tuberkuloziT daavadebisadmiGgenetikuri winaswarganwyobis aspeqtebi

Nnona TadumaZe

tuberkulozisa da filtvis daavadebaTa erovnuli centri 22 Tebervali 2011

Temis aqtualoba

• faqti, rom M.tuberculosis-iT inficirebis mxolod 5-10% Rebulobs aqtiuri daavadebis formas, metyvelebs tuberkulozis ganviTarebaSi adamianis genomis individualuri variabelobis rolze

• antibiotikoTerapiis Tanamedrove krizisi

• axali samkurnalo strategiebis (maT Soris – imunointervenciaze damyarebuli) SemuSavebisa da gaumjobesebis aucilebloba

maspinZeli organizmis genomis funqciuri kvlevis mniSvneloba

• paTogenezis meqanizmebis ufro Rrma wvdoma

• axali, makroorganizmis resursebze dafuZnebuli, prevenciuli da Terapiuli RonisZiebebis SemuSaveba da ganviTareba

• imunointervenciaze damyarebuli strategiebis ganviTareba

tuberkulozisadmi gansxvavebuli mgrZnobeloba Tagvis genetikur xazebSi

• A/Sn – tuberkulozisadmi mdgradi xazi

• I/St – tuberkulozisadmi maRalmgrZnobiare xazi (genomi - Slc11a1(r)):

inficirebis Sedegad daavadebis myisieri ganviTareba mZime mimdinareoba xSiri leTaluri gamosavali makrofagebiT infiltracia makrofaguli derivatebis maRali homogenizacia filtvis qsovilSi neitrofilebis akumulacia

DdaavadebaTa klasifikacia genetikuri da garemo faqtorebis

xvedriTi wilis mixedviT

I jgufi – qromosomuli sindromebi

II jgufi _ monogenuri daavadebebi

III jgufi _ multifaqtoruli (poligenuri) daavadebebi

IV jgufi _ minimaluri genetikuri komponentiT

Kkoncefcia: geni →→ cila →→ funqcia

PAMP (Pathogen associated molecular Patterns) ↔ PRRs (Pattern recognition Receptors)

• paTogenis mitaceba alveoluri makrofagebis (Mφ) mier (PRRs receptorebis gziT) da fagocituri aqtivacia citokinebiT (IFN-γ)

•baqteriebis daSlis iniciacia reaqtiuli oqsigenuri intermediatoruli (ROI) da reaqtiuli nitrogenuli intermediatoruli (RNI) faqtorebis saSualebiT, intrafagocituri NO-is produqcia

• dendruli ujredebis saSualebiT mikobaqteriis transporti filtvis mukozidan limfur kvanZebSi

• T -sistemis aqtivacia Mφ-is (antigen-asocirebuli sxva ujredebis) saSualebiT

• T-sistemis mier citokinebisa da qemokinebis aqtivacia

•qemokinebis mier damatebiTi fagocituri ujredebis mobilizacia infeqciis keraSi

•T-helperuli sistemis bipotenturiprekursorebi _ ThP stimulirdeba, romlebic, Tavis mxriv, stimulireben Th citokinebs

• CD-mediatoruli hipersensitiuri reaqciis Sedegad tuberkulozuri granulomis Camoyalibeba

PRRs (Pattern Recognition Receptors) tipebi

I – membranuli faqtorebi:

• receptoruli kinazebi • Toll-like receptorebi (TLRs)• manozas receptorebi (MRs)

II – citoplazmuri faqtorebi:

• NOD-like receptorebi (NLRs)• NOD-receptorebi (NODs)• IL1-asocirebuli kinazebi (IRAKs)

TLR (Toll-like) receptorebi

funqcia: mikrobul agentebze sapasuxod citokinebisa da imunuri ujredebis aqtivacia

meqanizmi: signalis transduqcia birTvul faqtorebad, romlebic aqtivireben an inhibireben pirvelad imunur reaqcias, rac, Tavis mxriv, modificirebs citokinebis realizacias

genetikuri cvalebadobis Sedegi:

kappa-B signalis transduqciisa da intracitoplazmuli cilebis: nukleotiduri oligomeruli domenebisa (NOD) da kaspazas sistemis blokireba, Sedegad _ imunuri reaqciis inhibireba da Sesabamisiklinikuri efeqti

