‹ –Š‡ •‹ ‹ ‰‡‡”ƒŽ ƒ’’‡ƒ”• –‘ ‹†— ‡ ’‘‘” ”‡•’‘•‡• –‘ ‘– ‘Ž› •’ „—– ƒŽ•‘ –‘ ‘–Š‡” Žƒ–‡ › ƒ–‹‰‡• ‘ˆ M. tuberculosisǤ

(75)  ‘–”ƒ•–ǡˆ‘ŽŽ‘™‹‰‡š’‘•—”‡–‘ǡ•‹‰‹ˆ‹ ƒ–”‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡•ƒ”‡•‡‡Ǥ  ImmuneresponsestoDosRregulonantigensinmice.

(76)  ‘”†‡” –‘ †‡–‡”‹‡ ™Š‡–Š‡”   ˜ƒ ‹ƒ–‹‘ ƒŽ•‘ ˆƒ‹Ž• –‘ ‹†— ‡ ƒ†‡“—ƒ–‡ Ǧ ‡ŽŽ ”‡•’‘•‡• –‘ M. tuberculosis Žƒ–‡ › ƒ–‹‰‡• ‹ ‹ ‡ǡ Ȁ  ‹ ‡ ™‡”‡ ˜ƒ ‹ƒ–‡† •—„ —–ƒ‡‘—•Ž›™‹–Š ȋα͵ȌǤŠ‡‹ ‡™‡”‡•ƒ ”‹ˆ‹ ‡†Ͷ™‡‡•ƒ†͵‘–Š•ƒˆ–‡”   ˜ƒ ‹ƒ–‹‘ ‹ ‘”†‡” –‘ –‡•– •’Ž‡‘ ›–‡• ˆ‘”

(77) J ’”‘†— –‹‘ ‹ ”‡•’‘•‡ –‘ Žƒ–‡ › ƒ–‹‰‡•ǡ –Š‡ Š‘‘Ž‘‰‘—• ‘” •Šƒ”‡† › ‘„ƒ –‡”‹ƒŽ ƒ–‹‰‡ ‰ͺͷ ƒ† –Š‡ ˆ—•‹‘’”‘–‡‹‘ˆǦ͸ƒ† ǦͳͲ‘ˆM.tuberculosisȋʹͳȌǤ  B  A 1200 1200  1000 1000  800 800  600 600  400 400  200 200  0 0     C D 1200  6000 1000  5000 800  4000 600  3000 400 2000  200 1000  0 0      Figure 4. IFNJ responses to M. tuberculosis latency antigens in BALB/c mice following BCG  vaccination(s.c.)orvaccination(i.m.)withplasmidDNA.Supernatantsweretakenafter3days(72  hours) for measurement of IFNJ production. (A) Naïve, nonBCG vaccinated, tested as a pool, n=3. (B) Animals 4weeks post BCG vaccination, mice tested as a pool, n=3. (C) Animals 3months post BCG  vaccination, n=3. (D) Mice were immunized 3x with plasmid DNA encoding for one the eight latency  antigens,Ag85AorESAT6/CFP10.Splenocyteswereinvitrorestimulatedwiththeirrespectiveantigens,  n=4.. ͻͷ.

(78) Chapter4. ‘—” ™‡‡• ’‘•–Ǧ  ˜ƒ ‹ƒ–‹‘ǡ •’Ž‡‘ ›–‡• •Š‘™‡† ˜‡”› Ž‘™ –‘ ‘ ’”‘†— –‹‘ ‘ˆ

(79) J ™Š‡ •–‹—Žƒ–‡† ™‹–Š Žƒ–‡ › ƒ–‹‰‡• ȋ ‹‰—”‡ ͶȌǤ Š‡ Ž‡˜‡Ž• ‘ˆ

(80) J ™‡”‡ •‹‹Žƒ”Ž›Ž‘™ƒ•–Š‘•‡‘ˆƒÃ˜‡ ‘–”‘Ž‹ ‡ȋ ‹‰—”‡ͶȌǤ––Š‹••ƒ‡–‹‡’‘‹– ‡ŽŽ• ’”‘†— ‡†•‹‰‹ˆ‹ ƒ–ƒ‘—–•‘ˆ

(81) J–‘‰ͺͷȋ ‹‰—”‡ͶȌƒ†ȋ†ƒ–ƒ‘–•Š‘™ȌǤ • ‡š’‡ –‡†ǡ ”‡•’‘•‡• –‘ –Š‡ ˆ—•‹‘ ’”‘–‡‹ ͸Ǧ ǦͳͲ ™‡”‡ ƒ„•‡–Ǥ Š‡ ”‡•’‘•‡• ™‡”‡ ƒ••‡••‡† ƒ– ͵ ‘–Š• ’‘•–Ǧ‹—‹œƒ–‹‘ǡ •‹‹Žƒ” ”‡•—Ž–• ™‡”‡ ‘„–ƒ‹‡†ǣ

(82) J ”‡•’‘•‡• ‘ˆ •’Ž‡‘ ›–‡• ‘ˆ ˜ƒ ‹ƒ–‡† ‹ ‡ –‘ Žƒ–‡ › ƒ–‹‰‡• ”‡ƒ‹‡†ƒ–Ž‡˜‡Ž• ‘’ƒ”ƒ„Ž‡–‘–Š‘•‡‹ƒÃ˜‡‹ ‡ȋ ‹‰—”‡ͶȌǡƒ†‘Ž›–‘‰ͺͷ •‹‰‹ˆ‹ ƒ–

