結核病最近再度成為全球大眾健康的重要威脅，結核分枝桿菌是一個非常成功的致病菌，有良好的演化過程可以建立持續的感染。有確鑿的證據顯示宿主的遺傳因素會影響對結核病的易感染性，我們先前已發現在男性TLR8 -129C等位基因型在結核病患者出現的頻率較高於健康的對照組（24.1％對6.8％，P=0.001），從健康男性血液中分離出單核球，以體外實驗研究這些基因多型性對於防禦結核分枝桿菌的功能的影響，在對結核分枝桿菌吞噬能力的分析發現，TLR8 -129C基因型者比起TLR8 -129G基因型者有較強的吞噬能力（73.02％對34.62％，P=0.03）。此外，在體外，以去活化的結核分枝桿菌刺激健康男性受試者的全血，分析mRNA的表現量與細胞激素的產生，發現TLR8 -129C基因型者在經結核分枝桿菌刺激後，無論在TNFα的產生量或在TLR7的表現量皆較低。結核病的傳染最重要的決定因素為結核分枝桿菌在巨噬細胞內存活及複製的能力，我們利用PMA刺激THP-1 單核細胞株使活化成巨噬細胞，並且證實它對結核分枝桿菌的吞噬結果具有劑量與時間的依賴性，若再經由IFN-γ或TLR8刺激劑CL075所活化，則會明顯增加其對結核分枝桿菌的吞噬能力，分別增加為1.53倍及1.33倍，細胞內TLR8的表現量會分別增加為7.22倍及1.75倍，而當我們抑制TLR8的表現，發現細胞對結核分枝桿菌的吞噬能力明顯降低。總之，從我們的發現證明TLR8基因的多型性與結核分枝桿菌的易感染性有關，其作用模式是經由增加細胞對結核分枝桿菌的吞噬能力但減弱TLR8的訊息傳遞。

Tuberculosis (TB) has recently re-emerged as a major global public health threat and Mycobacterium tuberculosis (Mtb) is a highly successful pathogen that evolved remarkable strategies to establish persistent infection. There is strong evidence that host genetic factors influence individual susceptibility to TB. We have demonstrated that the frequency of the TLR8 -129C allele was higher in male patients with pulmonary TB than in healthy controls (24.1% vs. 6.8%, p=0.001). An ex vivo phagocytosis assay that examined the functional effects of these polymorphisms on the defense against Mtb revealed higher phagocytosis in monocytes from males with the TLR8 -129C genotype than in those with TLR8 -129G (73.02% vs. 34.6%, p=0.03). In addition, mRNA expression and cytokine production, analyzed in the whole blood of male healthy volunteers stimulated with inactivated Mtb ex vivo, TNFα production and TLR7 expression were lower in TLR8 -129C subjects after Mtb stimulation. The ability of Mtb to survive and replicate in macrophages is crucial for chronic persistent infection. We demonstrated that PMA-stimulated THP-1 cells showed high phagocytosis of Mtb in a Mtb dose- and time-dependent manner. The phagocytosis of Mtb was markedly influenced by IFN-γ and CL075 activation, and the efficiency of Mtb phagocytosis increased to 1.53 and 1.33 folds, respectively. TLR8 was unregulated to 7.22 and 1.75 folds in response to IFN-γ and CL075 stimulation. However, after silencing TLR8 expression, the phagocytosis of Mtb was significantly decreased in PMA-stimulated THP-1 cells. In conclusion, these findings provide evidence that TLR8 genetic polymorphisms are associated with susceptibility to Mtb infection, and the link is shaped by more effective Mtb phagocytosis but impaired TLR8 signaling.

中文摘要 + i
英文摘要 + ii
目錄 + iii
圖次 + iv
表次 + vi
第一章 緒論 + 1
第二章 Preliminary Data + 17
第三章 目的 + 20
第四章 材料與方法 + 21
第五章 結果 + 36
第六章 討論 + 44
第七章 結論 + 56
第八章 圖表 + 57
第九章 參考文獻 + 70
第十章 補充附件 + 89

Agrawal, S., Agrawal, A., Doughty, B., Gerwitz, A., Blenis, J., Van Dyke, T., & Pulendran, B. (2003). Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J Immunol, 171(10), 4984-4989.
Akashi-Takamura, S., & Miyake, K. (2008). TLR accessory molecules. Curr Opin Immunol, 20(4), 420-425.
Akira, S., & Takeda, K. (2004). Toll-like receptor signalling. Nat Rev Immunol, 4(7), 499-511.
Akira, S., Takeda, K., & Kaisho, T. (2001). Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol, 2(8), 675-680.
Akira, S., Uematsu, S., & Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell, 124(4), 783-801.
Altieri, D. C., & Edgington, T. S. (1988). The saturable high affinity association of factor X to ADP-stimulated monocytes defines a novel function of the Mac-1 receptor. J Biol Chem, 263(15), 7007-7015.
Antonucci, G., Girardi, E., Raviglione, M. C., & Ippolito, G. (1995). Risk factors for tuberculosis in HIV-infected persons. A prospective cohort study. The Gruppo Italiano di Studio Tubercolosi e AIDS (GISTA). JAMA, 274(2), 143-148.
Arbour, N. C., Lorenz, E., Schutte, B. C., Zabner, J., Kline, J. N., Jones, M. ,Frees, K., Watt, J. L., & Schwartz, D. A. (2000). TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet, 25(2), 187-191.
Arpaia, N., & Barton, G. M. (2013). The impact of Toll-like receptors on bacterial virulence strategies. Curr Opin Microbiol, 16(1), 17-22.
Arpaia, N., Godec, J., Lau, L., Sivick, K. E., McLaughlin, L. M., Jones. M. B., Dracheva, T., Peterson, S. N., Monack, D. M., & Barton, G. M. (2011). TLR signaling is required for Salmonella typhimurium virulence. Cell, 144(5), 675-688.
ATS (The American Thoracic Society). (2000). Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med, 161(4 Pt 1), 1376-1395.
Azad, A. K., Sadee, W., & Schlesinger, L. S. (2012). Innate immune gene polymorphisms in tuberculosis. Infect Immun, 80(10), 3343-3359.
Bach, E. A., Szabo, S. J., Dighe, A. S., Ashkenazi, A., Aguet, M., Murphy, K. M., & Schreiber, R. D. (1995). Ligand-induced autoregulation of IFN-gamma receptor beta chain expression in T helper cell subsets. Science, 270(5239), 1215-1218.
Bafica, A., Scanga, C. A., Feng, C. G., Leifer, C., Cheever, A., & Sher, A. (2005). TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med, 202(12), 1715-1724.
Bai, X., Feldman, N. E., Chmura, K., Ovrutsky, A. R., Su, W. L., Griffin, L., Pyeon, D., McGibney, M. T., Strand, M. J., Numata, M., Murakami, S., Gaido, L., Honda, J. R., Kinney, W. H., Oberley-Deegan, R. E., Voelker, D. R., Ordway, D. J., &Chan, E. D. (2013). Inhibition of nuclear factor-kappa B activation decreases survival of Mycobacterium tuberculosis in human macrophages. PLoS One, 8(4), e61925.
