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Identifying candidate diagnostic markers for tuberculosis: A critical role of co-expression and pathway analysis

1 School of Mathematics and Statistics, Southwest University, Chongqing 400715, China
2 State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, Chinese Academy of Sciences ,Beijing 100093, China
3 School of Life Sciences, Southwest University, Chongqing 400715, China
4 Laboratory for Industrial and Applied Mathematics; Center for Disease Modelling, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada

We conducted a systematic bioinformatics analysis to explore an important set of gene expression data with 39 samples infected at different time stages withW-Beijing families of Mycobacterium tuberculosis strains. We took a contrast on the samples at different infection time stages to characterize gene expression features of the THP1 cells to identify sensitive and specific molecular markers for diagnosis. We first confirmed, through the multidimensional scaling unsupervised clustering, that samples were clustered well according to different infection times. Building on this classification result and using the linear modelling and empirical Bayes moderation, we found 287 hits as most significant genes associated with tuberculosis. We generated a gene co-expression network map based on the mutual regulation between the differentially expressed genes. We found that 27 genes are regulatory genes associated with tuberculosis. We constructed 4 gene pathway figures to explain the pathogenicity process that involves 24 key genes. This study implicates that contrast on the gene expression of the classifications in different infection stages provides critical information for the detection of tuberculosis, and our method can be utilized to narrow down the shortlist of disease relevant genes and explore tuberculosis pathogenesis.
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1. A. Zumla, A. George, V. Sharma and R.H. Herbert, Baroness Masham of Ilton, Oxley A, Oliver M, The who 2014 global tuberculosis report-further to go, Lancet Glob. Health, 3 (2015), 10–12.

2. WHO Representative Office, China-Tuberculosis in China 2015. Available from: http://www. wpro.who.int/china/mediacentre/factsheets/tuberculosis/en/.

3. A. E. Gorna, R. P. Bowater and J. Dziadek, DNA repair systems and the pathogenesis of Mycobacterium tuberculosis: varying activities at different stages of infection, Clin. Sci., 119 (2010), 187–202.

4. B. J. Marais, K. Lönnroth, S. D. Lawn, G. B. Migliori, P. Mwaba, P. Glaziou, P. Glaziou, M. Bates, R. Colagiuri, L. Zijenah, S. Swaminathan, Z.A. Memish, M. Pletschette, M. Hoelscher, I. Abubakar, R. Hasan, A. Zafar, G. Pantaleo, G. Craig, P. Kim, M. Maeurer, M. Schito and A. Zumla, Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts, Lancet Infect. Dis., 13 (2013), 436–448.

5. D. Snchez, M. Rojas, I. Hernndez, D. Radzioch, L.F. Garca and L.F. Barrera, Role of TLR2- and TLR4-mediated signaling in Mycobacterium tuberculosis -induced macrophage death, Cell. Immunol., 260 (2010), 128–136.

6. J. Maertzdorf, D. Repsilber, S.K. Parida, K. Stanley, T. Roberts, G. Black, G. Walzl and S.H. Kaufmann, Human gene expression profiles of susceptibility and resistance in tuberculosis, Gene. Immu., 12 (2011), 15–22.

7. G. K. Smyth, Linear models and empirical bayes methods for assessing differential expression in microarray experiments, Statist. Appl. Genet. Molecul. Biol., 3 (2004), 1544–6115.

8. D. J. Mccarthy and G. K. Smyth,Testing significance relative to a fold-change threshold is a TREAT, Bioinformatics, 25 (2009), 765–771.

9. M. Platten, N. von Knebel Doeberitz, I. Oezen, W. Wick and K. Ochs, Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors, Front. Immunol., 5 (2014), 1–7.

10. F. Li, R. Zhang, S. Li and J. IDOL. Liu, An important immunotherapy target in cancer treatment, Int. Immunopharmacol., 47 (2017), 70–77.

11.I. N. Maria, C. E. Steenwijk and S. A. Ijpma,Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome, An. Rheumat. Dis., 76 (2016), 721–730.

12.A.R. Shenoy, D.A.Wellington, P. Kumar, H. Kassa, C.J. Booth, P. Cresswell and J.D. MacMicking, GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals, Science, 336 (2012), 481–485.

13. C. Krapp, D. Hotter, A. Gawanbacht, J. P. Mclaren, F. S. Kluge, M. C. Stürzel, K. Mack, E. Reith, S. Engelhart , A. Ciuff, V. Hornung, D. Sauter, A. Telenti, and F. Kirchhoff, Guanylate Binding Protein (GBP) 5 Is an Interferon-Inducible Inhibitor of HIV-1 Infectivity, Cell Host Microb., 19 (2016), 504–514.

14. E. T. Pronk,W. J. Veen, J. R. Vandebriel, V. H. Loveren, P. E. Vink and L. J. Pennings, Comparison of the molecular topologies of stress-activated transcription factors HSF1, AP-1, NRF2, and NF-kB in their induction kinetics of HMOX1, Biosystems, 124 (2014), 75–85.