• Toll-like receptorebisa (TLR) da interleikin-1 receptorebis (IL-1R) sasignalo komponentebi: adaptoruli cila _ MyD88 interaqtiuli cila _ TOLLIP proteinkinaza _ IRAK (IL-1R asocirebuli kinaza) TRAF6 (TNF-receptorTan asocirebuli cila)

• TRAF6 aqtivirebs birTvul B-faqtorebs: (NF- B) kinaza TAK1-is saSualebiT. agreTve – kinazebs: JNK da p38 MAP mitogeniT aqtivirebuli proteinkinazis saSualebiT

TLR evolucia

• evoluciurad uZvelesida maRalkonservatiuli sistema • ZuZumwovarTa saxeobebis umravlesobaSi 10-15 tipis

• adamianSi 13 tipis (TLRs1-TLRs13)

• saxeobrivi gansxvavebebi TLRs tipebis kombinaciebis mixedviT, rac winaaRmdegobas uqmnis cxovelebis, rogorc adamianis imunogenetikis modelis, Seswavlas am mimarTulebiT

TLR genetikuri struqtura

TLR polimorfizmi

• Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. Davila S, Hibberd ML, Hari Dass R, Wong HE, Sahiratmadja E, Bonnard C, Alisjahbana B, Szeszko JS, Balabanova Y, Drobniewski F, van Crevel R, van de Vosse E, Nejentsev S, Ottenhoff TH, Seielstad M. PLoS Genet. 2008 Oct;4(10):e1000218. Epub 2008 Oct 10

• gamovlinda, X-qromosomaze lokalizebuli, TLR8-genis arasinonimuri polimorfizmis _ rs3764880 (Met/Val) _ kavSiri tuberkulozis SemTxvevebTan mamakacebSi

• genis eqspresiis analizma aCvena, TLR8-transkriptis

mniSvnelovani up-regulacia daavadebis mwvave fazaSi

• Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Velez DR, Wejse C, Stryjewski ME, Abbate E, Hulme WF, Myers JL, Estevan R, Patillo SG, Olesen R, Tacconelli A, Sirugo G, Gilbert JR, Hamilton CD, Scott WK. Hum Genet. 2010 Jan;127(1):65-73. Epub 2009 Sep 22

• 474 individi afroamerikuli populaciidan 381 _ evropuli populaciidan 667 _ afrikuli populaciidan

• TLR1, TLR2, TLR4, TLR6, TLR9 71 saxis polimorfizmi

• aqtiuri tuberkulozis SemTxvevebis statistikurad sarwmuno korelacia TLR9 da TLR2 polimorfizmebTan

• Association of TIRAP (MAL) gene polymorphisms with susceptibility to tuberculosis in a Chinese population. Zhang YX, Xue Y, Liu JY, Zhao MY, Li FJ, Zhou JM, Wang HJ, Li JC. Genet Mol Res. 2011 Jan 4;10(1):7-15

• tuberkuloziT daavadebuli 212 pacienti da 215 janmrTeli individi

• Toll-like-receptorebis signalis adaptoruli faqtoris _ Toll-interleikin-1 receptoruli domenis (TIR) adaptoruli cilis _ATIRAP genis polimorfizmi

• 286AG genotipi mniSvnelovnad maRali iyo pacientebSi

kontrolTan SedarebiT

• Toll-like receptor and TIRAP gene polymorphisms in pulmonary tuberculosis patients of South India. Selvaraj P, Harishankar M, Singh B, Jawahar MS, Banurekha VV. Tuberculosis (Edinb). 2010 Sep;90(5):306-10. Epub 2010 Aug 24

• polimorfizmebi:

TLR-1 1805T/G (Ile602Ser)

TLR-2 2258G/A (Arg753Gln)

TLR-4 896A/G (Asp299Gly)

TLR-4 1196C/T (Thr399Ile)

TLR-6 745C/T (Ser249Pro)

TIRAP 975C/T (Ser180Leu)

TLR-9 1237C/T., 1486C/T

• RFLP genotipireba

• filtvis tuberkuloziT daavadebuli 206 pacienti da 212 janmrTeli individi

• Toll-IL1-receptoruli domenis adaptoruli cilis TIRAP genis polimorfuli (Ser180Leu) genotipis sixSire mniSvnelovnad maRalia tuberkuloziT daavadebuli pacientebis jgufSi