Barbalat, R., Ewald, S. E., Mouchess, M. L., & Barton, G. M. (2011). Nucleic acid recognition by the innate immune system. Annu Rev Immunol, 29, 185-214.
Barnes, P. F., Abrams, J. S., Lu, S., Sieling, P. A., Rea, T. H., & Modlin, R. L. (1993). Patterns of cytokine production by mycobacterium-reactive human T-cell clones. Infect Immun, 61(1), 197-203.
Basu, J., Shin, D. M., & Jo, E. K. (2012). Mycobacterial signaling through toll-like receptors. Front Cell Infect Microbiol, 2, 145.
Bell, J. K., Askins, J., Hall, P. R., Davies, D. R., & Segal, D. M. (2006). The dsRNA binding site of human Toll-like receptor 3. Proc Natl Acad Sci U S A, 103(23), 8792-8797.
Belvin, M. P., & Anderson, K. V. (1996). A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol, 12, 393-416.
Beutler, B. (2009). Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol Rev, 227(1), 248-263.
Blander, J. M., & Medzhitov, R. (2004). Regulation of phagosome maturation by signals from toll-like receptors. Science, 304(5673), 1014-1018.
Blander, J. M., & Medzhitov, R. (2006). Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature, 440(7085), 808-812.
Boone, D. L., Turer, E. E. , Lee, E. G., Ahmad, R. C., Wheeler, M. T, Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., McNally, E., Pickart, C., & Ma, A. (2004). The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol, 5(10), 1052-1060.
Boussiotis, V. A., Tsai, E. Y, Yunis, E. J., Thim, S., Delgado, J. C., Dascher, C.C., Berezovskaya, A., Rousset, D., Reynes, J. M., & Goldfeld, A. E. (2000). IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest, 105(9), 1317-1325.
Brassard, P., Kezouh, A., & Suissa, S. (2006). Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis, 43(6), 717-722.
Brennan, P. J., & Nikaido, H. (1995). The envelope of mycobacteria. Annu Rev Biochem, 64, 29-63.
Bruns, H., Meinken, C., Schauenberg, P., Härter, G., Kern, P., Modlin, R. L., Antoni, C., & Stenger S. (2009). Anti-TNF immunotherapy reduces CD8+ T cell-mediated antimicrobial activity against Mycobacterium tuberculosis in humans. J Clin Invest, 119(5), 1167-1177.
Canet, E., Dantal, J., Blancho, G., Hourmant, M., & Coupel, S. (2011). Tuberculosis following kidney transplantation: clinical features and outcome. A French multicentre experience in the last 20 years. Nephrol Dial Transplant, 26(11), 3773-3778.
Carvalho, A., Osório, N. S., Saraiva, M., Cunha, C., Almeida, A. J., Teixeira-Coelho, M., Ludovico, P., Pedrosa, J., Pitzurra, L., Aversa, F., Romani, L., Castro, A. G., & Rodrigues, F. (2011). The C allele of rs5743836 polymorphism in the human TLR9 promoter links IL-6 and TLR9 up-regulation and confers increased B-cell proliferation. PLoS One, 6(11), e28256.
Chao, M. C., & Rubin, E. J. (2010). Letting sleeping dos lie: does dormancy play a role in tuberculosis? Annu Rev Microbiol, 64, 293-311.
Chee, C. B., Sester, M., Zhang, W., & Lange, C. (2013). Diagnosis and treatment of latent infection with Mycobacterium tuberculosis. Respirology, 18(2), 205-216.
Choe, J., Kelker, M. S., & Wilson, I. A. (2005). Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science, 309(5734), 581-585.
Chuang, T., & Ulevitch, R. J. (2001). Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta, 1518(1-2), 157-161.
Cole, S. T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S. V., Eiglmeier, K., Gas, S., Barry, C. E. 3rd, Tekaia, F., Badcock, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R., Devlin, K., Feltwell, T., Gentles, S., Hamlin, N., Holroyd, S., Hornsby, T., Jagels, K., Krogh, A., McLean, J., Moule, S., Murphy, L., Oliver, K., Osborne, J., Quail, M. A., Rajandream, M. A., Rogers, J., Rutter, S., Seeger, K., Skelton, J., Squares, R., Squares, S., Sulston, J. E., Taylor, K., Whitehead, S., & Barrell, B. G. (1998). Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature, 393(6685), 537-544.
Constantoulakis, P., Filiou, E., Rovina, N., Chras, G., Hamhougia, A., Karabela, S., Sotiriou, A., Roussos, C., & Poulakis, N. (2010). In vivo expression of innate immunity markers in patients with Mycobacterium tuberculosis infection. BMC Infect Dis, 10, 243.
Dahl, K. E., Shiratsuchi, H., Hamilton, B. D., Ellner, J. J., & Toossi, Z. (1996). Selective induction of transforming growth factor beta in human monocytes by lipoarabinomannan of Mycobacterium tuberculosis. Infect Immun, 64(2), 399-405.
Dalgic, N., Tekin, D., Kayaalti, Z., Cakir, E., Soylemezoglu, T., & Sancar, M. (2011). Relationship between toll-like receptor 8 gene polymorphisms and pediatric pulmonary tuberculosis. Dis Markers, 31(1), 33-38.
Davila, S., Hibberd, M. L., Hari Dass, R., Wong, H. E., Sahiratmadja, E., Bonnard, C., Alisjahbana, B., Szeszko, J. S., Balabanova, Y., Drobniewski, F., van Crevel, R., van de Vosse, E., Nejentsev, S., Ottenhoff, T. H., & Seielstad, M. (2008). Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. PLoS Genet, 4(10), e1000218.
Delogu, G., Sali, M., & Fadda, G. (2013). The Biology of Mycobacterium Tuberculosis Infection. Mediterr J Hematol Infect Dis, 5(1), e2013070.
Dheda, K., Schwander, S. K., Zhu, B., van Zyl-Smit, R. N., & Zhang, Y. (2010). The immunology of tuberculosis: from bench to bedside. Respirology, 15(3), 433-450.
Dillon, S., Agrawal, A., Van Dyke, T., Landreth, G., McCauley, L., Koh, A., Maliszewski, C., Akira, S., & Pulendran, B. (2004). A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol, 172(8), 4733-4743.
Divanovic, S., Trompette, A., Atabani, S. F., Madan, R., Golenbock, D. T., Visintin, A., Finberg, R. W., Tarakhovsky, A., Vogel, S. N., Belkaid, Y., Kurt-Jones, E. A., & Karp, C. L. (2005). Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat Immunol, 6(6), 571-578.
Druszczynska, M., Kowalewicz-Kulbat, M., Fol, M., Wlodarczyk, M., & Rudnicka, W. (2012). Latent M. tuberculosis infection--pathogenesis, diagnosis, treatment and prevention strategies. Pol J Microbiol, 61(1), 3-10.
