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

Gokul Raj Kathamuthu,Kadar Moideen,Subash Babu,Nathella Pavan Kumar,Dina Nair,Rathinam Sridhar,Dhanaraj Baskaran,Vaithilingam V Banurekha

doi:10.3389/fimmu.2020.00419

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 (MMP-1, 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 MMP-1, 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.

Highlights

Mycobacterium tuberculosis (Mtb) kills nearly 1.5 million people globally and still poses a major threat with 90% of the disease occurring in developing countries [1, 2]
We show that the systemic levels of Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) were different between pulmonary TB (PTB) and extrapulmonary TB (EPTB) disease compared to the other study (LTB and healthy control (HC)) groups
The systemic levels of MMP-1 (geometric mean (GM) of PTB is 1522 pg/ml vs. GM of EPTB is 202.2 pg/ml vs. GM of latent TB (LTB) is 64.03 pg/ml and 61.36 pg/ml in HC), MMP-8 (GM of PTB is 4,722 pg/ml vs. GM of EPTB is 495.5 pg/ml vs. GM of LTB is 1,283 pg/ml and 1,342 pg/ml in HC), MMP-9 (GM of PTB is 9,270 pg/ml vs. GM of EPTB is 558.3 pg/ml vs. GM of LTB is 1,088 pg/ml and 1,171 pg/ml in HC) and MMP-12 (GM of PTB is 266.1 pg/ml vs. GM of EPTB is 204.7 pg/ml vs. GM of LTB is 206.6 pg/ml and 198.4 pg/ml in HC) were significantly higher in PTB individuals compared to EPTB, LTB, and HC individuals

Summary

Introduction

Mycobacterium tuberculosis (Mtb) kills nearly 1.5 million people globally and still poses a major threat with 90% of the disease occurring in developing countries [1, 2]. Depending upon the Mtb exposure, infected individuals progress to a wide array of disease manifestations from symptomless latent TB (LTB) to active pulmonary TB (PTB) or extrapulmonary TB (EPTB) [3]. Both PTB and EPTB suffer from diagnostic difficulties with low sensitivity of current diagnostic tests [4, 5]. Difficulties do arise due to insufficient sputum collection, presence of few bacilli (paucibacillary) or extrapulmonary form of TB infection [6]. The mortality rate of TB disease has reduced by 42% between the year 2000 and 2018, 3 million individuals are still undiagnosed or missed according to the World Health Organization (WHO) [7]

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Conclusion