(83) J ’”‘†— –‹‘ ™ƒ• ˆ‘—† ȋ ‹‰—”‡ ͶȌǤ ‘ ”—Ž‡ ‘—– –Šƒ– ƒ„•‡ ‡ ‘ˆ

(84) J ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ™ƒ• †—‡ –‘ ƒ ‹Š‡”‡– ‹ƒ„‹Ž‹–› ‘ˆ Ȁ  ‹ ‡ –‘ ”‡•’‘† –‘ –Š‡•‡ Žƒ–‡ › ƒ–‹‰‡•ǡ ‹ ‡ ™‡”‡ ˜ƒ ‹ƒ–‡† ™‹–Š Ǥ Ȁ  ‹ ‡ ȋαͶȌ ™‡”‡ ˜ƒ ‹ƒ–‡† –Š”‡‡ –‹‡• ™‹–Š –Š”‡‡ ™‡‡• ‹–‡”˜ƒŽ• ™‹–Š ƒ‡†  ’Žƒ•‹† ‡ ‘†‹‰ ‘‡ ‘ˆ ‡‹‰Š– †‹ˆˆ‡”‡– Žƒ–‡ › ƒ–‹‰‡•ǡ ‰ͺͷ ‘” Ǧ͸Ȁ ǦͳͲǤ ‘—” ™‡‡• ƒˆ–‡” –Š‡ Žƒ•– ‹—‹œƒ–‹‘ •’Ž‡‡ ‡ŽŽ

(85) J ’”‘†— –‹‘ ™ƒ• ƒƒŽ›œ‡†Ǥ ƒ ‹ƒ–‹‘ ™‹–Š •‹š ‘—– ‘ˆ ‡‹‰Š–  ’Žƒ•‹†• ‹†— ‡† •‹‰‹ˆ‹ ƒ– ƒ–‹‰‡ •’‡ ‹ˆ‹ 

(86) J ’”‘†— –‹‘ ȋ ‹‰—”‡ ͶȌǤ ‘„—•– Ž‡˜‡Ž• ‘ˆ

(87) J ™‡”‡ ’”‘†— ‡† ƒˆ–‡” in vitro ”‡Ǧ •–‹—Žƒ–‹‘ ™‹–Š ˜ͳ͹͵͵ ǡ •’ǡ ˜ʹͲ͵ʹ ǡ ˜ʹ͸ʹ͸ ǡ ˜ʹ͸ʹ͹  ƒ† ˜ʹ͸ʹͺǤ –‹‰‡• ˜ͳ͹͵ͺ ƒ† ˜ʹͲʹͻ  ƒ’’‡ƒ”‡† –‘ „‡ ‘– ˜‡”› ‹—‘‰‡‹  ˆ‘”  ‡ŽŽ• ‹ Ȁ  ‹ ‡ǡ ƒŽ„‡‹– •‹‰‹ˆ‹ ƒ– ƒ–‹„‘†› ”‡•’‘•‡• –‘ –Š‡ Žƒ––‡” ’”‘–‡‹ ‘—Ž† „‡ ‹†— ‡† ȋʹͻƒȌǤ ƒ ‹ƒ–‹‘ ™‹–Š  ’Žƒ•‹†• ‡ ‘†‹‰ ‰ͺͷ ‘” ͸Ǧ ǦͳͲ ˆ—•‹‘ ’”‘–‡‹ ™ƒ• ƒŽ•‘ ˜‡”› ‡ˆˆ‡ –‹˜‡ ‹ ‹†— ‹‰ •–”‘‰

(88) J ”‡•’‘•‡•Ǥ Š‡ ”‡•—Ž–• –Š—• †‡‘•–”ƒ–‡ –Šƒ– ‹ ‡ ƒ”‡ ƒ„Ž‡ –‘ ‰‡‡”ƒ–‡ •–”‘‰ Šͳ –›’‡ ‹—‡ ”‡•’‘•‡• –‘ Žƒ–‡ › ƒ–‹‰‡• ƒˆ–‡” ‹—‹œƒ–‹‘ ™‹–Š  ’Žƒ•‹† „—– –Šƒ– •—„ —–ƒ‡‘—•   ƒ†‹‹•–”ƒ–‹‘ˆƒ‹Ž•–‘‹†— ‡‹—‡”‡•’‘•‡•–‘M.tuberculosisŽƒ–‡ ›ƒ–‹‰‡•‹ Ȁ ‹ ‡Ǥ  . Discussion ‡Žƒ–‹˜‡Ž› Ž‹––Ž‡ ‹• ‘™ ƒ„‘—– –Š‡ ƒ–‹‰‡ •’‡ ‹ˆ‹ ‹–› ‘ˆ ‹—‡ ”‡•’‘•‡ ’”‘ˆ‹Ž‡• ˆ‘ŽŽ‘™‹‰   ˜ƒ ‹ƒ–‹‘ ‹ ”‡Žƒ–‹‘ –‘ ’”‘–‡ –‹‘ ƒ‰ƒ‹•– Ǥ

(89)  –Š‹• •–—†› ™‡ ƒ††”‡••‡†–Š‡“—‡•–‹‘™Š‡–Š‡” ˜ƒ ‹ƒ–‹‘‹†— ‡•‹—‡”‡•’‘•‡•–‘‘• ”‡‰—Ž‘‡ ‘†‡†ƒ–‹‰‡•ǡ‹’ƒ”–‹ —Žƒ”–‘–Š‘•‡Žƒ–‡ ›ƒ–‹‰‡•–Šƒ–ƒ”‡–ƒ”‰‡–‡† †—”‹‰’‡”•‹•–‡–M.tuberculosis‹ˆ‡ –‹‘ȋʹͶȌǤ ‘’ƒ”‹•‘ ‘ˆ ƒ˜ƒ‹Žƒ„Ž‡ ‰‡‘‡ •‡“—‡ ‡• ‘ˆ M. tuberculosis, M. bovis ƒ†   •Š‘™‡† –Šƒ– –Š‡ ‡–‹”‡ •‡– ‘ˆ ‘• ”‡‰—Ž‘ ‘†‹‰ •‡“—‡ ‡• ‹• ‘•‡”˜‡† ‹  Ǣ ‡š ‡’– ˆ‘” ƒ ˆ‡™ ‹‘” ’‘‹– —–ƒ–‹‘•ǡ ™Š‹ Š ƒ”‡ ‘– ‡š’‡ –‡† –‘ Šƒ˜‡ ƒ ƒŒ‘” ‹’ƒ – ‘ ‡š’”‡••‹‘ ‘” ‹—‘Ž‘‰‹  ”‡ ‘‰‹–‹‘ ‘ˆ –Š‡•‡ ƒ–‹‰‡•Ǥ —„•‡“—‡–Ž›ǡ –”ƒ• ”‹’–‹‘ƒŽƒƒŽ›•‹•‘ˆͳͶ†‹ˆˆ‡”‡– ˜ƒ ‹‡•–”ƒ‹•—†‡”invitro ‘†‹–‹‘•‘ˆ Ž‘™ ‘š›‰‡ ƒ† ‹–”‹  ‘š‹†‡ ‡š’‘•—”‡ ™‡”‡ •–—†‹‡†Ǥ —” ”‡•—Ž–• •Š‘™ –Šƒ–  ‡š’”‡••‹‘’”‘ˆ‹Ž‡•‘ˆ–Š‡‘•”‡‰—Ž‘Žƒ–‡ ›ƒ–‹‰‡•”‡’‘”–‡†‹–Š‹••–—†›ǡ™‡”‡ Š‹‰ŠŽ›•‹‹Žƒ”–‘–Š‘•‡’”‡˜‹‘—•Ž›”‡’‘”–‡†ˆ‘”M.tuberculosisȋͶͲȌǤ

