Aim:Mycobacterium tuberculosis (Mtb) growing within the phagosome of macrophases secretes siderophores, a small molecule having a high affinity for Fe+3 iron, to take up iron-loaded mycobactin (MBT) and carboxymycobactin (CMBT) from the environment to meet its iron (Fe) need. Mycobacterium tuberculosis is well capable to utilize Fe from heme and hemoglobin by the secretion of heme-binding protein, cell surface proteins, etc., by the mycobacteria. On the other hand, the measurement of serum total iron binding capacity (TIBC) denoting the maximum amount of Fe carried by transferrin (Tf) present in serum entails indirectly a measure of serum Tf level. The index author has interpreted the serum iron and serum TIBC level and the ratio of serum iron and serum TIBC as a preliminary survey to shortlist the suspected population deserving confirmatory test for tuberculosis (TB). This is to categorically declare that assay of these parameters is not to be used as TB diagnostic but only for shortlisting suspected TB patients from the general population.
Materials and methods: The study was conducted on total of 180 participants divided into 3 groups: Group I - normal control (n = 45); Group II - lung disease control (n = 45); and Group III - patients suffering from TB (3A: Pulmonary TB (n = 45) and 3B: Extrapulmonary TB (n = 45)). Serum Fe and TIBC levels were measured for all participants and also for group III and group II subjects after one month with the usual treatment. The level of significance was assessed using Student's t-test. All the subjects in this study had normal liver function tests and they did not suffer from iron overload diseases or any malabsorption of iron syndrome.
Result: At baseline, serum Fe was significantly high in TB patients whereas serum TIBC was significantly decreased. After one month's additional anti-TB (A-TB) drug treatment serum iron had increased but not significantly (p = 0.15) and serum TIBC had increased significantly (p = 0.04). Statistical computation of the ratio of serum Fe and serum TIBC in TB patients had shown to be as high as 0.63, and more than that.
Conclusion: From statistical computation, it might be conferred that serum Fe more than 149 µg/dL and the ratio of serum Fe to serum TIBC more than 0.63 (which is more important) in preliminary survey detecting TB patients would shortlist the TB suspects deserving confirmatory test for TB diagnosis.
Global Tuberculosis Programme. Global Tuberculosis Report 2020. World Health Organization. 2020. pp. 232. Available at: https://www.who.int/publications/i/item/9789240013131.
Maclean E, Broger T, Yerlikaya S, et al. A systemic review of biomarkers to detect active tuberculosis. Nat Microbiol 2019;4(5):748–758. DOI: 10.1038/s41564-019-0380-2.
Chattopadhyay DK. Serum glutamine synthetase activity as biomarker for tuberculosis diagnosis and monitoring anti-tubercular drug therapy success. Indian J Biochem Biophys 2019;56(6):427–432. DOI: 10.56042/ijbb.v56i6.29214.
Chattopadhyay DK. Superoxide dismutase: A biomarker for early diagnosis of tuberculosis. J Clin Diagn Res 2019;13(7):BC01–BC03. DOI: 10.7860/JCDR/2019/35298.12968.
Chattopadhyay DK. Decreased serum cholinesterase activity - A reliable diagnostic aid for tuberculosis. J Clin Diagn Res 2021; 15(3):BC16–BC19. DOI: 10.7860/JCDR/2021/46501.14657.
Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998;393:537–544. DOI: https://doi.org/10.1038/31159.
Griffiths E, Rogers HJ, Bullen JJ. Iron, plasmids and infection. Nature 1980;284:508–509. DOI: https://doi.org/10.1038/284508a0.
MacGillivary RT, Moore SA, Chen J, et al. Two high-resolution crystal structures of the recombinant N-lobe of human transferrin reveal a structural change implicated in iron release. Biochemistry 1998;37(22):7919–7928. DOI: 10.1021/bi980355j.
Hamilton TA, Gray PW, Adams DO. Expression of the transferring receptor on murine peritoneal macrophages is modulated by in vitro treatment with interferon gamma. Cell Immunol 1984;89(2):478–488. DOI: 10.1016/0008-8749(84)90348-4.
Rodriguez GM. Control of iron metabolism in mycobacterium tuberculosis. Trends Microbiol 2006;14(7):320–327. DOI: 10.1016/j.tim.2006.05.006.
Gobin J, Horwitz MA. Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M.tuberculosis cell wall. J Exp Med 1996;183(4):1527–1532. DOI: 10.1084/jem.183.4.1527.
Jones CM, Niederweis M. Mycobacterium tuberculosis can utilize heme as an iron source. J Bacteriol 2011;193(7):1767–1770. DOI: 10.1128/JB.01312-10.
Tullius MV, Harmston CA, Owens CP, et al. Discovery and characterization of a unique bacterial heme acquisition system. Proc Natl Acad Sci USA 2011;108(12):5051–5056. DOI: 10.1073/pnas.1009516108.
Mitra A, Speer A, Lin K, et al. PPE surface proteins are required for heme utilization by Mycobacterium tuberculosis. M Bio 2017;8(1):e01720–e017216. DOI: https://doi.org/10.1128/mBio.01720-16.