• Toll-like receptor 2 gene polymorphisms, pulmonary tuberculosis, and natural killer cell counts. Chen YC, Hsiao CC, Chen CJ, Chin CH, Liu SF, Wu CC, Eng HL, Chao TY, Tsen CC, Wang YH, Lin MC. BMC Med Genet. 2010 Jan 30;11:17

• tuberkuloziT daavadebisadmi sensiturobis korelacia TLR2 haplotipTan _ [A-G-(Insertion)-T]

• plevritebiT mimdinare SemTxvevebSi, plevritebis gareSe mimdinare SemTxvevebTan SedarebiT, maRali iyo 1350 CC genotipis sixSire

Aanionebis RviZlis satransporto sistema

• Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations. Weiner M, Peloquin C, Burman W, Luo CC, Engle M, Prihoda TJ, Mac Kenzie WR, Bliven-Sizemore E, Johnson JL, Vernon A. Antimicrob Agents Chemother. 2010 Oct;54(10):4192-200. Epub 2010 Jul 26

• Association of SLC11A1 with tuberculosis and interactions with NOS2A and TLR2 in African-Americans and Caucasians. Velez DR, Hulme WF, Myers JL, Stryjewski ME, Abbate E, Estevan R, Patillo SG, Gilbert JR, Hamilton CD, Scott WK. Int J Tuberc Lung Dis. 2009 Sep;13(9):1068-76

• Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Ho RH, Choi L, Lee W, Mayo G, Schwarz UI, Tirona RG, Bailey DG, Michael Stein C, Kim RB. Pharmacogenet Genomics. 2007 Aug;17(8):647-56

• anionebis RviZlis satrasporto sistemis SLCO1B1-genis polimorfizmis korelacia rifampicinis farmakokinetikuri maCveneblebis individualur variabelobasTan

• genis polimorfuli varianti _ 463C>A _ ganapirobebda rifampicinis

farmakologiuri moqmedebis daqveiTebas

• 463C>A polimorfizmi da Sedegad, rifampicinis farmakologiuri zemoqmedebis SedarebiT dabali maCvenebeli, upiratesad, aRiniSna Sav rasaSi

• D vitaminis metabolitebis imunomodulatoruli aqtivobis samizne: monocitebis aqtivaciis procesi imunoglobulinebis produqciis procesi citokinebis sekreciis procesi

• 1,25(OH)2D3 imunomodulatoruli potencia: dendruli ujredebis ko-stimulatorebis eqspresiis regulacia IL produqciis regulacia Th2 ganviTarebis stimulacia

• vitamin D-damokidebuli NO-produqciis stimulacia 1,25(OH)2D3 saSualebiT

• 1,25(OH)2D3 da D vitaminis receptorebis (VDR) saSualebiT adamianis antimikrobuli peptidebis eqspresiis regulacia

• D vitaminuri metabolitebi axorcieleben imunuri sistemis rogorc up-regulacias monocitebisa da makrofagebis populaciebis fagocitaruli ativaciis gziT, ise _ down-regulacias (MHC II inhibiciis gziT) SeZenili imunitetis farglebSi

vitamini D _ tuberkulozuri infeqciis supresori

• Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-gamma genes and its association with susceptibility to tuberculosis. Leandro AC, Rocha MA, Cardoso CS, Bonecini-Almeida MG. Braz J Med Biol Res. 2009 Apr;42(4):312-22

• Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa. Gibney KB, MacGregor L, Leder K, Torresi J, Marshall C, Ebeling PR, et al Clin Infect Dis 2008; 46: 443-446

• Solar ultraviolet radiation and vitamin D: a historical perspective.Rajakumar K, Greenspan SL, Thomas SB, Holick MF. Am J Public Health 2007; 97: 1746-1754

• sisxlis plazmaSi D vitaminis dabali koncentacia korelirebs tuberkulozis momatebul riskTan

• sisxlis plazmaSi D vitaminis maRali koncentracia korelirebs tuberkulozis nakleb SemTxvevebTan

• Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, et al. J Infect Dis 1999; 179: 721-724

