Expression studies of tuberculosis susceptibility genes

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The activating research interest in the problem of tuberculosis development is due to the increase in cases of drug resistance, coinfection with HIV and hepatitis, and the lack of an effective vaccine. However, the pathogenesis of tuberculosis remains insufficiently studied at present. A significant role is assigned to hereditary factors, as the majority of those infected with Mycobacterium tuberculosis remain resistant to tuberculosis, and only in 5—15% of cases does infection lead to the development of the disease. Despite a long history of research of genetic factors of susceptibility to tuberculosis infection — from the search for monogenic forms of immune dysfunction, associations of individual tuberculosis susceptibility genes, to the analysis of genome-wide associative studies and the assessment of the characteristics of the transcriptional profiles of patients, — the problem of obtaining clinically significant results for the identification and monitoring of risk groups remains particularly acute. The search of differentially expressed genes in groups with different status of the disease (non-infected, latent tuberculosis infection, presymptomatic state, active tuberculosis, recovery from tuberculosis, non-tuberculosis infection) led to identification of a large number of data which is not overlapped in different compared groups, different ethnic groups, in the studies of the whole blood and cellular models. Merging this wealth of data followed by its reanalysis helps to verify and update results. However, there still is a large number of questions concerning our understanding of the functioning of the human organism under the influence of M. tuberculosis. In recent years, new approaches have been used to develop test systems for the diagnosis of various forms of the disease. The review considers up to date results of expression studies of susceptibility to tuberculosis, namely, objects and approaches of research changing over time, forms of the host response to the mycobacteria infection studied, the influence of different factors on the results.

About the authors

N. P. Babushkina

Tomsk National Research Medical Center of the Russian Academy of Sciences

Author for correspondence.
ORCID iD: 0000-0001-6133-8986

Nadezhda P. Babushkina - PhD (Biology), Researcher, Laboratory of Population Genetics, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences.

634050, Tomsk, Ushaika emb., 10.

Phone: +7 (3822) 51-29-02; Fax: +7 (3822) 51-37-44

Russian Federation

E. Yu. Bragina

Tomsk National Research Medical Center of the Russian Academy of Sciences

ORCID iD: 0000-0002-1103-3073

PhD (Biology), Senior Researcher, Laboratory of Population Genetics, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences.

634050, Tomsk, Ushaika emb., 10.