Tullius MV, Nava S, Horwitz MA. PPE 37 Is Essential for Mycobacterium tuberculosis Heme-Iron Acquisition (HIA) and a defective PPE 37 in Mycobacterium bovis BCG Prevents HIA. Infect Immun 2019;87(2):e00540–e005418. DOI: 10.1128/IAI.00540-18.
Yamanishi H, Iyama S, Yamaguchi Y, et al. Total iron-binding capacity calculated from serum transferrin concentration or serum iron concentration and unsaturated iron-binding capacity. Clin Chem 2003;49(1):175–178. DOI: 10.1373/49.1.175.
Dudchenko A, Averbakh M, Karpina N, et al. Capacities of blood serum Lipoarabinomannan in the diagnosis of tuberculosis at a late stage of HIV infection. Eur Respir J 2018;52(Suppl 62):PA4738. DOI: 10.1183/13993003.congress-2018.PA4738.
International Committee for Standardization in Haematology (Expert Panel on Iron). Revised recommendation for the measurements of serum iron in human blood. Br J Haematol 1990;75(4): 615–616. DOI: 10.1111/j.1365-2141.1990.tb07808.x.
International Committee for Standardization in Haematology. The measurement of total and unsaturated iron binding capacity in serum. Br J Haematol 1978:38(2):281–287. DOI: https://doi.org/10.1111/j.1365-2141.1978.tb01044.x.
Gordeuk VR, McLaren CE, MacPhail AP, et al. Association of iron overload in Africa with hepatocellular carcinoma and tuberculosis: Strachan's 1929 thesis revisited. Blood 1996;87(8):281–287. PMID: 8605366.
Owens CP, Chim N, Goulding CW. Insights on how the Mycobacterium tuberculosis heme uptake pathway can be used as a drug target. Future Med Chem 2013;5(12):1391–1403. DOI: 10.4155/fmc.13.109.
Reddy PV, Puri RV, Khera A, et al. Iron storage proteins are essential for the survival and pathogenesis of Mycobacterium tuberculosis in THP-1 macrophages and the guineapig model of infection. J Bacteriol 2012;194(3):567–575. DOI: 10.1128/JB.05553-11.
Rodriguez GM, Smith I. Identification of an ABC transporter required for iron acquisition and virulence in Mycobacterium tuberculosis. J Bacteriol 2006;188(2):424–430. DOI: 10.1128/JB.188.2.424-430.2006.
Ryndak MB, Wang S, Smith I, et al. The Mycobacterium tuberculosis high-affinity iron importer, IrtA; Contains an FAD-binding domain. J Bacteriol 2010;192(3):861–869. DOI: 10.1128/JB.00223-09.
Wells RM, Jones CM, Xi Z, et al. Discovery of a Siderophore export system essential for virulence of Mycobacterium tuberculosis. PLoS Pathog 2013;9(1):e1003120. DOI: 10.1371/journal.ppat.1003120.
Jones CM, Wells RM, Madduri AV, et al. Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling. Proc Natl Acad Sci USA 2014;111(5):1945–1950. DOI: 10.1073/pnas.1311402111.
DeVoss JJ, Rutter K, Schroeder BG, et al. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc Natl Acad Sci USA 2000;97(3): 1252–1257. DOI: 10.1073/pnas.97.3.1252.
McNerney R, Moyo M. A novel small molecule immunoassay to detect the mycobacterial siderophore carboxymycobactin. Biomed Biotechnol Res J 2017;1(1):37–41. DOI: 10.4103/bbrj.bbrj_20_17.
Varghese GM, Turaka VP, Janardhan J, et al. Serum siderocalin levels in patients with tuberculosis and HIV infection. Int J Infect Dis 2019;85:132–134. DOI: 10.1016/j.ijid.2019.05.020.
Mwandumba HC, Russel DG, Nyirenda MH, et al. Mycobacterium tuberculosis resides in nonacidified vacuoles in endocytically competent alveolar macrophages from patients with tuberculosis and HIV infection. J Immunol 2004;172(7):4592–4598. DOI: 10.4049/jimmunol.172.7.4592.
Cronje L, Edmondson N, Eisenach KD, et al. Iron and iron chelating agents modulate Mycobacterium tuberculosis growth and monocyte-macrophage viability and effector functions. FEMS Immunol Med Microbiol 2005;45(2):103–112. DOI: 10.1016/j.femsim. 2005.02.007.
Kojima N, Bates GW. The formation of Fe+3-transferrin-CO3(2-) via the binding and oxidation of Fe2+. J Biol Chem 1981;256(23):12034–12039. PMID: 7298642.
Kraemer SM. Iron oxide dissolution and solubility in the presence of siderophores. Aquat Sci 2004;66:3–18. DOI: https://doi.org/10.1007/s00027-003-0690-5.
Chattopadhyay DK. Ratio of serum superoxide dismutase and whole blood glutathione peroxidase: A noteworthy parameter for tuberculosis diagnosis. Indian J Med Biochem 2021;25(3):100–104. DOI: https://doi.org/10.5005/jp-journals-10054-0193.
Chattopadhyay DK. Zinc supplementation combats tuberculosis by reverting back to normal compartmentalized state of iron and hence increasing blood hemoglobin concentration. Indian J Med Biochem 2022;26(1):20–25. DOI: 10.5005/jp-journals-10054-0203.