(90) ƒ††‹–‹‘ǡ ‹• ”‡’‘”–‡†–‘„‡ ƒ’ƒ„Ž‡‘ˆƒ†ƒ’–‹‰–‘ƒƒ‡”‘„‹‘•‹•invitro„›•Š‹ˆ–‹‰†‘™–‘ƒ‘Ǧ ”‡’Ž‹ ƒ–‹‰’‡”•‹•–‡–•–ƒ–‡•‹‹Žƒ”–‘M.tuberculosisȋʹͷȌǤŠ‡–‡•–‡†‹–Š‡•‘Ǧ ƒŽŽ‡† ƒ›‡‘†‡Ž‘”‹•–ƒ†‹‰ȋi.e.Š›’‘š‹ Ȍ —Ž–—”‡•‹–™ƒ•’”‡˜‹‘—•Ž›•Š‘™–Šƒ– ‹•. ͻ͸.

(91) ImmunitytoTBlatencyantigensafterBCGvaccination. ƒ’ƒ„Ž‡‘ˆ’”‘†— ‹‰ƒ–Ž‡ƒ•–ˆ‘—”‘•”‡‰—Ž‘‡ ‘†‡†’”‘–‡‹•ǣ˜ʹ͸ʹ͵ǡ˜ʹ͸ʹ͸ ǡ •’ ȋ˜ʹͲ͵ͳ ǡ acrȌ ƒ† ‘• ȋ˜͵ͳ͵͵ Ȍ ȋͷǡ͸ȌǤ ‡ ‘ Ž—†‡ ˆ”‘ –Š‡•‡ in vitro ‘„•‡”˜ƒ–‹‘• –Šƒ–   Šƒ• ƒ ˆ— –‹‘ƒŽ ‘• ”‡‰—Ž‘ǡ ƒŽ–Š‘—‰Š ‘ ‘’Ž‡–‡ ’”‘–‡‘‹ •†ƒ–ƒ‹•ƒ˜ƒ‹Žƒ„Ž‡–‘†‡‘•–”ƒ–‡–Šƒ–‡˜‡”›•‹‰Ž‡’”‘–‡‹‡ ‘†‡†„›–Š‡ ”‡‰—Ž‘‹•‹†‡‡†‡š’”‡••‡†Ǥ ‡š– ™‡ ‘‹–‘”‡† ‹—‡ ”‡•’‘•‡• –‘ ƒ •‡”‹‡• ‘ˆ ‹—‘Ǧ†‘‹ƒ–  Žƒ–‡ › ƒ–‹‰‡•ˆ‘ŽŽ‘™‹‰ ˜ƒ ‹ƒ–‹‘ǡ„‘–Š‹ƒŽ‘‰‹–—†‹ƒŽƒ†ƒ ”‘••Ǧ•‡ –‹‘ƒŽ•–—†› ‹ –™‘ †‹ˆˆ‡”‡– Š—ƒ ‘Š‘”–•ǡ ƒ† ‘””‘„‘”ƒ–‡† ‘—” ˆ‹†‹‰• ‹ ƒ Ȁ  ‘—•‡ ‘†‡ŽǤ •‡–‹‘‡†„‡ˆ‘”‡ǡ‡‘ƒ–‡•˜ƒ ‹ƒ–‡†™‹–Š ƒ–„‹”–Š†‘‘–†‡˜‡Ž‘’‹—‡ ”‡•’‘•‡• –‘ –Š‡ Žƒ–‡ › ƒ–‹‰‡ •’ǡ ™Š‡”‡ƒ• –Š‡› ƒ”‡ ƒ’ƒ„Ž‡ ‘ˆ ‘—–‹‰ ”‡•’‘•‡• –‘ ‘–Š‡” ‘Ǧ†‘”ƒ › ƒ••‘ ‹ƒ–‡†  ƒ–‹‰‡• ȋ‹ Ž—†‹‰ Ȍ ȋ͵ͻȌǤ   ˜ƒ ‹ƒ–‡†ƒ†‘Ž‡• ‡–•ȋŽ‘‰‹–—†‹ƒŽ•–—†›Ȍƒ† ˜ƒ ‹ƒ–‡†ƒ†—Ž–•™Š‘Šƒ˜‡‘– „‡‡‡š’‘•‡†–‘ȋi.e.invitro‡‰ƒ–‹˜‡ˆ‘”’”‘†— –‹‘‘ˆ

(92) J–‘Ǧ͸ƒ†Ȁ‘” Ǧ ͳͲȌ ȋ ”‘••Ǧ•‡ –‹‘ƒŽ •–—†›Ȍǡ ‘—–‡† ‹—‡ ”‡•’‘•‡• –‘ •‡ ”‡–‡† ƒ–‹‰‡• ‘ˆ –Š‡ ‰ͺͷ ‘’Ž‡š ƒ† ǡ „—– †‹† ‘– †‡˜‡Ž‘’ ”‡•’‘•‡• –‘ •’ ƒ† ‘–Š‡” –‡•–‡† Žƒ–‡ ›ƒ–‹‰‡•ȋ ‹‰—”‡ʹǡ͵ȌǤ