• Association of vitamin D receptor genotypes with the susceptibility to pulmonary tuberculosis in female patients & resistance in female contacts. Selvaraj P, Narayanan PR, Reetha AM. Indian J Med Res 2000; 111: 172-179

• Association between vitamin D receptor gene polymorphisms and response to treatment of pulmonary tuberculosis. Roth DE, Soto G, Arenas F, Bautista CT, Ortiz J, Rodriguez R, et al. J Infect Dis 2004; 190: 920-927

• rogorc D vitaminis sinTezis variabeluroba, ise misi receptoruli genebis (VDR) polimorfizmi asocirebulia tuberkulozisadmi winaswarganwyobasTan

• VDR polimorfizmebi (12q12-14): BB, Bb,bb (Bsm I)

AA, Aa, aa (Apa I)

TT, Tt, tt (Taq I)

• tt genotipi (9 ekzoni) asocirebulia tuberkulozis dabal riskTan

• peruSi genotipi Tt dakavSirebuli iyo TerapiisSemdgom swraf kulturalur konversiasTan

citokinebi

• Interleukin-10 (IL-10) gene polymorphism as a potential host susceptibility factor in tuberculosis. Oral HB, Budak F, Uzaslan EK, Baştürk B, Bekar A, Akalin H, Ege E, Ener B, Göral G. Cytokine. 2006 Aug;35(3-4):143-7. Epub 2006 Sep 7

• dadgenilia IL-10 genis polimorfizmis korelacia tuberkuloziT daavadebis riskTan

• IL-10-1082G alelis sixSire mniSvnelovnad maRali iyo tuberkuloziT daavadebul pacientebSi janmrTel kontrolTan SedarebiT

• niSnis mixedviT statistikurad sarwmuno gansxvaveba ar iqna dafiqsirebuli daavadebis sxvadasxva klinikur formebs Soris

gama-interferoni

• gama-interferonis interaqtiuli funqcia araspecifikuri da specifikuri imunur sistemebs Soris

• genis polimorfizmi A/T 874 poziciaSi kavSirSia tuberkulozis riskTan

• genebi: IFN- γ - R1 (6q23-24)

IFN-γ - R2 (21q22.1-22.2)

• Toll-like receptors, tumor necrosis factor-α, and interleukin-10 gene polymorphisms in risk of pulmonary tuberculosis and disease severity. Ma MJ, Xie LP, Wu SC, Tang F, Li H, Zhang ZS, Yang H, Chen SL, Liu N, Liu W, Cao WC. Hum Immunol. 2010 Oct;71(10):1005-10. Epub 2010 Jul 30

• TNF-α (tumor necrosis factor- α ) genis genotipis -857 C/T

mniSvnelovani korelacia filtvis tuberkulozis dabal riskTan

• polimorfuli variantis -863 A/C korelacia filtvis tuberkulozis SemTxvevebTan

Kkomplementis sistema

• Major histocompatibility complex class III (C2, C4, factor B) and C3 gene variants in patients with pulmonary tuberculosis. Senbagavalli P, Kumar N, Kaur G, Mehra NK, Geetha ST, Ramanathan VD. Hum Immunol. 2011 Feb;72(2):173-8. Epub 2010 Nov 18.

• komplementis sistemis C2, C4, BF da C3 komponentebis genebis polimorfizmis Seswavla filtvis tuberkulozis SemTxvevebSi

• kvlevis monacemebis Sedareba janmrTel sakontrolo jgufTan

• tuberkuloziT daavadebul jgufSi, sakontrolosTan SedarebiT, maRali aRmoCnda C4AQ0, BF*FA da C3*F alelebis sixSire

• A polymorphism in the inducible nitric oxide synthase gene is associated with tuberculosis. Gómez LM, Anaya JM, Vilchez JR, Cadena J, Hinojosa R, Vélez L, Lopez-Nevot MA, Martín J. Tuberculosis (Edinb). 2007 Jul;87(4):288-94. Epub 2007 May 2.

• Investigation of chromosome 17 candidate genes in susceptibility to TB in a South African population. Möller M, Nebel A, Valentonyte R, van Helden PD, Schreiber S, Hoal EG. Tuberculosis (Edinb). 2009 Mar;89(2):189-94. Epub 2009 Jan 14.