Dubois, P. C., Trynka, G., Franke, L., Hunt, K. A., Romanos, J., Curtotti, A., Zhernakova, A., Heap, G. A., Adány, R., Aromaa, A., Bardella, M. T., van den Berg, L. H., Bockett, N. A., de la Concha, E. G., Dema, B., Fehrmann, R. S., Fernández-Arquero, M., Fiatal, S., Grandone, E., Green, P. M., Groen, H. J., Gwilliam, R., Houwen, R. H., Hunt, S. E., Kaukinen, K., Kelleher, D., Korponay-Szabo, I., Kurppa, K., MacMathuna, P., Mäki, M., Mazzilli, M. C., McCann, O. T., Mearin, M. L., Mein, C. A., Mirza, M. M., Mistry, V., Mora, B., Morley, K. I., Mulder, C. J., Murray, J. A., Núñez, C., Oosterom, E., Ophoff, R. A., Polanco, I., Peltonen, L., Platteel, M., Rybak, A., Salomaa, V., Schweizer, J. J., Sperandeo, M. P., Tack, G. J., Turner, G., Veldink, J. H., Verbeek, W. H., Weersma, R. K., Wolters, V. M., Urcelay, E., Cukrowska, B., Greco, L., Neuhausen, S. L., McManus, R., Barisani, D., Deloukas, P., Barrett, J. C., Saavalainen, P., Wijmenga, C., & van Heel, D. A. (2010). Multiple common variants for celiac disease influencing immune gene expression. Nat Genet, 42(4), 295-302.
Eder, W., Klimecki, W., Yu, L., von Mutius, E., Riedler, J., Braun-Fahrländer, C., Nowak, D., & Martinez, F. D. (2004). Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol, 113(3), 482-488.
Edfeldt, K., Swedenborg, J., Hansson, G. K., & Yan, Z. Q. (2002). Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation, 105(10), 1158-1161.
Edwards, D., & Kirkpatrick, C. H. (1986). The immunology of mycobacterial diseases. Am Rev Respir Dis, 134(5), 1062-1071.
Erkens, C. G., Kamphorst, M., Abubakar, I., Bothamley, G. H., Chemtob, D., Haas, W., Migliori, G. B., Rieder, H. L., Zellweger, J. P., & Lange, C. (2010). Tuberculosis contact investigation in low prevalence countries: a European consensus. Eur Respir J, 36(4), 925-949
Fekonja, O., Avbelj, M., & Jerala, R. (2012). Suppression of TLR signaling by targeting TIR domain-containing proteins. Curr Protein Pept Sci, 13(8), 776-788.
Ferguson, J. S., Martin, J. L., Azad, A. K., McCarthy, T. R., Kang, P. B., Voelker, D. R., Crouch, E. C., & Schlesinger, L. S. (2006). Surfactant protein D increases fusion of Mycobacterium tuberculosis-containing phagosomes with lysosomes in human macrophages. Infect Immun, 74(12), 7005-7009.
Fitzgerald, K. A., Rowe, D. C., Barnes, B. J., Caffrey, D. R., Visintin, A., Latz, E., Monks, B., Pitha, P. M., & Golenbock, D. T. (2003). LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med, 198(7), 1043-1055.
Flo, T. H., Halaas, O., Torp, S., Ryan, L., Lien, E., Dybdahl, B., Sundan, A., & Espevik, T. (2001). Differential expression of Toll-like receptor 2 in human cells. J Leukoc Biol, 69(3), 474-481.
Flynn, J. L., & Chan, J. (2001). Tuberculosis: latency and reactivation. Infect Immun, 69(7), 4195-4201.
Foster, S. L., Hargreaves, D. C., & Medzhitov, R. (2007). Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature, 447(7147), 972-978.
Fox, W., Ellard, G. A., & Mitchison, D. A. (1999). Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. Int J Tuberc Lung Dis, 3(10 Suppl 2), S231-279.
Fulton, S. A., Cross, J. V., Toossi, Z. T., & Boom, W. H. (1998). Regulation of interleukin-12 by interleukin-10, transforming growth factor-beta, tumor necrosis factor-alpha, and interferon-gamma in human monocytes infected with Mycobacterium tuberculosis H37Ra. J Infect Dis, 178(4), 1105-1114.
Galloway, J. B., Hyrich, K. L., Mercer, L. K., Dixon, W. G., Fu, B., Ustianowski, A. P., Watson, K. D., Lunt, M., & Symmons, D. P. (2011). Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford), 50(1), 124-131.
Gengenbacher, M., & Kaufmann, S. H. (2012). Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev, 36(3), 514-532.
Gerosa, F., Nisii, C., Righetti, S., Micciolo, R., Marchesini, M., Cazzadori, A., & Trinchieri, G. (1999). CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol, 92(3), 224-234.
Gewirtz, A. T., Vijay-Kumar, M., Brant, S. R., Duerr, R. H., Nicolae, D. L., & Cho, J. H. (2006). Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease. Am J Physiol Gastrointest Liver Physiol, 290(6), G1157-1163.
Gilchrist, M., Thorsson, V., Li, B., Rust, A. G., Korb, M., Roach, J. C., Kennedy, K., Hai, T., Bolouri, H., & Aderem A. (2006). Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature, 441(7090), 173-178.
Girardi, E., Antonucci, G., Ippolito, G., Raviglione, M. C., Rapiti, E., Di Perri, G., & Babudieri, S. (1997). Association of tuberculosis risk with the degree of tuberculin reaction in HIV-infected patients. The Gruppo Italiano di Studio Tubercolosi e AIDS. Arch Intern Med, 157(7), 797-800.
Glaziou, P., Falzon, D., Floyd, K., & Raviglione, M. (2013). Global epidemiology of tuberculosis. Semin Respir Crit Care Med, 34(1), 3-16.
Gong, J. H., Zhang, M., Modlin, R. L., Linsley, P. S., Iyer, D., Lin, Y., & Barnes, P. F. (1996). Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression. Infect Immun, 64(3), 913-918.
Hansson, G. K., & Edfeldt, K. (2005). Toll to be paid at the gateway to the vessel wall. Arterioscler Thromb Vasc Biol, 25(6), 1085-1087.
Hawn, T. R., Dunstan, S. J., Thwaites, G. E., Simmons, C. P., Thuong, N. T., Lan, N. T., Quy, H. T., Chau, T. T., Hieu, N. T., Rodrigues, S., Janer, M., Zhao, L. P., Hien, T. T., Farrar, J. J., & Aderem, A. (2006). A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. J Infect Dis, 194(8), 1127-1134.
Hawn, T. R., Scholes, D., Li, S. S., Wang, H., Yang, Y., Roberts, P. L., Stapleton, A.E , Janer, M., Aderem, A., Stamm, W. E., Zhao, L. P., & Hooton, T. M. (2009). Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS One, 4(6), e5990.