15. K. Ramsauer, M. Farlik, G. Zupkovitz, C. Seiser and T. Decker, Distinct modes of action applied by transcription factors STAT1 and IRF1 to initiate transcription of the IFN- inducible gbp2 gene, Proceed. Nat. Aca. Sci. US Am., 104 (2007), 2849–2854.

16.M. Qi, M. Ge and L. Huang, Up-regulation of GBP2 is Associated with Neuronal Apoptosis in Rat Brain Cortex Following Traumatic Brain Injury, Neurochem. Res., 42 (2017), 1515–1523.

17. D. Hober and P. Sauter, Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host, Nat. Rev. Endocrinol., 6 (2010), 279–289.

18. H. Takedatsu, S. K. Michelsen, B. Wei, J. C. Landers, S. L. Thomas, D. Dhall, J. Braun and S.R. Targan, TL1A (TNFSF15) Regulates the Development of Chronic Colitis By Modulating both T helper (TH) 1 and TH17 Activation, Gastroenterology, 135 (2008), 552–567.

19. H. Deng, H. Liu, B. Zhai, K. Zhang, G. Xu, X. Peng, Q. Zhang and L. Li, Vascular endothelial growth factor suppressesTNFSF15 production in endothelial cells by stimulating miR-31 and miR- 20a expression via activation of Akt and Erk signals, Febs. Open Biol., 7 (2017), 108–117.

20. F. Mackay and P. Schneider , TACI, an enigmatic BAFF/APRIL receptor, with new unappreciated biochemical and biological properties, Cytok. Growth Factor Rev., 19 (2008), 263–276.

21. Y. E. APAMoon, H. J. Lee, W. J. Lee, H. J. Song and S. Pyo, ROS/Epac1-mediated Rap1/NF-$\kappa$B activation is required for the expression of BAFF in Raw264.7 murine macrophages, Cell. Signal., 23 (2011), 1479–1488.

22. H. Akca, A. Demiray, O. Tokgun and J. Yokota, Invasiveness and anchorage independent growth ability augmented by PTEN inactivation through the PI3K/AKT/NF-$\kappa$B pathway in lung cancer > cells, Lung Cancer, 73 (2011), 302–309.

23. M. Vucur, C. Roderburg, K. Bettermann, F. Tacke, M. Heikenwalder, C. Trautwein and T. Luedde, Mouse models of hepatocarcinogenesis: what can we learn for the prevention of human hepatocellular carcinoma?, Oncotarget, 1 (2010), 373–378.

24.H. P. Krammer, R. Arnold and I. N. Lavrik, Life and death in peripheral T cells, Nat. Rev. Immunol., 7 (2007), 532–542.

25.K. Ozato, M. D. Shin, H. T. Chang, Iii and H. C. M,TRIM family proteins and their emerging roles in innate immunity, Nat. Rev. Immunol., 8 (2008), 849–860.

26. Z. Sepehri, Z. Kiani, F. Javadian, A. N. Akbar, F. Kohan, S. Sepehrikia, S.S. Javan, H. Aali, H. Daneshvar and D. Kennedy, TLR3 and its roles in the pathogenesis of type 2 diabetes, Cell Mol. Biol. (Noisy-le-grand), 61 (2015), 46–50.

27. Z. Xia, G. Xu , X. Yang, N. Peng, Q. Zuo, S. Zhu, H. Hao, S. Liu and Y. Zhu, Inducible TAP1 Negatively Regulates the Antiviral Innate Immune Response by Targeting the TAK1 Complex, J. Immunol., 198 (2017), 3690–3704.

28.M. Trapecar, A. Goropevsek, M. Gorenjak, L. Gradisnik and S. M. Rupnik, A Co-Culture Model of the Developing Small Intestine Offers New Insight in the Early Immunomodulation of Enterocytes and Macrophages by Lactobacillus spp. through STAT1 and NF-$\kappa$B p65 Translocation, Plos One, 9 (2014), 1–8.

29. M. Mondini, S. Costa, S. Sponza, F. Gugliesi, M. Gariglio and S. Landolfo, The interferoninducible HIN-200 gene family in apoptosis and inflammation: implication for autoimmunity, Autoimmunity, 43 (2010), 226–231.

30.A. Maji, R. Misra, K. A. Mondal, D. Kumar, D. Bajaj, A. Singhal, G. Arora, A. Bhaduri, A. Sajid, S. Bhatia, S. Singh, H. Singh, V. Rao, D. Dash, S.E. Baby, M.J. Sarojini, A. Chaudhary, R.S. Gokhale and Y. Singh, Expression profiling of lymph nodes in tuberculosis patients reveal inflammatory milieu at site of infection, Sci. Rep., 5 (2015), 1–10.

31. M. Bawadekar, M. A. De, I. C. Lo, G. Baldanzi, V. Caneparo, A. Graziani, S. Landolfo and M. Gariglio, The Extracellular IFI16 Protein Propagates Inflammation in Endothelial Cells Via p38 MAPK and NF-$\kappa$B p65 Activation, J. Interferon. Cytokine. Res., 35 (2015), 441–453.