(93)  ‘–”ƒ•––‘–Š‡ƒ„‘˜‡ǡ ˜ƒ ‹ƒ–‡†ƒ†—Ž–•™‹–Š’”‡˜‹‘—•‡š’‘•—”‡–‘ȋi.e.in vitro ’‘•‹–‹˜‡ ’”‘†— –‹‘ ‘ˆ

(94) J –‘ Ǧ͸ ƒ†Ȁ‘”  ǦͳͲȌ ‹ –Š‡ ”‘••Ǧ•‡ –‹‘ƒŽ •–—†›•Š‘™‡†•‹‰‹ˆ‹ ƒ–Ž›Š‹‰Š‡”

(95) J”‡•’‘•‡•–‘•‡Ž‡ –‡†Žƒ–‡ ›ƒ–‹‰‡•‡š– –‘ ‹ ”‡ƒ•‡† ƒ† •‹‰‹ˆ‹ ƒ– ȋ‘Ž› ‰ͺͷȌ ”‡•’‘•‡• –‘ ‘‘  ƒ–‹‰‡•Ǥ Š‡•‡ ”‡•—Ž–• ƒ‰”‡‡ ™‹–Š ‘—” ”‡ ‡– ˆ‹†‹‰• –Šƒ–  ‡ŽŽ• ˆ”‘ ‹†‹˜‹†—ƒŽ• ™‹–Š Žƒ–‡–  ‹ˆ‡ –‹‘’”‡ˆ‡”‡–‹ƒŽŽ›”‡ ‘‰‹œ‡ƒ•‡–‘ˆŽƒ–‡ ›ƒ–‹‰‡•ȋi.e.˜ͳ͹͵͵ ǡ˜ʹͲʹͻ  ƒ† ˜ʹ͸ʹ͹ Ȍ ™Š‹Ž‡ ’ƒ–‹‡–• ™‹–Š ȋ’ƒ•– ‘” ƒ –‹˜‡Ȍ  †‹•‡ƒ•‡ ’”‡ˆ‡”‡–‹ƒŽŽ› ”‡ ‘‰‹œ‡†•‡ ”‡–‡†ƒ–‹‰‡••— Šƒ• ǦͳͲƒ†Ǧ͸ȋͳͶǡʹͶȌǤ Š‡ƒ„•‡ ‡‘ˆinvitro†‡–‡ –ƒ„Ž‡”‡•’‘•‡•–‘M.tuberculosisŽƒ–‡ ›ƒ–‹‰‡•‹  ˜ƒ ‹ƒ–‡† ƒ†—Ž–• ƒ› ‹ ’ƒ”– „‡ ‡š’Žƒ‹‡† „› –Š‡ ‘‘ „‡Ž‹‡ˆ –Šƒ–  Ǧ‹†— ‡† ’”‘–‡ –‹‘ –‘  ™ƒ‡• ‘˜‡” ƒ ’‡”‹‘† ‘ˆ ͳͲǦͳͷ ›‡ƒ”• ȋ͵ͶȌǤ ‹ ‡ –‹‡ ƒˆ–‡”   ˜ƒ ‹ƒ–‹‘ ‹ ‘—” •–—†› ‰”‘—’ ˜ƒ”‹‡† „‡–™‡‡ ͳ ƒ† ͵͹ ›‡ƒ”• ™‡ ƒ––‡’–‡† –‘ ‘””‡Žƒ–‡–Š‡Ž‡˜‡Ž‘ˆ”‡•’‘•‡•–‘Žƒ–‡ ›ƒ–‹‰‡•–‘–‹‡‡Žƒ’•‡†•‹ ‡˜ƒ ‹ƒ–‹‘ǡ „—–ˆ‘—†‘•‹‰‹ˆ‹ ƒ–ƒ••‘ ‹ƒ–‹‘•Ǥ ‘‡™Šƒ–—‡š’‡ –‡†Ž›ǡͶ͸Ψ‘ˆ–Š‡ƒ†‘Ž‡• ‡–•™Š‘–‡•–‡†‡‰ƒ–‹˜‡‹–Š‡ ‡ƒˆ•‹ –‡•–’”‹‘”–‘ ˜ƒ ‹ƒ–‹‘ǡ•Š‘™‡†invitro”‡•’‘•‡•–‘Ǥ—”‘™‘„•‡”˜ƒ–‹‘• ȋ—’—„Ž‹•Š‡† ‘„•‡”˜ƒ–‹‘•Ȍ ƒ† –Š‘•‡ ‘ˆ ‘–Š‡”• ȋͶȌ •Š‘™ –Šƒ– in vitro †‡–‡ –ƒ„Ž‡ ‹—‡”‡•’‘•‡•–‘ ƒ„‡‘„•‡”˜‡†‹ƒ•‹‰‹ˆ‹ ƒ–‰”‘—’‘ˆƒ–‘—š‡‰ƒ–‹˜‡ǡ ‘Ǧ  ˜ƒ ‹ƒ–‡† ƒ†  —‡š’‘•‡†ǡ Š‡ƒŽ–Š› ‹†‹˜‹†—ƒŽ•Ǥ Š‹• ’Š‡‘‡‘ ‹• Ž‹‡Ž› ƒ—•‡†„›’”‡˜‹‘—•‡š’‘•—”‡–‘ ”‘••Ǧ”‡ƒ –‹˜‡‡˜‹”‘‡–ƒŽ› ‘„ƒ –‡”‹ƒȋͶǡ ͹ǡ ͳ͸ǡ ʹ͸ȌǤ