Hawn, T. R., Verbon, A., Lettinga, K. D., Zhao, L. P., Li, S. S., Laws, R. J., Skerrett, S. J., Beutler, B., Schroeder, L., Nachman, A., Ozinsky, A., Smith, K. D., & Aderem, A. (2003). A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J Exp Med, 198(10), 1563-1572.
Hawn, T. R., Wu, H., Grossman, J. M., Hahn, B. H., Tsao, B. P., & Aderem, A. (2005). A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci U S A, 102(30), 10593-10597.
Henderson, R. A., Watkins, S. C., & Flynn, J. L. (1997). Activation of human dendritic cells following infection with Mycobacterium tuberculosis. J Immunol, 159(2), 635-643.
Hilda, J. N., Selvaraj, A., & Das, S. D. (2012). Mycobacterium tuberculosis H37Rv is more effective compared to vaccine strains in modulating neutrophil functions: an in vitro study. FEMS Immunol Med Microbiol, 66(3), 372-381.
Hirsch, C. S., Toossi, Z., Othieno, C., Johnson, J. L., Schwander, S. K., Robertson, S., Wallis, R. S., Edmonds, K., Okwera, A., Mugerwa, R., Peters, P., & Ellner, J. J. (1999). Depressed T-cell interferon-gamma responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. J Infect Dis, 180(6), 2069-2073.
Hoheisel, G., Izbicki, G., Roth, M., Chan, C. H., Leung, J. C., Reichenberger, F., Schauer, J., & Perruchoud, A. P. (1998). Compartmentalization of pro-inflammatory cytokines in tuberculous pleurisy. Respir Med, 92(1), 14-17.
Honda, K., Yanai, H., Mizutani, T., Negishi, H., Shimada, N., Suzuki, N., Ohba, Y., Takaoka, A., Yeh, W. C., & Taniguchi, T. (2004). Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci U S A, 101(43), 15416-15421.
Horsburgh, C. R. Jr, O'Donnell, M., Chamblee, S., Moreland, J. L., Johnson, J., Marsh, B. J., Narita, M., Johnson, L. S., & von Reyn, C. F. (2010). Revisiting rates of reactivation tuberculosis: a population-based approach. Am J Respir Crit Care Med, 182(3), 420-425.
Hu, X., Chakravarty, S. D., & Ivashkiv, L. B. (2008). Regulation of interferon and Toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol Rev, 226, 41-56.
Hu, X., Herrero, C., Li, W. P., Antoniv, T. T., Falck-Pedersen, E., Koch, A. E., Woods, J. M., Haines, G. K., & Ivashkiv, L. B. (2002). Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. Nat Immunol, 3(9), 859-866.
Janssens, S., Burns, K., Vercammen, E., Tschopp, J., & Beyaert, R. (2003). MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression. FEBS Lett, 548(1-3), 103-107.
Jayachandran, R., Scherr, N., & Pieters, J. (2012). Elimination of intracellularly residing Mycobacterium tuberculosis through targeting of host and bacterial signaling mechanisms. Expert Rev Anti Infect Ther, 10(9), 1007-1022.
Jin, M. S., Kim, S. E., Heo, J. Y., Lee, M. E., Kim, H. M., Paik, S. G., Lee, H., & Lee, J. O. (2007). Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell, 130(6), 1071-1082.
Jo, E. K., Yang, C. S., Choi, C. H., & Harding, C. V. (2007). Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors. Cell Microbiol, 9(5), 1087-1098.
Juarez, E., Nunez, C., Sada, E., Ellner, J. J., Schwander, S. K., & Torres, M. (2010). Differential expression of Toll-like receptors on human alveolar macrophages and autologous peripheral monocytes. Respir Res, 11, 2.
Jung, S. B., Yang, C. S., Lee, J. S., Shin, A. R., Jung, S. S., Son, J. W., Harding, C. V., Kim, H. J., Park, J. K., Paik, T. H., Song, C. H., & Jo, E. K. (2006). The mycobacterial 38-kilodalton glycolipoprotein antigen activates the mitogen-activated protein kinase pathway and release of proinflammatory cytokines through Toll-like receptors 2 and 4 in human monocytes. Infect Immun, 74(5), 2686-2696.
Kalayoglu, M. V., Libby, P., & Byrne, G. I. (2002). Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA, 288(21), 2724-2731.
Kang, J. Y., Nan, X., Jin, M. S., Youn, S. J., Ryu, Y. H., Mah, S., Han, S. H., Lee, H., Paik, S. G., & Lee, J. O. (2009). Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. Immunity, 31(6), 873-884.
Kang, T. J., & Chae, G. T. (2001). Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol, 31(1), 53-58.
Kang, T. J., Lee, S. B., & Chae, G. T. (2002). A polymorphism in the toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy. Cytokine, 20(2), 56-62.
Kaufmann, S. H. (2001). How can immunology contribute to the control of tuberculosis? Nat Rev Immunol, 1(1), 20-30.
Kawai, T., & Akira, S. (2006). Innate immune recognition of viral infection. Nat Immunol, 7(2), 131-137.
Kawai, T., & Akira, S. (2007). TLR signaling. Semin Immunol, 19(1), 24-32.
Kawai, T., & Akira, S. (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol, 11(5), 373-384.
Keane, J., Gershon, S., Wise, R. P., Mirabile-Levens, E., Kasznica, J., Schwieterman, W. D., Siegel, J. N., & Braun, M. M. (2001). Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med, 345(15), 1098-1104.
Khor, C. C., Chapman, S. J., Vannberg, F. O., Dunne, A., Murphy, C., Ling, E. Y., Frodsham, A. J., Walley, A. J., Kyrieleis, O., Khan, A., Aucan, C., Segal, S., Moore, C. E., Knox, K., Campbell, S. J., Lienhardt, C., Scott, A., Aaby, P., Sow, O. Y., Grignani, R. T., Sillah, J., Sirugo, G., Peshu, N., Williams, T. N., Maitland, K., Davies, R. J., Kwiatkowski, D. P., Day, N. P., Yala, D., Crook, D. W., Marsh, K., Berkley, J. A., O'Neill, L. A., & Hill, A. V. (2007). A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet, 39(4), 523-528.
Kindler, V., Sappino, A. P., Grau, G. E., Piguet, P. F., & Vassalli, P. (1989). The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell, 56(5), 731-740.
Kleinnijenhuis, J., Oosting, M., Joosten, L. A., Netea, M. G., & Van Crevel, R. (2011). Innate immune recognition of Mycobacterium tuberculosis. Clin Dev Immunol, 2011, 405310.
Kobayashi, K., Yuliwulandari, R., Yanai, H., Naka, I., Lien, L. T., Hang, N. T., Hijikata, M., Keicho, N., & Tokunaga, K. (2012). Association of TLR polymorphisms with development of tuberculosis in Indonesian females. Tissue Antigens, 79(3), 190-197.
Korbel, D. S., Schneider, B. E., & Schaible, U. E. (2008). Innate immunity in tuberculosis: myths and truth. Microbes Infect, 10(9), 995-1004.