• me-17 qromosoma (17q11.2-12)

• NOS2A (NO sinTetaza) polimorfizmebis korelacia tuberkulozTan sxvadasxva populaciebSi

• tuberkulozis 800 SemTxveva

• NOS2A promotoris ori haplotipis (rs9282799 da rs8078340) mtkice korelacia tuberkulozis SemTxvevbTan

• mniSvnelovani gansxvaveba NOS2A CCTTT polimorfizmis mixedviT sakvlev da sakontrolo jgufebs Soris, gansakuTrebiT _ mokle (8-11) ganmeorebadobebisTvis

• Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. Thuong NT, Dunstan SJ, Chau TT, Thorsson V, Simmons CP, Quyen NT, Thwaites GE, Thi Ngoc Lan N, Hibberd M, Teo YY, Seielstad M, Aderem A, Farrar JJ, Hawn TR. PLoS Pathog. 2008 Dec;4(12):e1000229. Epub 2008 Dec 5.

• 273 _ tuberkulozis SemTxveva

• 188 _ sakontrolo

• genis eqspresiis Sedareba ex vivo M.tuberculosis -iT stimulirebul da arastimulirebul makrofagebSi

• qemotaqsisuri citokinuri ligadis CCL1 genis 6 saxis polimorfizmi iyo asocirebuli tuberkulozTan

5-lipoqsigenaza _ ALOX5 polimorfizmi

• adamianis imunuri ujredebisa da citokinebis produqciis procesis modulatori _ imunuri ujredebis funqcionirebisa da citokinebis maregulirebeli faqtorebis _ leikotrinebisa da lipoqsinebis _ biosinTezis gziT

• ALOX5 (10q11.2) warmodgenilia 14 ekzoniT da 13 introniT da GC mdidari promotoriT

• 2179 da 256 fuZeTa wyvilis regionSi identificirebulia variabeluri tandemuri ganmeorebadobebi (50-GGGCGG-30), romelic warmoadgens Sp1-transkrifciuli faqtoris bmis samiznes

• tubekuloziT daavadebuli 1916 nacxdadebiTi pacienti ganas

regionidan

• ekzonuri alelis g.760A(Glu254Lys) arasinonimuri variabelobis mniSvnelovani korelacia tuberkulozis maRal riskTan

• naCvenebia populaciuri gansxvavebebi variabelobis sixSiris mixedviT

• ALOX5 variants associated with susceptibility to human pulmonary tuberculosis. Florian Herb, Thorsten Thye, Stefan Niemann, Edmund N.L. Browne, Margaret A. Chinbuah, John Gyapong, Ivy Osei, Ellis Owusu-Dabo, Oliver Werz, Sabine Ru¨ sch-Gerdes, Rolf D. Horstmann, Christian G. Meyer, Human Molecular Genetics, 2008, Vol. 17, No. 7 1052–106

• ALOX5 genotipebi: homozigoturi veluri tipi _ ‘5/’5

heterozigoturi varianti _ ‘5/non5’

homozigoturi varianti _ ‘non5/ non5’

• tuberkuloziT daavadebuli pacientebis jgufSi, sakontrolosTan

SedarebiT, mniSvnelovnad xSiri iyo genotipi _ ‘5/non5’

imunitetTan asocirebuli gtf-aza (IRG-cila) intraujreduli paTogenebis autofagiis komponenti

• ori struqturuli subojaxebi:

1. GKS

2. GMS – Irgm1, Irgm2, Irgm3 – GKS cilebis gtf-azuri ciklis umTavres regulatorebad. gansxvavebiT GKS cilebisagan, Seicaven meTionins lizinis nacvlad G1poziciaSi.

