The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy

Stek, Cari; Allwood, Brian; Walker, Naomi F.; Wilkinson, Robert J.; Lynen, Lutgarde; Meintjes, Graeme

doi:10.3389/fmicb.2018.02603

Cited by 73 publications

(65 citation statements)

References 194 publications

(246 reference statements)

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“…TIMPs are very important factors for TB disease, involved in tissue remodeling and repair upon destruction created by MMPs (17,18). Previous studies have identified MMPs as markers of disease severity, bacterial burdens and as a biomarker for disease in PTB and EPTB (17,(19)(20)(21). Relatively, few studies have focused on examining the circulating levels of MMPs and TIMPs as immune biomarkers in both PTB and EPTB.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Current drug regimens are mainly directed at various targets on the Mtb bacillus [9,10]; this means that even after cure, TB patients are at risk of residual damage due to inflammatory effects (post TB fibrosis and bronchiectasis) [11]. Thus, supplementing anti-TB drug treatment with host immune modulators may lead to shorter treatment time, reduced lung damage, lower risk of relapse or reinfection and also improvement of other clinical outcomes [2,10,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

The effects of anti-inflammatory agents as host-directed adjunct treatment of tuberculosis in humans: a systematic review and meta-analysis

et al. 2020

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Background: The potential role of adjunctive anti-inflammatory therapy to enhance tuberculosis (TB) treatment has recently received increasing interest. There is, therefore, a need to broadly examine current host-directed therapies (HDTs) that could accelerate treatment response and improve TB outcomes. Methods: This systematic review and meta-analysis included randomised controlled trials of vitamin D and other HDT agents in patients receiving antibiotic treatment for pulmonary TB. Sputum smear conversion rate at 4-8 weeks was the primary outcome. Secondary outcomes included blood indices associated with infectivity and inflammation, chest radiology and incidence of adverse events. Results: Fifty-five studies were screened for eligibility after the initial search, which yielded more than 1000 records. Of the 2540 participants in the 15 trials included in the meta-analysis, 1898 (74.7%) were male, and the age at entry ranged from 18 to 70 years. There was a 38% significantly (RR 1.38, 95% CI = 1.03-1.84) increased sputum smear negativity in patients administered with vitamin D in addition to standard TB treatment than those receiving only the TB treatment. Patients treated with other HDT anti-inflammatory agents in addition to TB treatment also had a 29% significantly increased sputum smear conversion rate (RR 1.29, 95% CI = 1.09-1.563). Lymphocyte to monocyte ratio was significantly higher in the vitamin D treatment groups compared to the controls (3.52 vs 2.70, 95% CI for difference 0.16-1.11, p = 0.009) and (adjusted mean difference 0.4, 95% CI 0.2-0.6; p = 0.001); whilst tumour necrosis factor-alpha (TNF-α) showed a trend towards a reduction in prednisolone (p < 0.001) and pentoxifylline (p = 0.27) treatment groups. Vitamin D and N-acetylcysteine also accelerated radiographic resolution in treatment compared to placebo at 8 weeks. No differences were observed in the occurrence of adverse events among all HDT treatments.

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“…Immunosuppressive state induced by HIV infection has been shown to hinder immune responses in tuberculosis infection affecting granuloma formation and fibrosis in HIV/tuberculosis co-infected patients. Hence, although these patients are at a higher risk of developing extrapulmonary tuberculosis (EPTB) (Mohammed et al, 2018), the extent of lung damage in pulmonary tuberculosis (PTB) is limited in them (Swaminathan et al, 2007;Stek et al, 2018). Furthermore the co-infected patients are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) in nearly half of the cases (48%) (Hattori et al, 2016;Lai et al, 2016) highlighting importance of understanding immunopathogenesis of this co-infection.…”

Section: Introductionmentioning

confidence: 99%

Elevated Levels of Galectin-9 but Not Osteopontin in HIV and Tuberculosis Infections Indicate Their Roles in Detecting MTB Infection in HIV Infected Individuals

et al. 2020

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Galectin-9 (Gal-9) and osteopontin (OPN) play immunomodulatory roles in tuberculosis and HIV infections. Evaluation of their levels as well as their interplay with different pro-inflammatory cytokines is critical to understand their role in immunopathogenesis of HIV/tuberculosis co-infection considering the complexity of the disease. Plasma levels of these proteins were measured by ELISAs in HIV-negative individuals with pulmonary (n = 21), extrapulmonary (n = 33), and latent tuberculosis (n = 22) and in HIV infected patients with pulmonary (n = 14), latent tuberculosis (n = 17), and without tuberculosis (n = 41). Levels of pro-inflammatory cytokines were estimated by Luminex assay. Receiver operated characteristic curve analysis was performed to evaluate discriminatory roles of these proteins. Spearman's correlation analysis was performed with the markers of HIV and tuberculosis disease progression to evaluate their immunopathogenic roles. Gal-9 and OPN levels were higher in HIV uninfected patients with active tuberculosis than with latent tuberculosis. Gal-9 but not OPN levels were higher in HIV infected patients with active tuberculosis than with latent tuberculosis. Area under curve for Galectin-9 was >0.9 in HIV/tuberculosis coinfection and extrapulmonary tuberculosis. OPN and IL-6 levels were higher in patients with severe chest X-ray grade indicating its association with severity of the disease and positively correlated with each other. Stronger positive and negative correlations of Gal-9 levels, respectively, with viral loads and CD4 cell counts in HIV infected patients were observed than OPN levels indicating their association with HIV disease progression. Thus, significantly elevated Gal-9 levels were reported for the first time in HIV/tuberculosis co-infection and extrapulmonary tuberculosis in our study than single infections with HIV and tuberculosis. The study indicated a need for further evaluation of monitoring role of Gal-9 for detection of developing tuberculosis in HIV infected individuals. The findings also indicated differential roles of Gal-9 and OPN in the pathogenesis of tuberculosis and HIV infections.

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The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy

Cited by 73 publications

References 194 publications

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

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

The effects of anti-inflammatory agents as host-directed adjunct treatment of tuberculosis in humans: a systematic review and meta-analysis

Elevated Levels of Galectin-9 but Not Osteopontin in HIV and Tuberculosis Infections Indicate Their Roles in Detecting MTB Infection in HIV Infected Individuals

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