Korch, S. B., Contreras, H., & Clark-Curtiss, J. E. (2009). Three Mycobacterium tuberculosis Rel toxin-antitoxin modules inhibit mycobacterial growth and are expressed in infected human macrophages. J Bacteriol, 191(5), 1618-1630.
Krieg, A. M. (2002). CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol, 20, 709-760.
Krishnan, J., Selvarajoo, K., Tsuchiya, M., Lee, G., & Choi, S. (2007). Toll-like receptor signal transduction. Exp Mol Med, 39(4), 421-438.
Kumar, A., Toledo, J. C., Patel, R. P., Lancaster, J. R., Jr., & Steyn, A. J. (2007). Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor. Proc Natl Acad Sci U S A, 104(28), 11568-11573.
Kumar, H., Kawai, T., & Akira, S. (2009). Toll-like receptors and innate immunity. Biochem Biophys Res Commun, 388(4), 621-625.
Ladel, C. H., Blum, C., Dreher, A., Reifenberg, K., Kopf, M., & Kaufmann, S. H. (1997). Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect Immun, 65(11), 4843-4849.
Lambeth, J. D. (2004). NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol, 4(3), 181-189.
Lasker, M. V., & Nair, S. K. (2006). Intracellular TLR signaling: a structural perspective on human disease. J Immunol, 177(1), 11-16.
Law, K., Weiden, M., Harkin, T., Tchou-Wong, K., Chi, C., & Rom, W. N. (1996). Increased release of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis. Am J Respir Crit Care Med, 153(2), 799-804.
Lazarus, R., Raby, B. A., Lange, C., Silverman, E. K., Kwiatkowski, D. J., Vercelli, D., Klimecki, W. J., Martinez, F. D., & Weiss, S. T. (2004). TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples. Am J Respir Crit Care Med, 170(6), 594-600. doi: 10.1164/rccm.200404-491OC
Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M., & Hoffmann, J. A. (1996). The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell, 86(6), 973-983.
Liu, P. T., & Modlin, R. L. (2008). Human macrophage host defense against Mycobacterium tuberculosis. Curr Opin Immunol, 20(4), 371-376.
Lorenz, E., Mira, J. P., Frees, K. L., & Schwartz, D. A. (2002). Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med, 162(9), 1028-1032.
Lyon, H., Lange, C., Lake, S., Silverman, E. K., Randolph, A. G., Kwiatkowski, D., Raby, B. A., Lazarus, R., Weiland, K. M., Laird, N., & Weiss, S. T. (2004). IL10 gene polymorphisms are associated with asthma phenotypes in children. Genet Epidemiol, 26(2), 155-165.
Ma, X., Liu, Y., Gowen, B. B., Graviss, E. A., Clark, A. G., & Musser, J. M. (2007). Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS One, 2(12), e1318.
MacMicking, J. D., North, R. J., LaCourse, R., Mudgett, J. S., Shah, S. K., & Nathan, C. F. (1997). Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci U S A, 94(10), 5243-5248.
Mansell, A., Smith, R., Doyle, S. L., Gray, P., Fenner, J. E., Crack, P. J., Nicholson, S. E., Hilton, D. J., O'Neill, L. A., & Hertzog, P. J. (2006). Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol, 7(2), 148-155.
Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A., Jr. (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature, 388(6640), 394-397.
Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadlen, A., Chen, C., Ghosh, S., & Janeway, C. A., Jr. (1998). MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell, 2(2), 253-258.
Miller, B. H., & Shinnick, T. M. (2001). Identification of two Mycobacterium tuberculosis H37Rv ORFs involved in resistance to killing by human macrophages. BMC Microbiol, 1, 26.
Miyake, K., Shimazu, R., Kondo, J., Niki, T., Akashi, S., Ogata, H., Yamashita, Y., Miura, Y., & Kimoto, M. (1998). Mouse MD-1, a molecule that is physically associated with RP105 and positively regulates its expression. J Immunol, 161(3), 1348-1353.
Miyoshi-Akiyama, T., Matsumura, K., Iwai, H., Funatogawa, K., & Kirikae, T. (2012). Complete annotated genome sequence of Mycobacterium tuberculosis Erdman. J Bacteriol, 194(10), 2770.
Montoya-Rodriguez, A., Milan-Carrillo, J., Dia, V. P., Reyes-Moreno, C., & Gonzalez de Mejia, E. (2014). Pepsin-pancreatin protein hydrolysates from extruded amaranth inhibit markers of atherosclerosis in LPS-induced THP-1 macrophages-like human cells by reducing expression of proteins in LOX-1 signaling pathway. Proteome Sci, 12, 30.
Moore, K. W., de Waal Malefyt, R., Coffman, R. L., & O'Garra, A. (2001). Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol, 19, 683-765.
Murray, P. J., Wang, L., Onufryk, C., Tepper, R. I., & Young, R. A. (1997). T cell-derived IL-10 antagonizes macrophage function in mycobacterial infection. J Immunol, 158(1), 315-321.
Murray, P. J., & Young, R. A. (1999). Increased antimycobacterial immunity in interleukin-10-deficient mice. Infect Immun, 67(6), 3087-3095.
Murray, P. R., Rosenthal, K. S., Kobayashi, G. S., & Pfaller, M. A. (1998). Medical Microbiology ,third edition
Nahum, A., Dadi, H., Bates, A., & Roifman, C. M. (2011). The L412F variant of Toll-like receptor 3 (TLR3) is associated with cutaneous candidiasis, increased susceptibility to cytomegalovirus, and autoimmunity. J Allergy Clin Immunol, 127(2), 528-531.
Nahum, A., Dadi, H., Bates, A., & Roifman, C. M. (2012). The biological significance of TLR3 variant, L412F, in conferring susceptibility to cutaneous candidiasis, CMV and autoimmunity. Autoimmun Rev, 11(5), 341-347.
Najmi, N., Kaur, G., Sharma, S. K., & Mehra, N. K. (2010). Human Toll-like receptor 4 polymorphisms TLR4 Asp299Gly and Thr399Ile influence susceptibility and severity of pulmonary tuberculosis in the Asian Indian population. Tissue Antigens, 76(2), 102-109.
Netea, M. G., Wijmenga, C., & O'Neill, L. A. (2012). Genetic variation in Toll-like receptors and disease susceptibility. Nat Immunol, 13(6), 535-542.
Nguyen, T. H., Mai, N. L., Le, T. P., Ha, V., Nguyen, T. C., Tran, T. H., Nguyen, T. H., Farrar, J. J., & Dunstan, S. J. (2009). Toll-like receptor 4 (TLR4) and typhoid fever in Vietnam. PLoS One, 4(3), e4800.
Norbis, L., Miotto, P., Alagna, R., & Cirillo, D. M. (2013). Tuberculosis: lights and shadows in the current diagnostic landscape. New Microbiol, 36(2), 111-120.
