Enzymes of purine metabolism and lymphocyte subpopulations in patients with drug-sensitive and drug-resistant infiltrative pulmonary tuberculosis

The purpose of our study was to evaluate the enzyme profile of purinergic system and lymphocyte subsets in patients with newly diagnosed infiltrative pulmonary tuberculosis (IPT), depending on the drug resistance of Mycobacterium tuberculosis (Mtb) to anti-tuberculosis drugs. In 109 patients with drug-sensitive Mtb (significant or less pronounced improvement after intensive phase of chemotherapy), or in drug-resistant cases, the activity of adenosine deaminase (eADA-1, 2), concentration of ecto-5’-nucleotidase (eNT5E), CD26 (DPPIV), and the composition of lymphocyte subsets were evaluated before treatment. The IPT patients with drug-sensitive Mtb strains who achieved a “less pronounced improvement” exhibited higher concentrations and activity of ectoenzymes responsible for production of extracellular adenosine (eNT5E) and its transformation (eADA-1 and eADA-2). The proportion of cytotoxic T cells was also higher compared with patients who achieved significant improvement. Patients isolating drug-resistant Mtb strains who achieved a “less pronounced improvement” had lower absolute counts of T lymphocytes and helper T cells with an increased proportion of cytotoxic T cells and elevated eADA-2 activity compared with individuals who achieved significant improvement. Thus, prior to initiation of tuberculosis chemotherapy, the activity of purine metabolism enzymes and the subpopulation profile of lymphocytes were not associated with the characteristics of Mtb drug resistance. A relationship between the parameters of purinergic regulation enzymes and numbers/ ratio of lymphocytes was revealed in patients who achieved significant improvement. Such relationships were not revealed in the group with less pronounced improvement, regardless of the drug resistance of Mtb. These findings suggest an imbalance of inflammatory factors and immune response to Mtb in the patients who showed worse clinical outcomes after intensive chemotherapy. Taking into consideration each component of protective reactions is required for administration of adequate chemotherapy, pathogenetic treatment, and immunocorrective treatment in order to prevent progression of the disease.

1. Vishnevskiy B.I., Yablonskiу P.K. The persistence of Mycobacterium tuberculosis аs the basis of latent tuberculosis (review). Meditsinskii alyans = Medical Alliance, 2020, Vol. 8, no. 2, pp. 14-20. (In Russ.)

2. Zabolotnykh N.V., Vinogradova T.I., Dogonadze M.Z., Vitovskaya M.L., Ariel A.B., Vasilyev K.A., Shurygina A.-P.S., Buzitskaya Zh.V., Stukova M.A. Vector vaccine Flu/ESAT-6 application in the regimen of complex therapy of drug-sensitive and drug-resistant experimental tuberculosis estimation of the efficiency. Meditsinskii alyans = Medical Alliance, 2020, Vol. 8, no. 4, pp. 6-15. (In Russ.)

3. Novicky V.V., Strelis A.K., Urazova O.I., Voronkova O.V., Sinitsina V.A., Tkachenko S.B., Filiniuk O.V., Zemlianaya N.A., Shil’ko T.A., Esimova I.Ye. The featutures of surface phenotype of blood lymphocytes in the patients with tuberculosis. Meditsinskaya immunologiya = Medical Immunology (Russia), 2005, Vol. 7, no. 5-6, pp. 587-592. (In Russ.) doi: 10.15789/1563-0625-2005-5-6-587-592.

4. Shovkun L.А., Kudlay D.А., Nikolenko N.Yu., Kampos E.D., Kharseeva G.G. Specific features of the immune response to tuberculosis when drug susceptible and drug resistant strains of M. tuberculosis are detected. Tuberkylez i bolezni legkikh = Tuberculosis and Lung Diseases, 2019, Vol. 97, no. 6, pp. 44-49. (In Russ.)

5. Andersson J., Samarina A., Fink J., Rahman S., Grundström S. Impaired expression of perforin in CD8+ T cells at the site of infection in human chronic pulmonary tuberculosis. Infect. Immun., 2007, Vol. 75, no. 11, pp. 5210-5222.

6. Antonioli L., Blandizzi C., Pacher P., Hasko G. Immunity, inflammation and cancer: a leading role for adenosine. Nat. Rev. Cancer, 2013, Vol. 13, no. 12, pp. 842-857.

7. Antonioli L., Csóka B., Fornai M., Colucci R., Kókai E., Drandizzi C. and Haskó Adenosine and inflammation: what’s new on the horizon? Drug Discov. Today, 2014, Vol. 19, no. 8, pp. 1051-1068.

8. Antonioli L., Formai M., Blandizzi C., Pacher P., Hasko G. Adenosine signaling and the immune system: when a lot could be too much. Immunol. Lett., 2019, Vol. 205, pp. 9-15.

9. Barreira da Silva R., Laird M.E., Yatim N., Fiette L., Ingersoll M.A., Albert M.L. Dipeptidylpeptidas 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat. Immunol., 2015, Vol. 16, no. 8, pp. 850-858.

10. Becerra M.C., Huang C.-C., Lecca L., Bayona J., Contreras C., Calderon R., Yataco R., Galea J., Zhang Z., Atwood S., Cohen T., Mitnick C.D., Farmer P., Murray M. Transmissibility and potential for disease progression of drug resistant Mycobacterium tuberculosis: prospective cohort study. BMJ, 2019, Vol. 367, l5894. doi: 10.1136/bmj.l5894.

