Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Are Potential Biomarkers of Pulmonary and Extra-Pulmonary Tuberculosis

Abstract

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) are potential regulators of tuberculosis (TB) pathology. Whether they are candidates for non-sputum-based biomarkers for pulmonary TB (PTB) and extra-pulmonary TB (EPTB) is not fully understood. Hence, to examine the association of MMPs and TIMPs with PTB and EPTB, we have measured the circulating levels of MMPs 2,3,7,8,9,12, and 13) and TIMPs (TIMP-1, 2, 3, and 4) in PTB, EPTB and compared them with latent tuberculosis (LTB) or healthy control (HC) individuals. We have also assessed their circulating levels before and after the completion of anti-tuberculosis treatment (ATT). Our data describes that systemic levels of 8,9,12 were significantly increased in PTB compared to EPTB, LTB, and HC individuals. In contrast, MMP-7 was significantly reduced in PTB compared to EPTB individuals. Likewise, the systemic levels of MMP-1, 7, 13 were significantly increased in EPTB in comparison to LTB and HC individuals. In contrast, MMP-8 was significantly reduced in EPTB individuals compared to LTB and HC individuals. In addition, the systemic levels of TIMP-1, 2, 3 were significantly diminished and TIMP-4 levels were significantly enhanced in PTB compared to EPTB, LTB, and HC individuals. The circulating levels of TIMP-2 was significantly reduced and TIMP-3 was significantly elevated in EPTB individuals in comparison with LTB and HCs. Some of the MMPs (7,8,9,12, 13 in PTB and 1,7,8, 9 in EPTB) and TIMPs (1, 2, 3, 4 in PTB and 4 in EPTB) were significantly modulated upon treatment completion. ROC analysis showed that MMP-1, 9 and TIMP-2, 4 could clearly discriminate PTB from EPTB, LTB and HCs and MMP-13 and TIMP-2 could clearly discriminate EPTB from LTB and HCs. Additionally, multivariate analysis also indicated that these alterations were independent of age and sex in PTB and EPTB individuals. Therefore, our data demonstrates that MMPs and TIMPs are potential candidates for non-sputum-based biomarkers for differentiating PTB and EPTB from LTB and HC individuals.

Association of Plasma Matrix Metalloproteinase and Tissue Inhibitors of Matrix Metalloproteinase Levels With Adverse Treatment Outcomes Among Patients With Pulmonary Tuberculosis

“…In a variety of settings, MMPs and TIMPs are known biomarkers of pulmonary and extrapulmonary TB. 10 , 11 , 20 Several MMPs are upregulated in blood, sputum, and bronchoalveolar lavage of individuals with active TB. 15 , 35 , 36 , 37 , 38 , 39 In addition, MMP levels correlate with lung pathology, with plasma concentrations of several MMPs being associated with radiologic abnormalities.…”

“…18,19 Both MMPs and TIMPs are also biomarkers of extrapulmonary TB. 20 We hypothesized that baseline plasma levels of MMPs and TIMPs would be associated with adverse treatment outcomes among patients with PTB. To test this hypothesis, we examined the baseline levels of MMPs and TIMPs in 2 different nested case-control studies of favorable vs adverse treatment outcomes in a cohort of individuals with PTB in Chennai, India.…”

Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases

“…A biomarker analysis conducted in patients with HIV/OI revealed that levels of Tr-Gal-9 markedly reflect the disease severity of the co-infected individuals [ 53 , 96 ]. The Tr-Gal-9 may be generated via cleavage by MMP-9, which has also been proposed to be a non-sputum-based biomarker for differentiating pulmonary TB and extrapulmonary TB [ 97 ].…”

Cytokine Biosignature of Active and Latent Mycobacterium Tuberculosis Infection in Children

“…Among the studied proteins, MMP-2 had the highest discriminative potential shown on the basis of the area under the ROC curve (AUC) in both 3-group and 2-group comparisons as well as the cross-validation based elastic-net feature selection. There are several reports on the role of MMP-2 in TB, but none indicate a diagnostic potential of the enzyme in pediatric TB [ 37 , 41 , 42 , 43 , 44 ]. In a cellular model of TB meningitis, Green et al demonstrated that conditioned medium from M.tb -infected primary human monocytes down-regulated the microglial constitutive MMP-2 gene expression and secretion [ 37 ].…”