Noss, E. H., Pai, R. K., Sellati, T. J., Radolf, J. D., Belisle, J., Golenbock, D. T., Boom, W. H., & Harding, C. V. (2001). Toll-like receptor 2-dependent inhibition of macrophage class II MHC expression and antigen processing by 19-kDa lipoprotein of Mycobacterium tuberculosis. J Immunol, 167(2), 910-918.
O'Neill, L. A., & Bowie, A. G. (2007). The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol, 7(5), 353-364.
Oh, D. R., Kang, H. W., Kim, J. R., Kim, S., Park, I. K., Rhee, J. H., Oh, W. K., & Kim, Y. R. (2014). PMA Induces Vaccine Adjuvant Activity by the Modulation of TLR Signaling Pathway. Mediators Inflamm, 2014, 406514.
Orme, I. M., & Cooper, A. M. (1999). Cytokine/chemokine cascades in immunity to tuberculosis. Immunol Today, 20(7), 307-312.
Palmer, S. M., Burch, L. H., Davis, R. D., Herczyk, W. F., Howell, D. N., Reinsmoen, N. L., & Schwartz, D. A. (2003). The role of innate immunity in acute allograft rejection after lung transplantation. Am J Respir Crit Care Med, 168(6), 628-632.
Papadopoulos, A. I., Ferwerda, B., Antoniadou, A., Sakka, V., Galani, L., Kavatha, D., Panagopoulos, P., Poulakou, G., Kanellakopoulou, K., van der Meer, J. W., Giamarellos-Bourboulis, E. J., & Netea, M. G. (2010). Association of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms with increased infection risk in patients with advanced HIV-1 infection. Clin Infect Dis, 51(2), 242-247.
Pathak, S. K., Basu, S., Basu, K. K., Banerjee, A., Pathak, S., Bhattacharyya, A., Kaisho, T., Kundu, M., & Basu, J. (2007). Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nat Immunol, 8(6), 610-618.
Perez-Perez, G. I., Shepherd, V. L., Morrow, J. D., & Blaser, M. J. (1995). Activation of human THP-1 cells and rat bone marrow-derived macrophages by Helicobacter pylori lipopolysaccharide. Infect Immun, 63(4), 1183-1187.
Pernis, A., Gupta, S., Gollob, K. J., Garfein, E., Coffman, R. L., Schindler, C., & Rothman, P. (1995). Lack of interferon gamma receptor beta chain and the prevention of interferon gamma signaling in TH1 cells. Science, 269(5221), 245-247.
Plain, K. M., Purdie, A. C., Begg, D. J., de Silva, K., & Whittington, R. J. (2010). Toll-like receptor (TLR)6 and TLR1 differentiation in gene expression studies of Johne's disease. Vet Immunol Immunopathol, 137(1-2), 142-148.
Plantinga, T. S., Johnson, M. D., Scott, W. K., van de Vosse, E., Velez Edwards, D. R., Smith, P. B., Alexander, B. D., Yang, J. C., Kremer, D., Laird, G. M., Oosting, M., Joosten, L. A., van der Meer, J. W., van Dissel, J. T., Walsh, T. J., Perfect, J. R., Kullberg, B. J., & Netea, M. G. (2012). Toll-like receptor 1 polymorphisms increase susceptibility to candidemia. J Infect Dis, 205(6), 934-943.
Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., & Beutler, B. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science, 282(5396), 2085-2088.
Pompei, L., Jang, S., Zamlynny, B., Ravikumar, S., McBride, A., Hickman, S. P., & Salgame, P. (2007). Disparity in IL-12 release in dendritic cells and macrophages in response to Mycobacterium tuberculosis is due to use of distinct TLRs. J Immunol, 178(8), 5192-5199.
Pulendran, B., Kumar, P., Cutler, C. W., Mohamadzadeh, M., Van Dyke, T., & Banchereau, J. (2001). Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J Immunol, 167(9), 5067-5076.
Qin, Z. (2012). The use of THP-1 cells as a model for mimicking the function and regulation of monocytes and macrophages in the vasculature. Atherosclerosis, 221(1), 2-11.
Radstake, T. R., Franke, B., Hanssen, S., Netea, M. G., Welsing, P., Barrera, P., Joosten, L. A., van Riel, P. L., & van den Berg. W. B. (2004). The Toll-like receptor 4 Asp299Gly functional variant is associated with decreased rheumatoid arthritis disease susceptibility but does not influence disease severity and/or outcome. Arthritis Rheum, 50(3), 999-1001.
Rahman, A., Sobia, P., Gupta, N., Kaer, L. V., & Das, G. (2014). Mycobacterium tuberculosis subverts the TLR-2-MyD88 pathway to facilitate its translocation into the cytosol. PLoS One, 9(1), e86886.
Randhawa, A. K., Shey, M. S., Keyser, A., Peixoto, B., Wells, R. D., de Kock, M., Lerumo, L., Hughes, J., Hussey, G., Hawkridge, A., Kaplan, G., Hanekom, W. A., & Hawn, T. R. (2011). Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. PLoS Pathog, 7(8), e1002174.
Redecke, V., Hacker, H., Datta, S. K., Fermin, A., Pitha, P. M., Broide, D. H., & Raz, E. (2004). Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol, 172(5), 2739-2743.
Redfern, R. L., Reins, R. Y., & McDermott, A. M. (2011). Toll-like receptor activation modulates antimicrobial peptide expression by ocular surface cells. Exp Eye Res, 92(3), 209-220.
Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., & Jackson, R. B. Campbell Biology (Global ninth ed.).
Roach, D. R., Bean, A. G., Demangel, C., France, M. P., Briscoe, H., & Britton, W. J. (2002). TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol, 168(9), 4620-4627.
Rodriguez-Martinez, S., Cancino-Diaz, M. E., & Cancino-Diaz, J. C. (2006). Expression of CRAMP via PGN-TLR-2 and of alpha-defensin-3 via CpG-ODN-TLR-9 in corneal fibroblasts. Br J Ophthalmol, 90(3), 378-382.
Rudofsky, G., Jr., Reismann, P., Witte, S., Humpert, P. M., Isermann, B., Chavakis, T., Tafel, J., Nosikov, V. V., Hamann, A., Nawroth, P., & Bierhaus, A. (2004). Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with type 2 diabetes. Diabetes Care, 27(1), 179-183.
Saiga, H., Shimada, Y., & Takeda, K. (2011). Innate immune effectors in mycobacterial infection. Clin Dev Immunol, 2011, 347594.
Sakula, A. (1982). Robert Koch: centenary of the discovery of the tubercle bacillus, 1882. Thorax, 37(4), 246-251.
Sanders, M. S., van Well, G. T., Ouburg, S., Lundberg, P. S., van Furth, A. M., & Morre, S. A. (2011). Single nucleotide polymorphisms in TLR9 are highly associated with susceptibility to bacterial meningitis in children. Clin Infect Dis, 52(4), 475-480.
Sandor, F., & Buc, M. (2005). Toll-like receptors. I. Structure, function and their ligands. Folia Biol (Praha), 51(5), 148-157.
