Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard anti-tuberculosis or metformin treatment

Nathella P Kumar, Kadar Moideen, Vijay Viswanathan, Basavaradhya S Shruthi, Shanmugam Sivakumar, Pradeep A Menon, Hardy Kornfeld, Subash Babu, Nathella P Kumar, Kadar Moideen, Vijay Viswanathan, Basavaradhya S Shruthi, Shanmugam Sivakumar, Pradeep A Menon, Hardy Kornfeld, Subash Babu

Abstract

Background: Matrix metalloproteinases (MMPs) are considered to be key mediators of tuberculosis (TB) pathology but their role in tuberculosis - diabetes comorbidity (TB-DM) is not well understood.

Methods: To study the association of MMP levels with severity and extent of disease as well as bacterial burden in TB-DM, we examined the systemic levels of MMP-1, - 2, - 3, - 7, - 8, - 9, - 10, - 12 and - 13 in individuals with TB-DM and compared them to those with TB alone (TB) or healthy controls (HC).

Results: Circulating levels of MMP-1, - 2, - 3, - 7, - 10 and - 12 were significantly higher in TB-DM compared to both TB and HC and MMP -13 levels were higher in comparison to HC alone. To understand the effect of standard anti-tuberculosis therapy (ATT) on these MMP levels in TB-DM, we measured the levels of MMPs at the end of treatment (post-treatment). Our findings indicate that ATT is associated with a significant reduction in the levels of MMP-1, - 2, - 3, - 8 and - 13 post-treatment. Moreover, the levels of MMP-1, - 2, - 3, - 9 and - 12 were significantly higher in TB-DM individuals with cavitary disease and/or bilateral disease at baseline but not post-treatment. Similarly, the levels of MMP -1, - 2, - 3 and - 8 exhibited a significant positive relationship with bacterial burden and HbA1c levels at baseline but not post-treatment. Within the TB-DM group, those known to be diabetic before incident TB (KDM) exhibited significantly higher levels of MMP-1, - 2, - 10 and - 12 at baseline and of MMP-1 and -3 post-treatment compared to those newly diagnosed with DM (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of MMP-1, - 2, - 3, - 7, - 9 and - 12 at baseline and of MMP-7 post-treatment.

Conclusions: Our data demonstrate that systemic MMP levels reflect baseline disease severity and extent in TB-DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy.

Keywords: Diabetes mellitus; Matrix metalloproteinases; Mycobacterium tuberculosis.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Ethics Committees of the Prof. M. Viswanathan Diabetes Research Center and NIRT. Informed written consent was obtained from all participants.

Consent for publication

Not applicable” in this section.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Elevated circulating levels of MMPs in TB-DM individuals. (a) The plasma levels of MMPs were measured in TB-DM (n = 64), TB (n = 24) and HC (n = 24) individuals at baseline. The data are represented as scatter plots with each circle representing a single individual. P values were calculated using the Kruskal-Wallis test with Dunn’s post-hoc for multiple comparisons (b) The plasma levels of MMPs were measured in TB-DM individuals at baseline (pre-T) and at 6 months of ATT (post-T). The data are presented as line graphs with each line representing a single individual. P values were calculated using the Wilcoxon signed rank test
Fig. 2
Fig. 2
Elevated circulating levels of MMPs in cavitary disease in TB-DM individuals. The plasma levels of MMPs were measured in TB-DM individuals with cavitary versus non-cavitary disease at baseline. The data are represented as scatter plots with each circle representing a single individual. P values were calculated using the Mann-Whitney test with Holm’s correction for multiple comparisons
Fig. 3
Fig. 3
Elevated circulating levels of MMPs in bilateral disease in TB-DM individuals. The plasma levels of MMPs were measured in TB-DM individuals with bilateral versus unilateral disease at baseline. The data are represented as scatter plots with each circle representing a single individual. P values were calculated using the Mann-Whitney test with Holm’s correction for multiple comparisons
Fig. 4
Fig. 4
Circulating MMPs are marker of bacterial burden in TB-DM. The relationship between the plasma levels of MMPs and smear grades as estimated by sputum smears was examined in TB-DM individuals at baseline. The data are represented as scatter plots with each circle representing a single individual. P values were calculated using the Linear trend post – test
Fig. 5
Fig. 5
Significant correlation between circulating levels of MMPs and glycemic parameters in all TB-DM individuals. The relationship between the plasma levels of MMPs and HbA1c levels was examined in all PTB individuals with and without DM at baseline. The data are represented as scatter plots with each circle representing a single individual. P values were calculated using the Spearman Rank Correlation
Fig. 6
Fig. 6
Elevated circulating levels of MMPs in KDM individuals. (a) The plasma levels of MMPs were measured in TB-DM individuals with known diabetes. (KDM) versus newly diagnosed diabetes (NDM) at baseline. (b) The plasma levels of MMPs were measured in TB-DM individuals with known diabetes (KDM) versus newly diagnosed diabetes (NDM) at 6 months of ATT. The data are represented as scatter plots with each circle representing a single individual. P values were calculated using the Mann-Whitney test with Holm’s correction for multiple comparisons
Fig. 7
Fig. 7
Diminished circulating levels of MMPs in KDM individuals on metformin treatment. (a) MMPs were measured in KDM individuals on metformin treatment versus no metformin treatment at baseline. (b) The plasma levels of MMPs were measured in KDM individuals on metformin treatment versus no metformin treatment at 6 months of ATT. The data are represented as scatter plots with each circle representing a single individual. P values were calculated using the Mann-Whitney test with Holm’s correction for multiple comparisons