(96)  ƒ††‹–‹‘ǡ’”‡˜‹‘—• ‡š’‘•—”‡ –‘ ‡˜‹”‘‡–ƒŽ › ‘„ƒ –‡”‹ƒ‹‰Š–ƒŽ•‘ Šƒ˜‡ ‹†— ‡† Ž‘™ Ž‡˜‡Ž ‘ˆ ”‡•’‘•‡• ȋͶǤͷΨǦ͵͵Ψ ”‡•’‘†‡”•Ȍ ‹ –Š‡ ’”‡Ǧ˜ƒ ‹ƒ–‡†  ‰”‘—’‹–Š‡Ž‘‰‹–—†‹ƒŽ•–—†›ȋ ‹‰—”‡ʹȌ•‹ ‡‘•‡ ‘†‡†ƒ–‹‰‡•Šƒ˜‡‘– „‡‡”‡’‘”–‡†–‘„‡•‘Ž‡Ž›‡š’”‡••‡†‹M.tuberculosis. —” ˆ‹†‹‰• ‹ Š—ƒ• ™‡”‡ ‘””‘„‘”ƒ–‡† ‹   ˜ƒ ‹ƒ–‡† Ȁ  ‹ ‡Ǥ ’‘ •—„ —–ƒ‡‘—• ˜ƒ ‹ƒ–‹‘ ™‹–Š  ǡ –Š‡ ‹ ‡ ‰‡‡”ƒ–‡† ‹—‡ ”‡•’‘•‡• –‘ –Š‡ ‘‘ M. tuberculosis ƒ–‹‰‡• ‰ͺͷ ƒ† Ǥ

(97)  ‘–”ƒ•–ǡ ’‘‘” ”‡•’‘•‡• ™‡”‡ †‡–‡ –ƒ„Ž‡ ƒ‰ƒ‹•– M. tuberculosis Žƒ–‡ › ƒ–‹‰‡• „‘–Š ‘‡ ƒ† –Š”‡‡ ‘–Š• ’‘•–Ǧ ˜ƒ ‹ƒ–‹‘Ǥ‡–ǡ˜ƒ ‹ƒ–‹‘™‹–Š”‡ ‘„‹ƒ–’Žƒ•‹†•‹†— ‡†ƒ•–”‘‰ ‡ŽŽ ͻ͹.

(98) Chapter4. ”‡•’‘•‡ –‘ •‡˜‡”ƒŽ Žƒ–‡ › ƒ–‹‰‡• ‹ Ž—†‹‰ ˜ͳ͹͵͵ ǡ •’ǡ ˜ʹͲ͵ʹǡ ˜ʹ͸ʹ͸ ǡ ˜ʹ͸ʹ͹  ƒ† ˜ʹ͸ʹͺǡ ƒ• ™‡ŽŽ ƒ• ‰ͺͷ ƒ† ͸Ǧ ǦͳͲ ˆ—•‹‘ ’”‘–‡‹Ǥ  ’Žƒ•‹†• ‡ ‘†‹‰ ˜ͳ͹͵ͺ ƒ† ˜ʹͲʹͻ  ™‡”‡ ‘– ‹—‘‰‡‹  ‹ ‹ ‡Ǥ Š‹• †‡‘•–”ƒ–‡†–Šƒ––Š‡‹ ‡™‡”‡ƒ„Ž‡–‘‰‡‡”ƒ–‡•–”‘‰Šͳ–›’‡‹—‡”‡•’‘•‡• –‘ M. tuberculosis Žƒ–‡ › ƒ–‹‰‡• ™Š‡ ‹—‹œ‡† ™‹–Š  ’Žƒ•‹†•ǡ „—– –Šƒ– •—„ —–ƒ‡‘—• ƒ†‹‹•–”ƒ–‹‘ˆƒ‹Ž‡†–‘‹†— ‡‹—‡”‡•’‘•‡•–‘•— Šƒ–‹‰‡• ‹Ȁ ‹ ‡Ǥ•‹‰ Ǧ–”ƒ•‰‡‹ ‹ ‡ȋͳͻǡʹͲȌƒ•‹‹Žƒ”‘„•‡”˜ƒ–‹‘ ‘ ‡”‹‰ •’™ƒ•”‡ ‡–Ž›ƒ†‡‹‘—”Žƒ„‘”ƒ–‘”›ǣ‹ ‡˜ƒ ‹ƒ–‡†™‹–Š †‹†‘–†‡˜‡Ž‘’ ‹—‡”‡•’‘•‡•–‘ •’™Š‡”‡ƒ•‹—‹œƒ–‹‘™‹–Š •’†‹†‹†— ‡”‡•’‘•‡•–‘ •’ƒ†‹–•’”‡†‡ˆ‹‡† ‡ŽŽ‡’‹–‘’‡•ȋͳͲǡʹͲƒȌǤ ˆ‹–‡”‡•–‹•‘—”‘„•‡”˜ƒ–‹‘–Šƒ––Š‡”‡ ‘‰‹–‹‘’ƒ––‡”‘ˆŽƒ–‡ ›ƒ–‹‰‡••‡‡•–‘ „‡ †‹ˆˆ‡”‡– „‡–™‡‡ Š—ƒ• ƒ† Ȁ  ‹ ‡Ǥ