Sato, S., Sugiyama, M., Yamamoto, M., Watanabe, Y., Kawai, T., Takeda, K., & Akira, S. (2003). Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol, 171(8), 4304-4310.
Schildberger, A., Rossmanith, E., Eichhorn, T., Strassl, K., & Weber, V. (2013). Monocytes, peripheral blood mononuclear cells, and THP-1 cells exhibit different cytokine expression patterns following stimulation with lipopolysaccharide. Mediators Inflamm, 2013, 697972.
Schindler, R., Mancilla, J., Endres, S., Ghorbani, R., Clark, S. C., & Dinarello, C. A. (1990). Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood, 75(1), 40-47.
Schnare, M., Barton, G. M., Holt, A. C., Takeda, K., Akira, S., & Medzhitov, R. (2001). Toll-like receptors control activation of adaptive immune responses. Nat Immunol, 2(10), 947-950.
Schroder, K., Hertzog, P. J., Ravasi, T., & Hume, D. A. (2004). Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol, 75(2), 163-189.
Schroder, N. W., & Schumann, R. R. (2005). Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis, 5(3), 156-164.
Selvaraj, P., Harishankar, M., Singh, B., Jawahar, M. S., & Banurekha, V. V. (2010). Toll-like receptor and TIRAP gene polymorphisms in pulmonary tuberculosis patients of South India. Tuberculosis (Edinb), 90(5), 306-310.
Sharif, O., Bolshakov, V. N., Raines, S., Newham, P., & Perkins, N. D. (2007). Transcriptional profiling of the LPS induced NF-kappaB response in macrophages. BMC Immunol, 8, 1.
Sharma, S. K., & Mohan, A. (2013). Tuberculosis: From an incurable scourge to a curable disease - journey over a millennium. Indian J Med Res, 137(3), 455-493.
Shaw, T. C., Thomas, L. H., & Friedland, J. S. (2000). Regulation of IL-10 secretion after phagocytosis of Mycobacterium tuberculosis by human monocytic cells. Cytokine, 12(5), 483-486.
Shey, M. S., Randhawa, A. K., Bowmaker, M., Smith, E., Scriba, T. J., de Kock, M., Mahomed, H., Hussey, G., Hawn, T. R., & Hanekom, W. A. (2010). Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion. Genes Immun, 11(7), 561-572.
Shiratsuchi, H., Johnson, J. L., & Ellner, J. J. (1991). Bidirectional effects of cytokines on the growth of Mycobacterium avium within human monocytes. J Immunol, 146(9), 3165-3170.
Skvarc, M., Kopitar, A. N., Kos, J., Obermajer, N., & Tepes, B. (2014). Differences in the antigens of Helicobacter pylori strains influence on the innate immune response in the in vitro experiments. Mediators Inflamm, 2014, 287531.
Smeekens, S. P., van de Veerdonk, F. L., Kullberg, B. J., & Netea, M. G. (2013). Genetic susceptibility to Candida infections. EMBO Mol Med, 5(6), 805-813.
Smith, N. H., Hewinson, R. G., Kremer, K., Brosch, R., & Gordon, S. V. (2009). Myths and misconceptions: the origin and evolution of Mycobacterium tuberculosis. Nat Rev Microbiol, 7(7), 537-544.
Stetson, D. B., & Medzhitov, R. (2006). Type I interferons in host defense. Immunity, 25(3), 373-381.
Strohmeier, G. R., & Fenton, M. J. (1999). Roles of lipoarabinomannan in the pathogenesis of tuberculosis. Microbes Infect, 1(9), 709-717.
Stucki, D., & Gagneux, S. (2013). Single nucleotide polymorphisms in Mycobacterium tuberculosis and the need for a curated database. Tuberculosis (Edinb), 93(1), 30-39.
Takeuchi, O., & Akira, S. (2010). Pattern recognition receptors and inflammation. Cell, 140(6), 805-820.
Taniguchi, T., & Takaoka, A. (2001). A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol, 2(5), 378-386.
Tantisira, K., Klimecki, W. T., Lazarus, R., Palmer, L. J., Raby, B. A., Kwiatkowski, D. J., Silverman, E., Vercelli, D., Martinez, F. D., & Weiss, S. T. (2004). Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun, 5(5), 343-346.
Tauszig, S., Jouanguy, E., Hoffmann, J. A., & Imler, J. L. (2000). Toll-related receptors and the control of antimicrobial peptide expression in Drosophila. Proc Natl Acad Sci U S A, 97(19), 10520-10525.
Texereau, J., Chiche, J. D., Taylor, W., Choukroun, G., Comba, B., & Mira, J. P. (2005). The importance of Toll-like receptor 2 polymorphisms in severe infections. Clin Infect Dis, 41 Suppl 7, S408-415.
Thada, S., Valluri, V. L., & Gaddam, S. L. (2013). Influence of Toll-like receptor gene polymorphisms to tuberculosis susceptibility in humans. Scand J Immunol, 78(3), 221-229.
Thayil, S. M., Ho, Y. C., Bollinger, R. C., Blankson, J. N., Siliciano, R. F., Karakousis, P. C., & Page, K. R. (2012). Mycobacterium tuberculosis complex enhances susceptibility of CD4 T cells to HIV through a TLR2-mediated pathway. PLoS One, 7(7), e41093.
Thirunavukkarasu, S., de Silva, K., Whittington, R. J., & Plain, K. M. (2013). In vivo and in vitro expression pattern of Toll-like receptors in Mycobacterium avium subspecies paratuberculosis infection. Vet Immunol Immunopathol, 156(1-2), 20-31.
Thuong, N. T., Hawn, T. R., Thwaites, G. E., Chau, T. T., Lan, N. T., Quy, H. T., Hieu, N. T., Aderem, A., Hien, T. T., Farrar, J. J., & Dunstan, S. J. (2007). A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun, 8(5), 422-428.
Tiwari, R. L., Singh, V., Singh, A., & Barthwal, M. K. (2011). IL-1R-associated kinase-1 mediates protein kinase Cdelta-induced IL-1beta production in monocytes. J Immunol, 187(5), 2632-2645.
Torre-Cisneros, J., Doblas, A., Aguado, J. M., San Juan, R., Blanes, M., Montejo, M., Cervera, C., Len, O., Carratala, J., Cisneros, J. M., Bou, G., Muñoz P, Ramos, A., Gurgui, M., Borrell, N., Fortún, J., Moreno, A., & Gavalda, J. (2009). Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis, 48(12), 1657-1665.
Torrelles, J. B., & Schlesinger, L. S. (2010). Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host. Tuberculosis (Edinb), 90(2), 84-93.
Trombetta, E. S., Ebersold, M., Garrett, W., Pypaert, M., & Mellman, I. (2003). Activation of lysosomal function during dendritic cell maturation. Science, 299(5611), 1400-1403.
Tsenova, L., Bergtold, A., Freedman, V. H., Young, R. A., & Kaplan, G. (1999). Tumor necrosis factor alpha is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system. Proc Natl Acad Sci U S A, 96(10), 5657-5662.
