Omics technologies in the diagnostics of Mycobacterium tuberculosis

Bespyatykh JA1,2, Basmanov DV1
About authors

1 Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia

2 Mendeleev University of Chemical Technology of Russia, Moscow, Russia

Correspondence should be addressed: Julia A. Bespyatykh
Malaya Pirogovskaya, 1a, Moscow, 119435, Russia; gro.mcpcr@seBailuJ

About paper

Funding: the study was supported by RSF grant № 20-75-10144.

Author contribution: Bespyatykh JA — study concept, manuscript writing and editing; Basmanov DV — analysis of raw data on biosensors and microarrays, manuscript writing.

Received: 2022-04-12 Accepted: 2022-04-27 Published online: 2022-05-16
  1. Rachow A, Ivanova O, Wallis R, Charalambous S, Jani I, Bhatt N, et al. TB sequel: Incidence, pathogenesis and risk factors of longterm medical and social sequelae of pulmonary TB — A study protocol 11 Medical and Health Sciences 1117 Public Health and Health Services. BMC Pulm Med. 2019; 19: 1–9. DOI: 10.1186/ S12890-018-0777-3/TABLES/2.
  2. Podany AT, Swindells S. Current strategies to treat tuberculosis. F1000Research. 2016; 5. DOI: 10.12688/F1000RESEARCH.7403.1/ DOI.
  3. Tiberi S, Scardigli A, Centis R, D’Ambrosio L, Muñoz-Torrico M, Salazar-Lezama MÁ, et al. Classifying new anti-tuberculosis drugs: rationale and future perspectives. Int J Infect Dis. 2017; 56: 181–4. DOI: 10.1016/J.IJID.2016.10.026.
  4. Migliori GB, Tiberi S, Zumla A, Petersen E, Chakaya JM, Wejse C, et al. MDR/XDR-TB management of patients and contacts: Challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network. Int J Infect Dis. 2020; 92S: S15–S25. DOI: 10.1016/J.IJID.2020.01.042.
  5. Patterson B, Wood R. Is cough really necessary for TB transmission? Tuberculosis. 2019; 117: 31–35. DOI: 10.1016/J. TUBE.2019.05.003.
  6. Chai Q, Wang L, Liu CH, Ge B. New insights into the evasion of host innate immunity by Mycobacterium tuberculosis. Cell Mol Immunol. 2020; 17: 901–13. DOI: 10.1038/s41423-020-0502-z.
  7. Bradfute SB, Castillo EF, Arko-Mensah J, Chauhan S, Jiang S, Mandell M, et al. Autophagy as an immune effector against tuberculosis. Curr Opin Microbiol. 2013; 16: 355. DOI: 10.1016/J. MIB.2013.05.003.
  8. Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria. Immunol Rev. 2015; 264: 182–203. DOI: 10.1111/IMR.12266. PMID: 25703560.
  9. Ehlers S, Schaible UE. The granuloma in tuberculosis: dynamics of a host-pathogen collusion. Front Immunol. 2013; 3. DOI: 10.3389/FIMMU.2012.00411. PMID: 23308075.
  10. Qiang L, Wang J, Zhang Y, Ge P, Chai Q, Li B, et al. Mycobacterium tuberculosis Mce2E suppresses the macrophage innate immune response and promotes epithelial cell proliferation. Cell Mol Immunol. 2019; 16: 380–91. DOI: 10.1038/S41423-018-0016-0. PMID: 29572547.
  11. Su H, Zhu S, Zhu L, Kong C, Huang Q, Zhang Z, et al. Mycobacterium tuberculosis latent antigen Rv2029c from the multistage DNA vaccine A39 drives TH1 responses via TLRmediated macrophage activation. Front Microbiol. 2017; 8: 2266. DOI: 10.3389/FMICB.2017.02266/BIBTEX.
  12. Peng H, Wang X, Barnes PF, Tang H, Townsend JC, Samten B. The Mycobacterium tuberculosis Early Secreted Antigenic Target of 6 kDa Inhibits T Cell Interferon-γ Production through the p38 Mitogen-activated Protein Kinase Pathway. J Biol Chem. 2011; 286: 24508–18. DOI: 10.1074/JBC.M111.234062. PMID: 21586573.
  13. Wang X, Barnes PF, Huang F, Alvarez IB, Neuenschwander PF, Sherman DR, et al. Early secreted antigenic target of 6-kDa protein of Mycobacterium tuberculosis primes dendritic cells to stimulate Th17 and inhibit Th1 immune responses. J Immunol. 2012; 189: 3092–103. DOI: 10.4049/JIMMUNOL.1200573. PMID: 22904313.