32.R. N. Han, A. H. Oh, Y. S. Nam, D. P. Moon,W. D. Kim, M. H. Kim, and H.J. Jeong, TSLP Induces Mast Cell Development and Aggravates Allergic Reactions through the Activation of MDM2 and STAT6, J. Invest. Dermatol., 134 (2014), 2521–2530.

33. K. Yao, Q. Chen, Y. Wu, F. Liu, X. Chen and Y. Zhang, Unphosphorylated STAT1 represses apoptosis in macrophages during Mycobacterium tuberculosis infection, J. Cell Sci., 130 (2017), 1740–1751.

34. Z. Cheng, Y. Yi, S. Xie, H. Yu, H. Peng and G. Zhang, The effect of the JAK2 inhibitor TG101209 against T cell acute lymphoblastic leukemia (T-ALL) is mediated by inhibition of JAK-STAT signaling and activation of the crosstalk between apoptosis and autophagy signaling, Oncotarget, 8 (2017), 106753–106763.

35. W. He, Q. Wang, J. Xu, X. Xu, MT. Padilla, G. Ren, X. Gou and Y. Lin, Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2- and RIPK1/RIP1-mediated MAPK8/JNK activation, Autophagy, 8 (2012), 1811–1821.

36.M. Yang, L. Liu, M. Xie, X. Sun, Y. Yu, R. Kang, L. Yang, S. Zhu, L. Cao and D. Tang, Poly-ADPribosylation of HMGB1 regulates TNFSF10/TRAIL resistance through autophagy, Autophagy, 11 (2015), 214–224.

37.L.X. Xu, S. Grimaldo, J.W. Qi, G.L. Yang, T.T. Qin, H.Y. Xiao, R. Xiang, Z. Xiao, L.Y. Li and Z.S. Zhang, Death receptor 3 mediates TNFSF15- and TNF-induced endothelial cell apoptosis, Int. J. Biochem. Cell Biol., 55 (2014), 109–118.

38. A. Shrivastava, VEGI, a new member of the TNF family activates Nuclear Factor-$\kappa$B and c-Jun N-terminal kinase and modulates cell growth, Oncogene, 18 (1999), 6496–6504.

39. Y. Piao, C. Thomas, L. Holmes, V. Henry and D. J. Groot, ET-45KNOCKDOWN of TNFSF13B induces glioma stem cell apoptosis, Neuro-Oncology, 16 (2014), 79–95.

40. R. Rosell, T. G. Bivona and N. Karachaliou, Genetics and biomarkers in personalisation of lung cancer treatment, Lancet, 382 (2013), 720–731.

41. U. Gaur and B. B. Aggarwal, Regulation of proliferation, survival and apoptosis by members of the TNF superfamily, Biochem. Pharmacol., 66 (2003), 1403–1408.

42. X. Zhao, X. Liu and S. Ling, Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells, J. Experiment. Clin. Cancer Res., 33 (2014), 1–11.

43. F.H. Wu, Y. Yuan, D. Li, S.J. Liao, B. Yan, J.J. Wei, Y.H. Zhou, J.H. Zhu, G.M. Zhang and Z.H. Feng, Extracellular HSPA1A promotes the growth of hepatocarcinoma by augmenting tumor cell proliferation and apoptosis-resistance, Cancer Lett., 317 (2012), 157–164.

44. F.H. Wu, Y. Yuan, D. Li, S.J. Liao, B. Yan, J.J. Wei, Y.H. Zhou, J.H. Zhu, G.M. Zhang and Z.H. Feng,Mycobacterium tuberculosis PE13 (Rv1195) manipulates the host cell fate via p38-ERK-NF- $\kappa$B axis and apoptosis, Apoptosis, 21 (2016), 795–808.

45.X. Yu, C. Li,W. Hong,W. Pan and J. Xie, Autophagy during Mycobacterium tuberculosis infection and implications for future tuberculosis medications, Cellul. Signal., 25 (2013), 1272–1278.

46. D.M. Shin, B.Y. Jeon, H.M. Lee, H.S. Jin, J.M. Yuk, C.H. Song, S.H. Lee, Z.W. Lee, S.N. Cho, J.M. Kim, R.L. Friedman and E.K. Jo, Mycobacterium tuberculosis Eis Regulates Autophagy, Inflammation, and Cell Death through Redox-dependent Signaling, Plos Pathogens, 6 (2010), 1–15.

47. J. Lee, G. H. Remold, H. M. Ieong and H. Kornfeld, Macrophage apoptosis in response to high intracellular burden of Mycobacterium tuberculosis is mediated by a novel caspase-independent pathway, J. Immunol., 176 (2006), 4267–4274.

48. M. J. Yuk and E. K. Jo, Host immune responses to mycobacterial antigens and their implications for the development of a vaccine to control tuberculosis, Clin. Experiment. Vac. Res., 3 (2014), 155–167.

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