Tsuchiya, S., Yamabe, M., Yamaguchi, Y., Kobayashi, Y., Konno, T., & Tada, K. (1980). Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer, 26(2), 171-176.
Uciechowski, P., Imhoff, H., Lange, C., Meyer, C. G., Browne, E. N., Kirsten, D. K., Schröder, A. K., Schaaf, B., Al-Lahham, A., Reinert, R. R., Reiling, N., Haase, H., Hatzmann, A., Fleischer D, Heussen N, Kleines M, Rink L. (2011). Susceptibility to tuberculosis is associated with TLR1 polymorphisms resulting in a lack of TLR1 cell surface expression. J Leukoc Biol, 90(2), 377-388.
Underhill, D. M., & Ozinsky, A. (2002). Phagocytosis of microbes: complexity in action. Annu Rev Immunol, 20, 825-852.
Underhill, D. M., Ozinsky, A., Hajjar, A. M., Stevens, A., Wilson, C. B., Bassetti, M., & Aderem, A. (1999). The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature, 401(6755), 811-815.
Underhill, D. M., Ozinsky, A., Smith, K. D., & Aderem, A. (1999). Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc Natl Acad Sci U S A, 96(25), 14459-14463.
Valone, S. E., Rich, E. A., Wallis, R. S., & Ellner, J. J. (1988). Expression of tumor necrosis factor in vitro by human mononuclear phagocytes stimulated with whole Mycobacterium bovis BCG and mycobacterial antigens. Infect Immun, 56(12), 3313-3315.
van Crevel, R., Ottenhoff, T. H., & van der Meer, J. W. (2002). Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev, 15(2), 294-309.
Van Gool, S. W., Vandenberghe, P., de Boer, M., & Ceuppens, J. L. (1996). CD80, CD86 and CD40 provide accessory signals in a multiple-step T-cell activation model. Immunol Rev, 153, 47-83.
van Well, G. T., Sanders, M. S., Ouburg, S., van Furth, A. M., & Morre, S. A. (2012). Polymorphisms in Toll-like receptors 2, 4, and 9 are highly associated with hearing loss in survivors of bacterial meningitis. PLoS One, 7(5), e35837.
VanHeyningen, T. K., Collins, H. L., & Russell, D. G. (1997). IL-6 produced by macrophages infected with Mycobacterium species suppresses T cell responses. J Immunol, 158(1), 330-337.
Velez, D. R., Wejse, C., Stryjewski, M. E., Abbate, E., Hulme, W. F., Myers, J. L., Estevan, R., Patillo, S. G., Olesen, R., Tacconelli, A., Sirugo, G., Gilbert, J. R., Hamilton, C. D., & Scott, W. K. (2010). Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Hum Genet, 127(1), 65-73.
Victoria, S., Temerozo, J. R., Gobbo, L., Pimenta-Inada, H. K., & Bou-Habib, D. C. (2013). Activation of Toll-like receptor 2 increases macrophage resistance to HIV-1 infection. Immunobiology, 218(12), 1529-1536.
Vink, A., Schoneveld, A. H., van der Meer, J. J., van Middelaar, B. J., Sluijter, J.P, Smeets, M. B., Quax, P. H., Lim, S. K., Borst, C., Pasterkamp, G., & de Kleijn, D. P. (2002). In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Circulation, 106(15), 1985-1990.
Voskuil, M. I., Visconti, K. C., & Schoolnik, G. K. (2004). Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy. Tuberculosis (Edinb), 84(3-4), 218-227.
Walzl, G., Ronacher, K., Hanekom, W., Scriba, T. J., & Zumla, A. (2011). Immunological biomarkers of tuberculosis. Nat Rev Immunol, 11(5), 343-354.
Wang, C. H., Eng, H. L., Lin, K. H., Chang, C. H., Hsieh, C. A., Lin, Y. L., & Lin, T. M. (2011). TLR7 and TLR8 gene variations and susceptibility to hepatitis C virus infection. PLoS One, 6(10), e26235.
Wang, C. M., Chang, S. W., Wu, Y. J., Lin, J. C., Ho, H. H., Chou, T. C., Yang, B., Wu, J., & Chen, J. Y. (2014). Genetic variations in Toll-like receptors (TLRs 3/7/8) are associated with systemic lupus erythematosus in a Taiwanese population. Sci Rep, 4, 3792.
Wang, J. Y., Chang, H. C., Liu, J. L., Shu, C. C., Lee, C. H., Wang, J. T., & Lee, L. N. (2012). Expression of toll-like receptor 2 and plasma level of interleukin-10 are associated with outcome in tuberculosis. Eur J Clin Microbiol Infect Dis, 31(9), 2327-2333.
Wang, Y. P., Wang, P., Dong, L., Chen, H., Wu, Y. Q., Li, H. W., & Li, M. (2014). Relaxin inhibit cardiac fibrosis induced by phorbol 12-myristate 13-acetate. Biomed Environ Sci, 27(2), 138-141.
West, A. P., Brodsky, I. E., Rahner, C., Woo, D. K., Erdjument-Bromage, H., Tempst, P., Walsh, M. C., Choi, Y., Shadel, G. S., & Ghosh, S. (2011). TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature, 472(7344), 476-480.
Wheeler, D. A., Srinivasan, M., Egholm, M., Shen, Y., Chen, L., McGuire, A., He, W., Chen, Y. J., Makhijani, V., Roth, G. T., Gomes, X., Tartaro, K., Niazi, F., Turcotte, C. L., Irzyk, G. P., Lupski, J.R., Chinault, C., Song, X. Z., Liu, Y., Yuan, Y., Nazareth, L., Qin, X., Muzny, D. M., Margulies, M., Weinstock, G. M., Gibbs, R. A., & Rothberg, J. M. (2008). The complete genome of an individual by massively parallel DNA sequencing. Nature, 452(7189), 872-876.
WHO. (2012). Global tuberculosis report 2012. Geneva, Switzerland.
WHO. (2013). Global tuberculosis report 2013. Geneva, Switzerland.
Wood, R., Maartens, G., & Lombard, C. J. (2000). Risk factors for developing tuberculosis in HIV-1-infected adults from communities with a low or very high incidence of tuberculosis. J Acquir Immune Defic Syndr, 23(1), 75-80.
Xie, X., Li, F., Chen, J. W., & Wang, J. (2013). Risk of tuberculosis infection in anti-TNF-alpha biological therapy: From bench to bedside. J Microbiol Immunol Infect, 2013 May 30. pii: S1684-1182(13)00039-X..
Young, H. A., & Hardy, K. J. (1995). Role of interferon-gamma in immune cell regulation. J Leukoc Biol, 58(4), 373-381.
Zheng, S. L., Augustsson-Bälter, K., Chang, B., Hedelin, M., Li, L., Adami, H. O., Bensen, J., Li, G., Johnasson, J. E., Turner, A.R., Adams, T. S., Meyers, D. A., Isaacs, W. B., Xu, J., & Grönberg, H. (2004). Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res, 64(8), 2918-2922