(99) – ƒ’’‡ƒ”• –Šƒ– Š—ƒ• ”‡•’‘†‡† Š‹‰Š‡•––‘ƒ–‹‰‡•˜ͳ͹͵͵ ǡ˜ʹͲʹͻ ƒ†˜ʹ͸ʹ͹ ™Š‡”‡ƒ•‹ ‡”‡•’‘†‡†‘•––‘ ˜ͳ͹͵͵ ǡ˜ʹͲ͵ʹƒ†˜ʹ͸ʹ͸ ȋƒŽ–Š‘—‰Š„‘–Š‘–•–ƒ–‹•–‹ ƒŽŽ›•‹‰‹ˆ‹ ƒ–ȌǤ ‘™‡˜‡” –Š‹• ƒ› „‡ ”‡Žƒ–‡† –‘ †‹ˆˆ‡”‡– ‘†‡ ‘ˆ ƒ–‹‰‡ ‡š’‘•—”‡ „‡‹‰ ƒ–—”ƒŽ ‹ˆ‡ –‹‘ ‹ Š—ƒ•˜‡”•—•˜ƒ ‹ƒ–‹‘‹‹ ‡ǤŠ‹•‘„•‡”˜ƒ–‹‘‹‰Š–Šƒ˜‡‹’Ž‹ ƒ–‹‘•ˆ‘” ’”‘‘ˆ‘ˆ ‘ ‡’–•–—†‹‡•™Š‹ Š‹˜‘Ž˜‡Žƒ–‡ ›ƒ–‹‰‡•‹‘—•‡‘†‡Ž•ƒ†–Š‡‹” ‡š–”ƒ’‘Žƒ–‹‘–‘Žƒ–‡–‹Š—ƒ•Ǥ ‹ƒŽŽ›ǡ –™‘ ‘–Š‡” ƒ‹ƒŽ ‘†‡Ž• ‘ˆ‹”‡† –Š‡ Žƒ  ‘ˆ  ‡ŽŽ ”‡•’‘•‡• –‘ M. tuberculosis Žƒ–‡ › ƒ–‹‰‡• ˆ‘ŽŽ‘™‹‰   ˜ƒ ‹ƒ–‹‘Ǥ ‹”•–ǡ ƒ†—Ž– ƒŽ‡ ”Š‡•—• ‘‡›• ™‡”‡ ˜ƒ ‹ƒ–‡† ™‹–Š   ȋʹ͵Ȍ ƒ† in vitro ‹—‡ ”‡•’‘•‡• –‘ M. tuberculosisŽƒ–‡ ›ƒ–‹‰‡•™‡”‡‘‹–‘”‡†ƒ–‹‡™‡‡•’‘•–Ǧ˜ƒ ‹ƒ–‹‘Ǥ‹‹Žƒ” –‘‘„•‡”˜ƒ–‹‘•‹Š—ƒ•ƒ†‹ ‡ǡ•‹‰‹ˆ‹ ƒ–‹—‡”‡•’‘•‡•–‘™‡”‡•‡‡ ˆ‘ŽŽ‘™‹‰ ˜ƒ ‹ƒ–‹‘ǡ„—–‘”‡•’‘•‡•–‘M.tuberculosisŽƒ–‡ ›ƒ–‹‰‡•ȋ”  ‡””‡ ǡ ’‡”•‘ƒŽ ‘—‹ ƒ–‹‘ȌǤ ‡ ‘†ǡ ƒ––Ž‡ ™‡”‡ ˜ƒ ‹ƒ–‡† ™‹–Š   ‘” ‹ˆ‡ –‡† ™‹–Š M. bovis ȋͺȌƒ† ‹—‡ ”‡•’‘•‡• ™‡”‡ ‡ƒ•—”‡†ƒ‰ƒ‹•– ƒ•‡”‹‡• ‘ˆ Žƒ–‡ › ƒ–‹‰‡•ǡ ȋ„‘˜‹‡Ȍ  ƒ• ™‡ŽŽ ƒ• ͸Ǧ ǦͳͲ ˆ—•‹‘ ’”‘–‡‹Ǥ ‹‰‹ˆ‹ ƒ– ”‡•’‘•‡• –‘  ™‡”‡ ‘„•‡”˜‡† ƒ† ƒ‹ƒŽ• ‹ˆ‡ –‡† ™‹–Š ˜‹”—Ž‡– M. bovis ƒŽ•‘ ”‡•’‘†‡† •‹‰‹ˆ‹ ƒ–Ž› –‘ ͸ ƒ†  ǦͳͲǡ „—– ‘ •‹‰‹ˆ‹ ƒ– ”‡•’‘•‡•–‘ƒ› ‘ˆ –Š‡ –‡•–‡† Žƒ–‡ › ƒ–‹‰‡• ™‡”‡ ‘„•‡”˜‡† ȋ”  ‡‹• ƒ† ”  —††Ž‡ǡ ’‡”•‘ƒŽ ‘—‹ ƒ–‹‘ȌǤŽ–Š‘—‰Š‹–‹•†‹ˆˆ‹ —Ž––‘‡•–ƒ„Ž‹•Š’‘•‹–‹˜‡ ‘–”‘Ž•ˆ‘””‡•’‘•‡•–‘ Žƒ–‡ ›ƒ–‹‰‡•‹–Š‡•‡–™‘ƒ‹ƒŽ‘†‡Ž•ǡ–Š‡”‡•—Ž–•ƒ”‡Ž‹‡Ž›ƒ ‘—–‡†ˆ‘”„› –Š‡•ƒ‡‡ Šƒ‹••—†‡”Ž›‹‰–Š‡‘„•‡”˜‡†‡ˆˆ‡ –•‹Š—ƒ•ƒ†‹ ‡ˆ‘ŽŽ‘™‹‰  ˜ƒ ‹ƒ–‹‘Ǥ Š‡•–—†‹‡••—ƒ”‹œ‡†ƒ„‘˜‡Šƒ˜‡„‡‡’‡”ˆ‘”‡†™‹–Š†‹ˆˆ‡”‡–•–”ƒ‹•‘ˆ ƒ† –Š‹• ƒ› ’‘–‡–‹ƒŽŽ› ‘ˆ‘—† ‹–‡”’”‡–ƒ–‹‘ ƒ† ‘’ƒ”‹•‘ ‘ˆ ”‡•—Ž–•Ǥ ‘™‡˜‡” ‹ ”‘Ǧƒ””ƒ› ‡š’”‡••‹‘ ’”‘ˆ‹Ž‹‰ ‘ˆ ͳͶ †‹ˆˆ‡”‡–   ˜ƒ ‹‡ •–”ƒ‹• •Š‘™‡† Š‹‰ŠŽ› •‹‹Žƒ” ”‡‰—Žƒ–‹‘ ‘ˆ –Š‡ ‘• ”‡‰—Ž‘Ǥ Š‹• ”ƒ–Š‡” •—‰‰‡•–• –Šƒ– Žƒ  ‘ˆ ‹—‡ ”‡•’‘•‡• –‘  Žƒ–‡ › ƒ–‹‰‡• ˆ‘ŽŽ‘™‹‰   ˜ƒ ‹ƒ–‹‘ ‹• ‘– ƒ •–”ƒ‹Ǧ•’‡ ‹ˆ‹  ’Š‡‘‡‘ǡ„—–ƒ‹–”‹•‹ ’”‘’‡”–›‘ˆ†‡”ƒŽ˜ƒ ‹ƒ–‹‘™‹–Š Ǥ ’‘ƒ†‹‹•–”ƒ–‹‘‹–Š‡•‹ǡ ‹•‘”†‹ƒ”‹Ž›‘–‡š’‡ –‡†–‘’‡”•‹•–‹‹—‘Ǧ ‘’‡–‡– Š—ƒ•ǡ ƒŽ–Š‘—‰Š ”ƒ”‡ ƒ•‡• Šƒ˜‡ „‡‡ ”‡’‘”–‡† ‘ˆ ’‡”•‹•–‡ ‡ ƒ† ”‡ƒ –‹˜ƒ–‹‘ ‘ˆ   ‹ ‹†‹˜‹†—ƒŽ• ™Š‘ †‡˜‡Ž‘’‡† ‹—‡ †‡ˆ‹ ‹‡ ‹‡• ƒ› ›‡ƒ”• ƒˆ–‡”˜ƒ ‹ƒ–‹‘ȋͳǡʹ͹ǡ͵ͷǡ͵͸ȌǤ

(100) ––Š‡”‡ˆ‘”‡•‡‡•—Ž‹‡Ž›–Šƒ– ‹–Š‡•‹™‹ŽŽ ‡ ‘—–‡” –Š‡ ‡ ‡••ƒ”› ‡˜‹”‘‡–ƒŽ –”‹‰‰‡”• ‡‡†‡† –‘ ‡š’”‡•• –Š‡ Žƒ–‡ › ƒ–‹‰‡•ƒ†•—„•‡“—‡–Ž›–‘ –”‹‰‰‡” ‹—‡ ”‡•’‘•‡• ‘”‡‘˜‡”ǡ ƒ„•‡ ‡ ‘ˆ  ‡ŽŽ ͻͺ.

(101) ImmunitytoTBlatencyantigensafterBCGvaccination. ”‡•’‘•‡•ƒ”‡‘–†—‡–‘”‡•–”‹ –‹‘•‹ ‡ŽŽ”‡’‡”–‘‹”‡•‹ ‡‹ ‡”‡•’‘†–‘–Š‡•‡ ƒ–‹‰‡• ™Š‡ ‹—‹œ‡† ™‹–Š  ’Žƒ•‹†• ƒ†   ˜ƒ ‹ƒ–‡† ‹†‹˜‹†—ƒŽ• ‡š’‘•‡† –‘  ƒŽ•‘ ”‡•’‘† –‘ Žƒ–‡ › ƒ–‹‰‡• „›

(102) J ’”‘†— –‹‘Ǥ —”–Š‡” •–—†‹‡• ™‹ŽŽ„‡ƒ‹‡†ƒ–‹†‡–‹ˆ‹ ƒ–‹‘‘ˆ‡šƒ –‡ Šƒ‹••–Šƒ–ƒ”‡”‡•’‘•‹„Ž‡ˆ‘””‡‰—Žƒ–‹‘ ƒ† ‡š’”‡••‹‘ ‘ˆ –Š‡ ‘• ”‡‰—Ž‘ ƒ† ‘•‡ —–‹˜‡Ž› ‹—‹–› –‘ Žƒ–‡ › ƒ–‹‰‡• ˆ‘ŽŽ‘™‹‰ ˜ƒ ‹ƒ–‹‘Ǥ ‹ ‡–Š‡•–ƒ”–‘ˆ‹–•ˆ‹”•–—•‡‹–Š‡ͳͻʹͲ•ǡ͵„‹ŽŽ‹‘†‘•‡•‘ˆ Šƒ˜‡„‡‡†‡Ž‹˜‡”‡† –Š”‘—‰Š‘—– –Š‡ ™‘”Ž†ǡ —ˆ‘”–—ƒ–‡Ž› ™‹–Š ”‡Žƒ–‹˜‡Ž› Ž‹––Ž‡ ‹’ƒ – ‘ –Š‡ ‰Ž‘„ƒŽ  ‡’‹†‡‹ ǡ —†‡”Ž‹‹‰ –Š‡ ‡‡† ˆ‘” ƒ „‡––‡” ˜ƒ ‹‡ ”‡‰‹‡Ǥ —” ˆ‹†‹‰• •—‰‰‡•– ˆ—–—”‡•–—†‹‡•‡˜ƒŽ—ƒ–‹‰–Š‡’”‘–‡ –‹˜‡‡ˆˆ‹ ƒ ›‘ˆŽƒ–‡ ›ƒ–‹‰‡•ƒ‰ƒ‹•–ȋŽƒ–‡–Ȍ ƒ†’‘–‡–‹ƒŽ—•‡‘ˆŽƒ–‡ ›ƒ–‹‰‡•ƒ•˜ƒ ‹‡ ƒ†‹†ƒ–‡•ǡ‡‹–Š‡”ƒŽ‘‡ǡ™‹–Š ‘” ƒŽ–‡”ƒ–‹˜‡Ž›ǡƒ•’‘•–Ǧ‡š’‘•—”‡˜ƒ ‹‡•Ǥ.  Acknowledgements  Š‹• ”‡•‡ƒ” Š ’”‘Œ‡ – ™ƒ• ˆ—†‡† „› ƒ ‰”ƒ– ˆ”‘ ‹ŽŽ Ƭ ‡Ž‹†ƒ ƒ–‡• ‘—†ƒ–‹‘ –Š”‘—‰Š –Š‡. ”ƒ† ŠƒŽŽ‡‰‡• ‹. Ž‘„ƒŽ ‡ƒŽ–Š

(103) ‹–‹ƒ–‹˜‡ ȋŠ––’ǣȀȀ™™™Ǥ‰”ƒ† ŠƒŽŽ‡‰‡•‰ŠǤ‘”‰Ȍ ȋ ”ƒ– ͓͵͹ͺͺͷǣ ̶”‡ Ž‹‹ ƒŽ ƒ† Ž‹‹ ƒŽ ˜ƒŽ—ƒ–‹‘ ‘ˆ ‘•–Ǧš’‘•—”‡  ƒ ‹‡̶ ƒ† ”ƒ– ͓͵͹͹͹ʹǣ ̶‹‘ƒ”‡”• ‘ˆ ’”‘–‡ –‹˜‡‹—‹–›ƒ†•—””‘‰ƒ–‡ƒ”‡”•‘ˆ†‹•‡ƒ•‡‹–Š‡ ‘–‡š–‘ˆ