References

    1. Woessner JF., Jr The family of matrix metalloproteinases. Ann N Y Acad Sci. 1994;732:11–21. doi: 10.1111/j.1749-6632.1994.tb24720.x.
    1. Izzo AA, Izzo LS, Kasimos J, Majka S. A matrix metalloproteinase inhibitor promotes granuloma formation during the early phase of Mycobacterium tuberculosis pulmonary infection. Tuberculosis (Edinb) 2004;84(6):387–396. doi: 10.1016/j.tube.2004.07.001.
    1. Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 2004;4(8):617–629. doi: 10.1038/nri1418.
    1. Ong CW, Elkington PT, Friedland JS. Tuberculosis, pulmonary cavitation, and matrix metalloproteinases. Am J Respir Crit Care Med. 2014;190(1):9–18. doi: 10.1164/rccm.201311-2106PP.
    1. Pavan Kumar N, Anuradha R, Andrade BB, Suresh N, Ganesh R, Shankar J, Kumaraswami V, Nutman TB, Babu S. Circulating biomarkers of pulmonary and extrapulmonary tuberculosis in children. Clin Vaccine Immunol. 2013;20(5):704–711. doi: 10.1128/CVI.00038-13.
    1. Andrade BB, Kumar NP, Sridhar R, Banurekha VV, Jawahar MS, Nutman TB, Sher A, Babu S. Heightened plasma levels of heme oxygenase-1 and tissue inhibitor of metalloproteinase-4 as well as elevated peripheral neutrophil counts are associated with TB-diabetes comorbidity. Chest. 2014;145(6):1244–1254. doi: 10.1378/chest.13-1799.
    1. Singhal A, Jie L, Kumar P, Hong GS, Leow MK, Paleja B, Tsenova L, Kurepina N, Chen J, Zolezzi F, et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014;6(263):263ra159. doi: 10.1126/scitranslmed.3009885.
    1. Degner NR, Wang JY, Golub JE, Karakousis PC. Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment. Clin Infect Dis. 2018;66(2):198–205. doi: 10.1093/cid/cix819.
    1. Martinez N, Kornfeld H. Diabetes and immunity to tuberculosis. Eur J Immunol. 2014;44(3):617–626. doi: 10.1002/eji.201344301.
    1. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis. 2009;9(12):737–746. doi: 10.1016/S1473-3099(09)70282-8.
    1. Pizzol D, Di Gennaro F, Chhaganlal KD, Fabrizio C, Monno L, Putoto G, Saracino A. Tuberculosis and diabetes: current state and future perspectives. Tropical Med Int Health. 2016;21(6):694–702. doi: 10.1111/tmi.12704.
    1. Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus. N Engl J Med. 1999;341(25):1906–1912. doi: 10.1056/NEJM199912163412507.
    1. Muller LM, Gorter KJ, Hak E, Goudzwaard WL, Schellevis FG, Hoepelman AI, Rutten GE. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005;41(3):281–288. doi: 10.1086/431587.
    1. Parks WC, Shapiro SD. Matrix metalloproteinases in lung biology. Respir Res. 2001;2(1):10–19.
    1. Elkington PT, D'Armiento JM, Friedland JS. Tuberculosis immunopathology: the neglected role of extracellular matrix destruction. Sci Transl Med. 2011;3(71):71ps76. doi: 10.1126/scitranslmed.3001847.
    1. Hunter RL. Pathology of post primary tuberculosis of the lung: an illustrated critical review. Tuberculosis (Edinb) 2011;91(6):497–509. doi: 10.1016/j.tube.2011.03.007.
    1. Seddon J, Kasprowicz V, Walker NF, Yuen HM, Sunpath H, Tezera L, Meintjes G, Wilkinson RJ, Bishai WR, Friedland JS, et al. Procollagen III N-terminal propeptide and desmosine are released by matrix destruction in pulmonary tuberculosis. J Infect Dis. 2013;208(10):1571–1579. doi: 10.1093/infdis/jit343.
    1. Sundararajan S, Babu S, Das SD. Comparison of localized versus systemic levels of matrix metalloproteinases (MMPs), its tissue inhibitors (TIMPs) and cytokines in tuberculous and non-tuberculous pleuritis patients. Hum Immunol. 2012;73(10):985–991. doi: 10.1016/j.humimm.2012.07.042.