  14. Jung BG, Wang X, Yi N, Ma J, Turner J, Samten B. Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL6 Production by Macrophages through Activation of STAT3. Sci Rep. 2017; 7. DOI: 10.1038/SREP40984. PMID: 28106119.
  15. Refai A, Gritli S, Barbouche MR, Essafi M. Mycobacterium tuberculosis Virulent Factor ESAT-6 Drives Macrophage Differentiation Toward the Pro-inflammatory M1 Phenotype and Subsequently Switches It to the Anti-inflammatory M2 Phenotype. Front Cell Infect Microbiol. 2018; 8. DOI: 10.3389/ FCIMB.2018.00327. PMID: 30283745.
  16. Lin J, Jiang Y, Liu D, Dai X, Wang M, Dai Y. Early secreted antigenic target of 6-kDa of Mycobacterium tuberculosis induces transition of macrophages into epithelioid macrophages by downregulating iNOS / NO-mediated H3K27 trimethylation in macrophages. Mol Immunol. 2020; 117: 189–200. DOI: 10.1016/J.MOLIMM.2019.11.013. PMID: 31816492.
  17. Yaseen I, Kaur P, Nandicoori VK, Khosla S. Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3. Nat Commun 2015 61. 2015; 6: 1–13. DOI: 10.1038/ncomms9922. PMID: 26568365.
  18. Schubert OT, Mouritsen J, Ludwig C, Röst HL, Rosenberger G, Arthur PK, et al. The Mtb proteome library: A resource of assays to quantify the complete proteome of mycobacterium tuberculosis. Cell Host Microbe. 2013; 13: 602–12. DOI: 10.1016/j.chom.2013.04.008.
  19. Kunnath-Velayudhan S, Porcelli SA. Recent Advances in Defining the Immunoproteome of Mycobacterium tuberculosis. Front Immunol. 2013; 0: 335. DOI: 10.3389/FIMMU.2013.00335.
  20. Беспятых Ю. А., Шитиков Е. А., Ильина Е. Н. Протеомные подходы в изучении микобактерий. Acta Naturae. 2017; 9, 1 (32): 16–26. DOI: 10.32607/20758251-2017-9-1-15-25. PMID: 28461970.
  21. Uddin R, Siddiqui QN, Sufian M, Azam SS, Wadood A. Proteomewide subtractive approach to prioritize a hypothetical protein of XDR-Mycobacterium tuberculosis as potential drug target. Genes Genomics. 2019; 41: 1281–92. DOI: 10.1007/S13258-01900857-Z. PMID: 31388979.
  22. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. Deciphering the biology of mycobacterium tuberculosis from the complete genome sequence. Nature. 1998; 537–44.
  23. Bespyatykh J, Shitikov E, Guliaev A, Smolyakov A, Klimina K, Veselovsky V, et al. System OMICs analysis of Mycobacterium tuberculosis Beijing B0/W148 cluster. Sci Rep. 2019; 9. DOI: 10.1038/s41598-019-55896-z. PMID: 31848428.
  24. Upadhyay S, Mittal E, Philips JA. Tuberculosis and the art of macrophage manipulation. Pathog Dis. 2018; 76: 37. DOI: 10.1093/FEMSPD/FTY037. PMID: 29762680.
  25. Tientcheu LD, Koch A, Ndengane M, Andoseh G, Kampmann B, Wilkinson RJ. Immunological consequences of strain variation within the Mycobacterium tuberculosis complex. Eur J Immunol. 2017; 47: 432. DOI: 10.1002/EJI.201646562. PMID: 28150302.
  26. Van Embden JD, Cave MD, Crawford JT, Dale JW, Eisenach KD, Gicquel B, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol. 1993; 31: 406–9. PMID: 8381814.
  27. Bespyatykh JA, Zimenkov DV, Shitikov EA, Kulagina EV, Lapa SA, Gryadunov DA, et al. Spoligotyping of Mycobacterium tuberculosis complex isolates using hydrogel oligonucleotide microarrays. Infect Genet Evol. 2014; 26. DOI: 10.1016/j.meegid.2014.04.024.
  28. Frothingham R, Meeker-O’Connell WA. Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats. Microbiology. 1998; 144 (Pt 5): 1189–96. DOI: 10.1099/00221287-144-5-1189. PMID: 9611793.
  29. Skvorcova TA, Azhikina TL. Analiz transkriptomov patogennyx bakterij v inficirovannom organizme: problemy i sposoby ix resheniya (obzornaya stat'ya). Bioorganicheskaya ximiya. 2010; 36: 596–606. Russian.
  30. Coppola M, Lai RPJ, Wilkinson RJ, Ottenhoff THM. The In Vivo Transcriptomic Blueprint of Mycobacterium tuberculosis in the Lung. Front Immunol. 2021; 12: 5212. DOI: 10.3389/ FIMMU.2021.763364/BIBTEX. PMID: 35003075.
  31. Bespyatykh J, Shitikov E, Butenko I, Altukhov I, Alexeev D, Mokrousov I, et al. Proteome analysis of the Mycobacterium tuberculosis Beijing B0/W148 cluster. Sci Rep. 2016; 6. DOI: 10.1038/srep28985.
  32. Bespyatykh J, Shitikov E, Bespiatykh D, Guliaev A, Klimina K, Veselovsky V, et al. Metabolic Changes of Mycobacterium tuberculosis during the Anti-Tuberculosis Therapy. Pathog (Basel, Switzerland). 2020; 9. DOI: 10.3390/PATHOGENS9020131. PMID: 32085490.
  33. Nataraj V, Varela C, Javid A, Singh A, Besra GS, Bhatt A. Mycolic acids: deciphering and targeting the Achilles’ heel of the tubercle bacillus. Mol Microbiol. 2015; 98: 7. DOI: 10.1111/MMI.13101. PMID: 26135034.
  34. Takayama K, Wang C, Besra GS. Pathway to Synthesis and Processing of Mycolic Acids in Mycobacterium tuberculosis. Clin Microbiol Rev. 2005; 18: 81. DOI: 10.1128/CMR.18.1.81101.2005. PMID: 15653820.
  35. Chandra N, Kumar D, Rao K. Systems biology of tuberculosis. Tuberculosis (Edinb). 2011; 91: 487–96. DOI: 10.1016/J. TUBE.2011.02.008. PMID: 21459043.
  36. Beste DJV, Hooper T, Stewart G, Bonde B, Avignone-Rossa C, Bushell ME, et al. GSMN-TB: A web-based genome-scale network model of Mycobacterium tuberculosis metabolism. Genome Biol. 2007; 8: 1–18. DOI: 10.1186/GB-2007-8-5-R89/ FIGURES/5. PMID: 17521419.
  37. Von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003; 31: 258–61. DOI: 10.1093/ NAR/GKG034. PMID: 12519996.
  38. Raman K, Vashisht R, Chandra N. Strategies for efficient disruption of metabolism in Mycobacterium tuberculosis from network analysis. Mol Biosyst. 2009; 5: 1740–51. DOI: 10.1039/ B905817F. PMID: 19593474.
  39. Goletti D, Lee MR, Wang JY, Walter N, Ottenhoff THM. Update on tuberculosis biomarkers: From correlates of risk, to correlates of active disease and of cure from disease. Respirology. 2018; 23: 455–66. DOI: 10.1111/RESP.13272. PMID: 29457312.
  40. La Manna MP, Orlando V, Li Donni P, Sireci G, Di Carlo P, Cascio A, et al. Identification of plasma biomarkers for discrimination between tuberculosis infection/disease and pulmonary non tuberculosis disease. PLoS One. 2018; 13. DOI: 10.1371/JOURNAL. PONE.0192664. PMID: 29543810.
  41. Togun TO, MacLean E, Kampmann B, Pai M. Biomarkers for diagnosis of childhood tuberculosis: A systematic review. PLoS One. 2018; 13: e0204029. DOI: 10.1371/JOURNAL. PONE.0204029. PMID: 30212540.
  42. Zimenkov DV, Antonova OV, Kuzmin AV, Isaeva YD, Krylova LY, Popov SA, et al. Detection of second-line drug resistance in Mycobacterium tuberculosis using oligonucleotide microarrays. BMC Infect Dis. 2013; 13: 1–8. DOI: 10.1186/1471-2334-13240/TABLES/4. PMID: 23705640.
  43. Bespyatyk YuA, Shitikov EA, Zimenkov DV, Kulagina EV, Gryadunov D. A, Nosova EYu, i dr. Opredelenie lekarstvennoj ustojchivosti i genotipirovanie klinicheskix shtammov Mycobacterium tuberculosis pri pomoshhi ehksperimental'nogo nabora «TBTEST». Pul'monologiya. 2013; 4: 77–81. DOI: 10.18093/08690189-2013-0-4-77-81. Russian.
  44. Satta G, Lipman M, Smith GP, Arnold C, Kon OM, McHugh TD. Mycobacterium tuberculosis and whole-genome sequencing: how close are we to unleashing its full potential? Clin Microbiol Infect. 2018; 24: 604–9. DOI: 10.1016/J.CMI.2017.10.030. PMID: 29108952.
  45. Allix-Bequec C, Arandjelovic I, Lijun Bi, Beckert P, Bonnet M, Bradley P, et al. Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing. N Engl J Med. 2018; 379: 1403–15. DOI: 10.1056/NEJMOA1800474. PMID: 30280646.