Russian Federation


  1. Рудко А.А., Брагина Е.Ю., Бабушкина Н.П., Гараева А.Ф., Фрейдин М.Б. Генетические факторы подверженности туберкулезу. Новосибирск: Изд-во Сибирского отделения Российской академии наук, 2017. 120 с.
  2. Alipoor S.D., Mortaz E., Tabarsi P., Farnia P., Mirsaeidi M., Garssen J., Movassaghi M., Adcock I.M. Bovis Bacillus Calmette-Guerin (BCG) infection induces exosomal miRNA release by human macrophages. J. Transl. Med., 2017, vol. 15, no. 1, pp. 105— 114. doi: 10.1186/s12967-017-1205-9
  3. Alipoor S.D., Mortaz E., Tabarsi P., Marjani M., Varahram M., Folkerts G., Garssen J., Adcock I.M. miR-1224 Expression is increased in human macrophages after infection with Bacillus Calmette-Guerin (BCG). Iran J. Allergy Asthma Immunol., 2018, vol. 7, no. 3, pp. 250—257.
  4. Barreiro L.B., Tailleux L., Pai A.A., Gicquel B., Marioni J.C., Gilad Y. Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection. Proc. Natl Acad. Sci. USA, 2012, vol. 109, no. 4, pp. 1204—1209. doi: 10.1073/pnas.1115761109
  5. Berry M.P., Graham C.M., McNab F.W., Xu Z., Bloch S.A., Oni T., Wilkinson K.A., Banchereau R., Skinner J., Wilkinson R.J., Quinn C., Blankenship D., Dhawan R., Cush J.J., Mejias A., Ramilo O., Kon O.M., Pascual V., Banchereau J., Chaussabel D., O'Garra A. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature, 2010, vol. 466, no. 7309, pp. 973—977. doi: 10.1038/nature09247
  6. Blankley S., Berry M.P., Graham C.M., Bloom C.I., Lipman M., O'Garra A. The application of transcriptional blood signatures to enhance our understanding of the host response to infection: the example of tuberculosis. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2014, vol. 369, no. 1645: 20130427. doi: 10.1098/rstb.2013.0427
  7. Blischak J.D., Tailleux L., Myrthil M., Charlois C., Bergot E., Dinh A., Morizot G., Cheny O., Platen C.V., Herrmann J.L., Brosch R., Barreiro L.B., Gilad Y. Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells. Sci. Rep., 2017, vol. 7, no. 1: 5702. doi: 10.1038/s41598-017-05878-w
  8. Bloom C.I., Graham C.M., Berry M.P., Rozakeas F., Redford P.S., Wang Y., Xu Z., Wilkinson K.A., Wilkinson R.J., Kendrick Y., Devouassoux G., Ferry T., Miyara M., Bouvry D., Valeyre D., Gorochov G., Blankenship D., Saadatian M., Vanhems P., Beynon H., Vancheeswaran R., Wickremasinghe M., Chaussabel D., Banchereau J., Pascual V., Ho L.P., Lipman M., O'Garra A. Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers. PLoS One, 2013, vol. 8, no. 8: e70630. doi: 10.1371/journal.pone.0070630
  9. Chaussabel D., Semnani R.T., McDowell M.A., Sacks D., Sher A., Nutman T.B. Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood, 2003, vol. 102, no. 2, pp. 672—681. doi: 10.1182/blood-2002-10-3232
  10. Cliff J.M., Lee J.S., Constantinou N., Cho J.E., Clark T.G., Ronacher K., King E.C., Lukey P.T., Duncan K., Van Helden P.D., Walzl G., Dockrell H.M. Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response. J. Infect. Dis., 2013, vol. 207, no. 1, pp. 18—29. doi: 10.1093/infdis/jis499
  11. De Araujo L.S., Vaas L.A., Ribeiro-Alves M., Geffers R., Mello F.C., de Almeida A.S., Moreira A.D., Kritski A.L., Lapa E., Silva J.R., Moraes M.O., Pessler F., Saad M.H. Transcriptomic biomarkers for tuberculosis: evaluation of DOCK9. EPHA4, and NPC2 mRNA expression in peripheral blood. Front. Microbiol., 2016, vol. 7: 1586. doi: 10.3389/fmicb.2016.01586
  12. Doosti-Irani A., Ayubi E., Mostafavi E. Tuberculin and QuantiFERON-TB-Gold tests for latent tuberculosis: a meta-analysis. Occup. Med., 2016, vol. 66, no. 6, pp. 437—445. doi: 10.1093/occmed/kqw035
  13. European Bioinformatics Institute (EMBL-EBI). URL: (10.10.2019)
  14. Esterhuyse M.M., Weiner J. 3rd, Caron E., Loxton A.G., Iannaccone M., Wagman C., Saikali P., Stanley K., Wolski W.E., Mollenkopf H.J., Schick M., Aebersold R., Linhart H., Walzl G., Kaufmann S.H. Epigenetics and proteomics join transcriptom-ics in the quest for tuberculosis biomarkers. MBio, 2015, vol. 6, no. 5: e01187-15. doi: 10.1128/mBio.01187-15
  15. Gliddon H.D., Kaforou M., Alikian M., Habgood-Coote D., Zhou C., Oni T., Anderson S.T., Brent A.J., Crampin A.C., Eley B., Kern F., Langford P.R., Ottenhoff T.H.M., Hibberd M.L., French N., Wright V.J., Dockrell H.M., Coin L.J., Wilkinson R.J., Levin M. on behalf of the ILULU Consortium. Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification. bioRxiv preprint, 2019. doi: 10.1101/583674
  16. Huang Z.K., Yao F.Y., Xu J.Q., Deng Z., Su R.G., Peng Y.P., Luo Q., Li J.M. Microarray expression profile of circular RNAs in peripheral blood mononuclear cells from active tuberculosis patients. Cell. Physiol. Biochem., 2018, vol. 45, no. 3, pp. 1230— 1240. doi: 10.1159/000487454
  17. Jacobsen M., Repsilber D., Gutschmidt A., Neher A., Feldmann K., Mollenkopf H.J., Ziegler A., Kaufmann S.H. Candidate biomarkers for discrimination between infection and disease caused by Mycobacterium tuberculosis. J. Mol. Med. (Berl.), 2007, vol. 85, no. 6,pp. 613-621. doi: 10.1007/s00109-007-0157-6
  18. Joosten S.A., Fletcher H.A., Ottenhoff T.H. A helicopter perspective on TB biomarkers: pathway and process based analysis of gene expression data provides new insight into TB pathogenesis. PLoS One, 2013, vol. 8, no. 9: e73230. doi: 10.1371/journal.pone.0073230
  19. Kaforou M., Wright V.J., Oni T., French N., Anderson S.T., Bangani N., Banwell C.M., Brent A.J., Crampin A.C., Dockrell H.M., Eley B., Heyderman R.S., Hibberd M.L., Kern F., Langford P.R., Ling L., Mendelson M., Ottenhoff T.H., Zgambo F., Wilkinson R.J., Coin L.J., Levin M. Detection of tuberculosis in HIV-Infected and -uninfected african adults using whole blood RNA expression signatures: a case-control study. PLoS Med., 2013, vol. 10, no. 10: e1001538. doi: 10.1371/journal.pmed.1001538
  20. Kim J.K., Lee H.M., Park K.S., Shin D.M., Kim T.S., Kim Y.S., Suh H.W., Kim S.Y., Kim I.S., Kim J.M., Son J.W., Sohn K.M., Jung S.S., Chung C., Han S.B., Yang C.S., Jo E.K. MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2. Autophagy, 2017, vol. 13, no. 2, pp. 423441. doi: 10.1080/15548627.2016.1241922
  21. Lavin Y., Winter D., Blecher-Gonen R., David E., Keren-Shaul H., Merad M., Jung S., Amit I. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell, 2014, vol. 159, no. 6, pp. 1312-1326. doi: 10.1016/j.cell.2014.11.01,8
  22. Lesho E., Forestiero F.J., Hirata M.H., Hirata R.D., Cecon L., Melo F.F., Paik S.H., Murata Y., Ferguson E.W., Wang Z., Ooi G.T. Transcriptional responses of host peripheral blood cells to tuberculosis infection. Tuberculosis (Edinb.), 2011, vol. 91, no. 5, pp. 390-399. doi: 10.1016/
  23. Lu C., Wu J., Wang H., Wang S., Diao N., Wang F., Gao Y., Chen J., Shao L., Weng X., Zhang Y., Zhang W. Novel biomarkers distinguishing active tuberculosis from latent infection identified by gene expression profile of peripheral blood mononuclear cells. PLoS One, 2011, vol. 6, no. 8: e24290. doi: 10.1371/journal.pone.0024290
  24. Maertzdorf J., Ota M., Repsilber D., Mollenkopf H.J., Weiner J., Hill P.C., Kaufmann S.H. Functional correlations of pathogenesis-driven gene expression signatures in tuberculosis. PLoS One, 2011, vol. 6: e26938. doi: 10.1371/journal.pone. 0026938
  25. Maertzdorf J., Repsilber D., Parida S.K., Stanley K., Roberts T., Black G., Walzl G., Kaufmann S.H. Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun., 2011, vol. 12, pp. 15—22. doi: 10.1038/gene.2010.51
  26. Maertzdorf J., Weiner 3rd J., Mollenkopf H.J., Network T.B., Bauer T., Prasse A., Muller-Quernheim J., Kaufmann S.H. Common patterns and diseaserelated signatures in tuberculosis and sarcoidosis. Proc. Natl Acad. Sci. USA, 2012, vol. 109, pp. 7853—7858. doi: 10.1073/pnas.1121072109
  27. Meng Q.L., Liu F., Yang X.Y., Liu X.M., Zhang X., Zhang C.L., Zhang Z.D. Identification of latent tuberculosis infection-related microRNAs in human U937 macrophages expressing Mycobacterium tuberculosis Hsp16.3. BMC Microbiol., 2014, vol. 14: 37. doi: 10.1186/1471-2180-14-37
  28. Mihret A., Loxton A.G., Bekele Y., Kaufmann S.H., Kidd M., Haks M.C., Ottenhoff T.H., Aseffa A., Howe R., Walzl G. Combination of gene expression patterns in whole blood discriminate between tuberculosis infection states. BMC Infect. Dis., 2014, vol. 14: 257. doi: 10.1186/1471-2334-14-257
  29. Mistry R., Cliff J.M., Clayton C.L., Beyers N., Mohamed Y.S., Wilson P.A., Dockrell H.M., Wallace D.M., van Helden P.D., Duncan K., Lukey P.T. Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis. J. Infect. Dis., 2007, vol. 195, no. 3, pp. 357-365.
  30. Mortaz E., Alipoor S.D., Tabarsi P., Adcock I.M., Garssen J., Velayati A.A. The analysis of exosomal micro-RNAs in peripheral blood mononuclear cell-derived macrophages after infection with bacillus Calmette-Guerin by RNA sequencing. Int. J. Mycobacteriol., 2016, suppl. 1, pp. S184-S185. doi: 10.1016/j.ijmyco.2016.09.045
  31. Nau G.J., Richmond J.F., Schlesinger A., Jennings E.G., Lander E.S., Young R.A. Human macrophage activation programs induced by bacterial pathogens. Proc. Natl Acad. Sci. USA, 2002, vol. 99, no. 3, pp. 1503-1508. doi: 10.1073/pnas.022649799
  32. Netea M.G., Joosten L.A., Latz E., Mills K.H., Natoli G., Stunnenberg H.G., O'Neill L.A., Xavier R.J. Trained immunity: a program of innate immune memory in health and disease. Science, 2016, vol. 352, no. 6284: aaf1098. doi: 10.1126/science.aaf1098
  33. Ottenhoff T.H., Dass R.H., Yang N., Zhang M.M., Wong H.E., Sahiratmadja E., Khor C.C., Alisjahbana B., van Crevel R., Marzuki S., Seielstad M., van de Vosse E., Hibberd M.L. Genome-wide expression profiling identifies type 1 interferon response pathways in active tuberculosis. PLoS One, 2012, vol. 7, no. 9: e45839. doi: 10.1371/journal.pone.0045839
  34. Perrin P. Human and tuberculosis co-evolution: an integrative view. Tuberculosis, 2015, vol. 95, suppl. 1, pp. S112-S116. doi: 10.1016/
  35. Public Health Genomics and Precision Health Knowledge Base (v6.0) (PHGKB). URL: (10.10.2019)
  36. Qian Z., Liu H., Li M., Shi J., Li N., Zhang Y., Zhang X., Lv J., Xie X., Bai Y., Ge Q., Ko E.A., Tang H., Wang T., Wang X., Wang Z., Zhou T., Gu W. Potential diagnostic power of blood circular RNA expression in active pulmonary tuberculosis. EbioMedicine, 2018, vol. 27, pp. 18-26. doi: 10.1016/j.ebiom.2017.12.007
  37. Ragno S., Romano M., Howell S., Pappin D.J., Jenner P.J., Colston M.J. Changes in gene expression in macrophages infected with Mycobacterium tuberculosis: a combined transcriptomic and proteomic approach. Immunology, 2001, vol. 104, no. 1, pp. 99108. doi: 10.1046/j.0019-2805.2001.01274.x
  38. Roe J.K., Thomas N., Gil E., Best K., Tsaliki E., Morris-Jones S., Stafford S., Simpson N., Witt K.D., Chain B., Miller R.F., Martineau A., Noursadeghi M. Blood transcriptomic diagnosis of pulmonary and extrapulmonary tuberculosis. JCI Insight, 2016, vol. 1, no. 16: e87238. doi: 10.1172/jci.insight.87238
  39. Roe J., Venturini C., Gupta R.K., Gurry C., Chain B.M., Sun Y., Southern J., Jackson C., Lipman M.C., Miller R.F., Martineau A.R., Abubakar I., Noursadeghi M. Blood transcriptomic stratification of short-term risk in contacts of tuberculosis. Clin. Infect. Dis., 2020, vol. 70, iss. 1, pp. 731-737. doi: 10.1093/cid/ciz252
  40. Sanarico N., Colone A., Grassi M., Speranza V., Giovannini D., Ciaramella A., Colizzi V., Mariani F. Different transcriptional profiles of human monocyte-derived dendritic cells infected with distinct strains of Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guerin. Clin. Dev. Immunol., 2011, vol. 2011: 741051. doi: 10.1155/2011/741051
  41. Shekhawat S.D., Purohit H.J., Taori G.M., Daginawala H.F., Kashyap R.S. Evaluation of heat shock proteins for discriminating between latent tuberculosis infection and active tuberculosis: a preliminary report. J. Infect. Public Health, 2016, vol. 9, no. 2, pp. 143-152. doi: 10.1016/j.jiph.2015.07.003
  42. Song Q., Li H., Shao H., Li C., Lu X. MicroRNA-365 in macrophages regulates Mycobacterium tuberculosis-induced active pulmonary tuberculosis via interleukin-6. Int. J. Clin. Exp. Med., 2015, vol. 8, no. 9, pp. 15458-15465.
  43. Subbian S., Tsenova L., Kim M.-J., Wainwright H.C., Visser A., Bandyopadhyay N., Bader J.S., Karakousis P.C., Murrmann G.B., Bekker L.-G., Russell D.G., Kaplan G. Lesion-specific immune response in granulomas of patients with pulmonary tuberculosis: a pilot study. PLoS One, 2015, vol. 10, no. 7: e0132249. doi: 10.1371/journal.pone.0132249
  44. Sun Q., Wei W., Sha W. Potential role for Mycobacterium tuberculosis specific IL-2 and IFNy responses in discriminating between latent infection and active disease after long-term stimulation. PLoS One, 2016, vol. 11, no. 12: e0166501. doi: 10.1371/journal.pone.0166501
  45. Suliman S., Thompson E.G., Sutherland J., Weiner J. 3rd, Ota M.O.C., Shankar S., Penn-Nicholson A., Thiel B., Erasmus M., Maertzdorf J., Duffy F.J., Hill P.C., Hughes E.J., Stanley K., Downing K., Fisher M.L., Valvo J., Parida S.K., van der Spuy G., Tromp G., Adetifa I.M.O., Donkor S., Howe R., Mayanja-Kizza H., Boom W.H., Dockrell H.M., Ottenhoff T.H.M., Hatherill M., Aderem A., Hanekom W.A., Scriba T.J., Kaufmann S.H.E., Zak D.E., Walzl G.; and the Grand Challenges 6-74 (GC6-74) and Adolescent Cohort Study (ACS) groups. Four-gene pan-african blood signature predicts progression to tuberculosis. Am. J. Respir. Crit. Care Med., 2018, vol. 197, no. 9, pp. 1198-1208. doi: 10.1164/rccm.201711-2340OC
  46. Sweeney T.E., Braviak L., Tato C.M., Khatri P. Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis. Lancet Respir. Med., 2016, vol. 4, no. 3, pp. 213-224. doi: 10.1016/S2213-2600(16)00048-5
  47. Thuong N.T., Dunstan S.J., Chau T.T., Thorsson V., Simmons C.P., Quyen N.T., Thwaites G.E., Thi Ngoc Lan N., Hibberd M., Teo Y.Y., Seielstad M., Aderem A., Farrar J.J., Hawn T.R. Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. PLoS Pathog., 2008, vol. 4, no. 12: e1000229. doi: 10.1371/journal.ppat.1000229
  48. Wang J.X., Xu J., Han Y.F., Zhu Y.B., Zhang W.J. Diagnostic values of microRNA-31 in peripheral blood mononuclear cells for pediatric pulmonary tuberculosis in Chinese patients. Genet. Mol. Res., 2015, vol. 14, no. 4, pp. 17235-17243. doi: 10.4238/2015. December.16.23
  49. Wu B., Huang C., Kato-Maeda M., Hopewell P.C., Daley C.L., Krensky A.M., Clayberger C. Messenger RNA expression of IL-8, FOXP3, and IL-12beta differentiates latent tuberculosis infection from disease. J. Immunol., 2007, vol. 178, no. 6, pp. 3688-3694. doi: 10.4049/jimmunol.178.6.3688
  50. Yuan Y., Lin D., Feng L., Huang M., Yan H., Li Y., Chen Y., Lin B., Ma Y., Ye Z., Mei Y., Yu X., Zhou K., Zhang Q., Chen T., Zeng J. Upregulation of miR-196b-5p attenuates BCG uptake via targeting SOCS3 and activating STAT3 in macrophages from patients with long-term cigarette smoking-related active pulmonary tuberculosis. J. Transl. Med., 2018, vol. 16, no. 1, pp. 284-297. doi: 10.1186/s12967-018-1654-9

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