IRG cilis struqtura

N-terminaluri gtf bmuli domeni (G-domeni)

maRalvariabeluri C-terminaluri domeni

IRG genTa ojaxi

• tandemuri Tanmimdevrobebis 21 klasteri (maT Soris _ fsevdogenebi) Tagvis genomSi, lokalizebuli me-7 qromosomaze

• mxolod 2 asli adamianis genomSi:

1. IRGC – lokalizebulia me-19 qromosomaze 89%-iT identuri Tagvis Irgc – ar aris CarTuli imunutetSi

2. IRGM – lokalizebulia me-5 qromosomaze (5q33.1) da mniSvnelovan rols asrulebs tuberkulozis, tifis, listeriozis, toqsoplazmozisa da qlamidiozis gamomwvevebis autofagur destruqciaSi

• adamianis IRGM m-rnm arsebobs xuTi, gansxvavebuli, 3′-splaisinguri izoformis (IRGM a–e) saxiT, 30 nw sigrZis ekzoniT

• klonirebulia IRGM-domenis Semcveli calkeuli traskripti

• umoklesi transkripti IRGM(a) Seicavs 181 aminomJavis makodirebel erT did da oTx mcire ekzons

IRG genis struqtura

• IRGM zogierTi polimorfizmi dakavSirebulia organizmis imunuri tolerantobis SemcirebasTan da intraujerduli paTogenebiT inficirebis momatebul riskTan

• IRGM polimorfuli varianti rs9637876 (−261 T) korelaciaSia Sesabamisi cilis eqspresiis zrdasTan da organizmis warmatebul winaaRmdegobisunarTan M.tuberculosis da sxva aratuberkulozuri mikobaqteriebs mimarT

• IRGM genotipi – 2261TT (gansakuTrebiT _ homozigoturi mdgomareoba) dakavSirebulia IRGM cilis eqspresiis gaZlierebasTan da tuberkulozisadmi SedarebiT mdgradobasTan, Sesabamisad _ negatiur korelaciaSia M.tuberculosis gamowveul tuberkulozis SemTxvevebTan

• IRGM alternatiuli splaisingi SesaZlo kritikuli meqanizmia transkriptis ujreduli donisTvis da Sesabamisad _ intraujreduli paTogenisadmi organizmis winaaRmdegobisunarianobisTvis

IRGM TanmimdevrobaTa struqturuli variantebisa da erTeuli nukleotiduri polimorfizmebis sqema

narinjisferiT aRniSnulia polimorfizmebi, romlebic cvlian genis eqspresias

IRGM evolucia

• Alu-inserciis safuZvelze IRGM warmoadgenda fsevdogens 50 milioni wlis win

• Zveli da axali samyaros maimunebSi IRGM arafunqciuria

• uZveles adamianSi IRGM funqcia aRsda ERV9-elementis, rogorc transkrifciis maregulirebeli faqtoris, genomSi integrirebis wyalobiT

• gibonebSi aRwerilia mocemuli genis, rogorc funqciuri, ise arafunqciuri mdgomareobebi

• ERV retrovirusuli elementebia, daaxloebiT 14 subojaxs aerTianebs da specifikuria primatebisaTvis

• ERV-elementebis roli adamianSi ucnobia, Tumca, zogierTi monacemis mixedviT, isini SeiZleba CarTulni iyon egzogenuri virusebis prevenciis meqanizmSi

daskvna

• arsebuli monacemebi miuTiTeben maspinZeli organizmis genetikuri faqtorebis rolze tuberkuloziT daavadebisadmi winaswarganwyobaSi

• tuberkulozisadmi genetikuri winaswarganwyobis meqanizmebSi

CarTulia rogorc araspecifikuri, ise specifikuri imunuri sistemis rgolebi

• tuberkuloziT daavadebaze pasuxismgebel kandidat genTa Sorisaa PRR receptorebis, citokinebis, nitrogenoqsigenuri sinTezis, komplementis sitemis, vitamini D metabolizmis makodirebeli da sxva imunomodulatoruli faqtorebis genebi

• aRniSnuli biologiuri sistemebis genetikuri regulaciis kvleva mniSvnelovani molekuluri meqanizmi SeiZleba gaxdes, romelsac daefuZneba intervencia

KmimarTulebis perspeqtiva

• tuberkulozuri infeqciuri procesis ganviTarebasTan dakavSirebuli genetikuri meqanizmebis dadgena

• maspinZeli organizmis resursebze damyarebuli axali, prevenciuli, RonisZiebebis ganviTareba

• imunointervenciaze dafuZnebuli Terapiuli strategiebis SemuSaveba

• masobrivi skriningi tuberkulozis, genetikurad ganpirobebuli, risk-jgufebis gamovlenis mizniT