  46. Cox H, Mizrahi V. The Coming of Age of Drug-Susceptibility Testing for Tuberculosis. N Engl J Med. 2018; 379: 1474–5. DOI: 10.1056/NEJME1811861. PMID: 30256713.
  47. Shitikov E, Kolchenko S, Mokrousov I, Bespyatykh J, Ischenko D, Ilina E, et al. Evolutionary pathway analysis and unified classification of East Asian lineage of Mycobacterium tuberculosis. Sci Rep. 2017; 7: 9227. DOI: 10.1038/s41598-017-10018-5.
  48. Ribeiro SCM, Gomes LL, Amaral EP, Andrade MRM, Almeida FM, Rezende AL, et al. Mycobacterium tuberculosis strains of the modern sublineage of the Beijing family are more likely to display increased virulence than strains of the ancient sublineage. J Clin Microbiol. 2014; 52: 2615–24. DOI: 10.1128/JCM.00498-14. PMID: 24829250.
  49. Bespyatykh YuA, Vinogradova TI, Manicheva OA, Zabolotnyx NV, Dogonadze MZ, Vitovskaya ML, i dr. Virulentnost' Mycobacterium tuberculosis genotipa Beijing v usloviyax in vivo. Infekciya i immunitet. 2019; 9 (1): 173–82. DOI: 10.15789/2220-76192019-1-173-182. Russian.
  50. Bespyatykh J, Smolyakov A, Guliaev A, Shitikov E, Arapidi G, Butenko I, et al. Proteogenomic analysis of Mycobacterium tuberculosis Beijing B0/W148 cluster strains. J Proteomics. 2019; 192: 18–26. DOI: 10.1016/j.jprot.2018.07.002.
  51. Konopsky VN, Karakouz T, Alieva EV, Vicario C, Sekatskii SK, Dietler G. Photonic Crystal Biosensor Based on Optical Surface Waves. Sensors. 2013; 13: 2566–78. DOI: 10.3390/S130202566. PMID: 23429517.
  52. Konopsky V, Mitko T, Aldarov K, Alieva E, Basmanov D, Moskalets A, et al. Photonic crystal surface mode imaging for multiplexed and high-throughput label-free biosensing. Biosens Bioelectron. 2020; 168. DOI: 10.1016/J.BIOS.2020.112575. PMID: 32892115.
  53. Mitko TV, Shakurov RI, Shirshikov FV, Sizova SV, Alieva EV, Konopskij VN, i dr. Sozdanie mikroflyuidnogo biosensora dlya diagnostiki i tipirovaniya Mycobacterium tuberculosis. Klinicheskaya praktika. 2021; 12 (2): 14–20. DOI: https://doi. org/10.17816/clinpract71815. Russian.
  54. Sizova S, Shakurov R, Mitko T, Shirshikov F, Solovyeva D, Konopsky V, et al. The Elaboration of Effective Coatings for Photonic Crystal Chips in Optical Biosensors. Polymers (Basel). 2021; 14. DOI: 10.3390/POLYM14010152. PMID: 35012173.
  55. WHO. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management [cited 2022 Apr 11]. Available from:
  56. Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev. 2014; 27: 3–20. DOI: 10.1128/CMR.00034-13. PMID: 24396134.
  57. Aggerbeck H, Ruhwald M, Hoff ST, Borregaard B, Hellstrom E, Malahleha M, et al. C-Tb skin test to diagnose Mycobacterium tuberculosis infection in children and HIV-infected adults: A phase 3 trial. PLoS One. 2018; 13. DOI: 10.1371/JOURNAL. PONE.0204554. PMID: 30248152.
  58. Ruhwald M, Aggerbeck H, Gallardo RV, Hoff ST, Villate JI, Borregaard B, et al. Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon — release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial. Lancet Respir Med. 2017; 5: 259–68. DOI: 10.1016/S2213-2600(16)30436-2. PMID: 28159608.
  59. Castro-Garza J, García-Jacobo P, Rivera-Morales LG, Quinn FD, Barber J, Karls R, et al. Detection of anti-HspX antibodies and HspX protein in patient sera for the identification of recent latent infection by Mycobacterium tuberculosis. PLoS One. 2017; 12. DOI: 10.1371/JOURNAL.PONE.0181714. PMID: 28813434.
  60. Dhiman A, Haldar S, Mishra SK, Sharma N, Bansal A, Ahmad Y, et al. Generation and application of DNA aptamers against HspX for accurate diagnosis of tuberculous meningitis. Tuberculosis (Edinb). 2018; 112: 27–36. DOI: 10.1016/J.TUBE.2018.07.004. PMID: 30205966.