11. Casrouge A., Sauer A.V., Barreira da Silva R., Tejera-Alhambra M., Sanchez-Ramon S., ICAReB, Cancrini C., Ingersoll M.A., Aiuti A., Albert M.L. Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4. Clin. Exp. Immunol., 2018, Vol. 194, no. 2, pp. 166-179.

12. Costa L.R., de Souza A.K.Y., School J.N., Figueiró F., Battastini A.M.O., dos Santos Jaques J.A., Zanoelo F.F. Biochemical characterization of adenosine deaminase (CD26; EC 3.5.4.4) activity in human lymphocyte-rich peripheral blood mononuclear cells. Braz. J. Med. Biol. Res., 2021, Vol.54, no. 8, 10850. doi: 10.1590/1414-431X2020e10850.

13. Cox J.R., Jennings M., Lenahan C., Manion M., Courville S., Blazeck J. Rational engineering of an improved adenosine deaminase 2 enzyme for weaponizing T-cell therapies. Immunooncol. Technol., 2023, Vol. 19, 100394. doi: 10.1016/j.iotech.2023.100394.

14. Chen L., Alabdullah M., Mahnke K. Adenosine, bridging chronic inflammation and tumor growth. Front. Immunol., 2023, Vol. 14, 1258637. doi: 10.3389/fimmu.2023.1258637.

15. Dheda K., Gumbo T.,Maartens G., Dooley K.E., McNerney R., Murray M., Furin J., Nardell E.A., London L., Lessem E., Theron G., Van Helden P., Niemann S., Merker M., Dowdy D., Van Rie A., Siu G.K.H., Pasipanodya J.G., Rodrigues C., Clark T.G., Sirgel F.A., Esmail A., Lin H.-H., Atre Sachin R., Schaaf H.S., Chang K.C., Lange C., Nahid P., Udwadia Z.F., Horsburgh C.R., Churchyard G.J., Menzies D., Hesseling A.C., Nuermberger E., McIlleron H., Fennelly K.P., Goemaere E., Jaramillo E., Low Marcus, Jara C.M., Padayatchi N., Warren R.M. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir. Med., 2017, Vol. 5, pp. 291-360.

16. Franco R., Pacheco R., Gatell J.M., Gallart T., Lluis C. Enzymatic and extraenzymatic role of adenosine deaminase 1 in T-cell-dendritic cell contacts and in alterations of the immune function. Crit. Rev. Immunol., 2007, Vol. 27, no. 6, pp. 495-509.

17. Hasko G., Cronstein B.N. Adenosine: an endogenous regulator of innate immunity. Trends Immunol., 2004, Vol. 25, no. 1, pp. 33-39.

18. Kaufmann S.H.E., Dorhoi A. Inflammation in tuberculosis: interactions, imbalances and interventions. Curr. Opin. Immunol., 2013, Vol. 25, no. 4, pp. 441-449.

19. Kotrulev M., Gomez-Tourino I., Cordero O.J. Soluble CD26: From suggested biomarker for cancer diagnosis to plausible marker for dynamic monitoring of immunotherapy. Cancers, 2024, Vol. 16, no. 13, 2427. doi: 10.3390/cancers16132427.

20. Lim H.-J., Jong Sun Park J.S., Cho Y.-J., Yoon H.I., Park K.U., Lee C.-T., Lee J.H. CD4+FoxP3+ T regulatory cells in drug-susceptible and multidrug-resistant tuberculosis. Tuberculosis, 2013, Vol. 93, no. 5, pp. 523-528.

21. Ohta A. A metabolic immune checkpoint: adenosine in tumor microenvironment. Front. Immunol., 2016, Vol. 29, no. 7, 109. doi: 10.3389/fimmu.2016.00109.

22. Sampath P., Rajamanickam A., Thiruvengadam K., Natarajan A.P., Hissar S., Dhanapal M., Thangavelu B., Jayabal L., Ramesh P.M., Devi Ranganathan U., Babu S., Bethunaickan R. Cytokine upsurge among drug-resistant tuberculosis endorse the signatures of hyper inflammation and disease severity. Sci. Rep., 2023, Vol. 13, 785. doi: 10.1038/s41598-023-27895-8.

23. Tadokoro H., Hirayama A., Kudo R., Hasebe M., Yoshioka Y., Matsuzaki J., Yamamoto Y., Sugimoto M., Soga T., Ochiya T. Adenosine leakage from perforin-burst extracellular vesicles inhibits perforin secretion by cytotoxic T-lymphocytes. PLoS ONE, 2020, Vol. 15, no. 4, e0231430. doi: 10.1371/journal.pone.0231430.

24. Zavialov A.V., Gracia E., Glaichenhaus N., Franco R., Zavialov A.V., Lauvau G. Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J. Leukoc. Biol., 2010, Vol. 88, no. 2, pp. 279-290.

25. Zavialov A.V., Yu X., Spillmann D., Lauvau G., Zavialov A.V. Structural basis for the growth factor activity of human adenosine deaminase ADA2. J. Biol. Chem., 2010, Vol. 285, no. 16, pp. 12367-12377.

26. Zhang T., Tong X., Zhang S., Wang D., Wang L., Wang Q., Fan H. The roles of dipeptidyl peptidase 4 (DPP4) and DPP4 inhibitors in different lung diseases: new evidence. Front. Pharmacol., 2021, Vol. 12, 731453. doi: 10.3389/fphar.2021.731453.

27. Zhulai G., Oleinik E., Shibaev, M., Ignatev K. Adenosine-metabolizing enzymes, adenosine kinase and adenosine deaminase, in cancer. Biomolecules, 2022, Vol. 12, no. 3, 418. doi: 10.3390/biom12030418.