(104) Ȁ

(105)  ‹ ˆ”‹ ƒ̶ȌǤ Š‹• ™‘” ™ƒ• •—’’‘”–‡† „› –Š‡ —”‘’‡ƒ ‘‹••‹‘ǡ ™‹–Š‹ –Š‡ ͸–Š ”ƒ‡™‘””‘‰”ƒ‡ǡ ‘–”ƒ –‘Ǥ ǦǦʹͲͲ͵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–‹‘ȌǤ‹••—’’‘”–‡†„›ƒ‰”ƒ– ˆ”‘ –Š‡ ‘—†ƒ–‹‘ ‹ ”‘„‹‘Ž‘‰› ‡‹†‡ǡ Š‡ ‡–Š‡”Žƒ†•Ǥ 

(106)  ‹• •—’’‘”–‡† „› ƒ 

(107) ‰”ƒ–ͳ

(108) Ͳ͸ͳͷͲͷǤ—„‡” —Ž‘•‹•‹ ”‘ƒ””ƒ›•™‡”‡’”‘˜‹†‡†ƒ•’ƒ”–‘ˆ–Š‡

(109) ǡ 

(110) 

(111) ‘–”ƒ –‘Ǥ ʹ͸͸ʹͲͲͶͲͲͲͻͳǡ‡–‹–Ž‡†̶—„‡” —Ž‘•‹•ƒ ‹‡‡•–‹‰ƒ† ‡•‡ƒ” Šƒ–‡”‹ƒŽ•ǡ̶ƒ™ƒ”†‡†–‘‘Ž‘”ƒ†‘–ƒ–‡‹˜‡”•‹–›Ǥ ‹•’ƒ”–‹ƒŽŽ›•—’’‘”–‡† „› ‰”ƒ–• ǤͲ͵͹͸ǤͲͷ ƒ† ͳǤͷǤͲʹ͸ǤͲ͹ ˆ”‘ –Š‡ ǦŽƒƒ†‡”‡ ƒ† „› –Š‡ ƒ‹ƒƒƒ–‹‡‡Ž‰‹—Ǥ ‡™‘—Ž†Ž‹‡–‘–ŠƒŠ”‹•–‹‡Ž‘ œ›•ƒǡ —†› Žƒƒ‰ƒƒ†”‹†̵ ƒŽŽ‘”ƒƒ† –Š‡ • Š‘‘Ž —”•‡•‘ˆ ‡†„”‹†‰‡ ƒ† ƒŽ–Šƒ ‘”‡•– ‡ƒŽ–Š —–Š‘”‹–› ˆ‘” –Š‡‹” Š‡Ž’ ™‹–Š –Š‡  • Š‘‘Ž •–—†›Ǣ –Š‡ •–ƒˆˆ ƒ† •–—†‡–• ‘ˆ Š‡ ƒƒ•  Š‘‘Ž ƒ† ˜‡Ž‹‰ ƒ”  Š‘‘Ž ˆ‘” –Š‡‹” ‘Ǧ‘’‡”ƒ–‹‘ ƒ† ’ƒ”–‹ ‹’ƒ–‹‘‹ –Š‹• ’”‘Œ‡ –Ǣ ‘•‡ Ž‹–œ ƒ† Šƒ—–ƒŽƒ ƒ–‡Ž ˆ‘” –Š‡‹” Š‡Ž’ ‘ • Š‘‘Ž •–—†› †ƒ›•Ǥ ‡ –Šƒ ‘”‹‡ ”‹• ˆ‘” Š‡” Š‡Ž’‹‘„–ƒ‹‹‰„Ž‘‘†•ƒ’Ž‡•ˆ‘”–Š‡ ”‘••Ǧ•‡ –‹‘ƒŽ •–—†›Ǥ Š‡ ‡š ‡ŽŽ‡– –‡ Š‹ ƒŽ ƒ••‹•–ƒ ‡ ‘ˆ ƒ„‹‡‡ —”‹‘ ƒ† ‹‡””‡Ǧ˜‡• †‡–ǡ 

(112) Ǧ ƒ•–‡—”

(113) •–‹–—–‡ǡ”—••‡Ž•ǡ‡Ž‰‹—‹•‰”ƒ–‡ˆ—ŽŽ›ƒ ‘™Ž‡†‰‡†Ǥ

(114) ƒ††‹–‹‘ǡ™‡–Šƒ •–”‹†˜ƒ ƒŽ–‡”‡ƒ†”‘ˆǤ‡‡•‡Ž‹‡ˆˆ‘” ”‹–‹ ƒŽŽ›”‡ƒ†‹‰–Š‡ƒ—• ”‹’–Ǥ . ͻͻ.

Referenties

Download het nu ( PDF - 19 pagina - 262.94 KB )

GERELATEERDE DOCUMENTEN

Tuberculosis vaccines: Opportunities and challenges

Considering the lack of efficient MVA85A vaccination mediated boosting against clinical tuberculosis in infants vaccinated with BCG 41 , this character of

Tuberculosis vaccines: Opportunities and challenges

Mycobacterial – whole cell or extract Mycobacterial – live.

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

tuberculosis  in  infected  murine  lung  tissue.  Five  dormancy  genes  were  selected 

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

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

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

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

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

Discovery of dormancy associated antigens of Mycobacterium tuberculosis : novel targets for the development of post-exposure or therapeutic tuberculosis vaccines Lin, M.Y...

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

Discovery of dormancy associated antigens of Mycobacterium tuberculosis : novel targets for the development of post-exposure or therapeutic tuberculosis vaccines Lin, M.Y...

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

ͳǦʹͲ ͳͳǦ͵Ͳ ʹͳǦͶͲ ͵ͳǦͷͲ ͶͳǦ͸Ͳ ͷͳǦ͹Ͳ ͸ͳǦͺͲ ͹ͳǦͻͲ ͺͳǦͳͲͲ ͻͳǦͳͳͲ ͳͲͳǦͳʹͲ ͳͳͳǦͳ͵Ͳ ͳʹͳǦͳͶͲ ͳ͵ͳǦͳͷͲ ͳͶͳǦͳ͸Ͳ ͳͷͳǦͳ͹Ͳ ͳ͸ͳǦͳͺͲ ͳ͹ͳǦͳͻͲ ͳͺͳǦʹͲͲ ͳͻͳǦʹͳͲ