    1. Sathyamoorthy T, Sandhu G, Tezera LB, Thomas R, Singhania A, Woelk CH, Dimitrov BD, Agranoff D, Evans CA, Friedland JS, et al. Gender-dependent differences in plasma matrix metalloproteinase-8 elevated in pulmonary tuberculosis. PLoS One. 2015;10(1):e0117605. doi: 10.1371/journal.pone.0117605.
    1. Ugarte-Gil CA, Elkington P, Gilman RH, Coronel J, Tezera LB, Bernabe-Ortiz A, Gotuzzo E, Friedland JS, Moore DA. Induced sputum MMP-1, −3 & -8 concentrations during treatment of tuberculosis. PLoS One. 2013;8(4):e61333. doi: 10.1371/journal.pone.0061333.
    1. Walker NF, Wilkinson KA, Meintjes G, Tezera LB, Goliath R, Peyper JM, Tadokera R, Opondo C, Coussens AK, Wilkinson RJ, et al. Matrix degradation in human immunodeficiency virus type 1-associated tuberculosis and tuberculosis immune reconstitution inflammatory syndrome: a prospective observational study. Clin Infect Dis. 2017;65(1):121–132. doi: 10.1093/cid/cix231.
    1. Hoheisel G, Sack U, Hui DS, Huse K, Chan KS, Chan KK, Hartwig K, Schuster E, Scholz GH, Schauer J. Occurrence of matrix metalloproteinases and tissue inhibitors of metalloproteinases in tuberculous pleuritis. Tuberculosis (Edinb) 2001;81(3):203–209. doi: 10.1054/tube.2000.0276.
    1. Sheen P, O'Kane CM, Chaudhary K, Tovar M, Santillan C, Sosa J, Caviedes L, Gilman RH, Stamp G, Friedland JS. High MMP-9 activity characterises pleural tuberculosis correlating with granuloma formation. Eur Respir J. 2009;33(1):134–141. doi: 10.1183/09031936.00127807.
    1. Park KJ, Hwang SC, Sheen SS, Oh YJ, Han JH, Lee KB. Expression of matrix metalloproteinase-9 in pleural effusions of tuberculosis and lung cancer. Respiration. 2005;72(2):166–175. doi: 10.1159/000084048.
    1. Matsuura E, Umehara F, Hashiguchi T, Fujimoto N, Okada Y, Osame M. Marked increase of matrix metalloproteinase 9 in cerebrospinal fluid of patients with fungal or tuberculous meningoencephalitis. J Neurol Sci. 2000;173(1):45–52. doi: 10.1016/S0022-510X(99)00303-2.
    1. Price NM, Farrar J, Tran TT, Nguyen TH, Tran TH, Friedland JS. Identification of a matrix-degrading phenotype in human tuberculosis in vitro and in vivo. J Immunol. 2001;166(6):4223–4230. doi: 10.4049/jimmunol.166.6.4223.
    1. Lee SW, Song KE, Shin DS, Ahn SM, Ha ES, Kim DJ, Nam MS, Lee KW. Alterations in peripheral blood levels of TIMP-1, MMP-2, and MMP-9 in patients with type-2 diabetes. Diabetes Res Clin Pract. 2005;69(2):175–179. doi: 10.1016/j.diabres.2004.12.010.
    1. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Kaski JC. High serum matrix metalloproteinase-9 level predict increased risk of in-hospital cardiac events in patients with type 2 diabetes and ST segment elevation myocardial infarction. Atherosclerosis. 2008;196(1):365–371. doi: 10.1016/j.atherosclerosis.2006.11.012.
    1. Walker NF, Clark SO, Oni T, Andreu N, Tezera L, Singh S, Saraiva L, Pedersen B, Kelly DL, Tree JA, et al. Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases. Am J Respir Crit Care Med. 2012;185(9):989–997. doi: 10.1164/rccm.201110-1769OC.
    1. Kornfeld H, West K, Kane K, Kumpatla S, Zacharias RR, Martinez-Balzano C, Li W, Viswanathan V. High prevalence and heterogeneity of diabetes in patients with TB in South India: a report from the effects of diabetes on tuberculosis severity (EDOTS) study. Chest. 2016;149(6):1501–1508. doi: 10.1016/j.chest.2016.02.675.
    1. Wallis RS, Hafner R. Advancing host-directed therapy for tuberculosis. Nat Rev Immunol. 2015;15(4):255–263. doi: 10.1038/nri3813.
    1. Marupuru S, Senapati P, Pathadka S, Miraj SS, Unnikrishnan MK, Manu MK. Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility. Braz J Infect Dis. 2017;21(3):312–316. doi: 10.1016/j.bjid.2017.01.001.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere