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.

Background Helminth infections are known to regulate cytokine responses in both pulmonary and latent tuberculosis infection. Whether helminth infections also modulate cytokine responses in extra-pulmonary tuberculosis, specifically tuberculous lymphadenitis (TBL), has not been examined thus far. Methodology Hence, to determine the cytokine profile in helminth-TBL coinfection, we measured the systemic and mycobacterial (TB)–antigen stimulated levels of Type 1, Type 2, Type 17, regulatory and pro-inflammatory cytokines in TBL individuals coinfected with or without Strongyloides stercoralis (Ss) infection. Significant findings TBL-Ss+ individuals have significantly higher bacterial burdens in the affected lymph nodes in comparison to TBL-Ss- individuals. TBL-Ss+ individuals exhibit significantly enhanced plasma levels of Type 2 (IL-5 and IL-13), Type 17 (IL-17 and IL-22) and regulatory (IL-10) cytokines in comparison to TBL-Ss- individuals. In contrast, TBL-Ss+ individuals exhibit significantly diminished plasma levels of pro-inflammatory cytokines (IL-1α and GM-CSF) in comparison to TBL-Ss- individuals. TBL-Ss+ individuals also exhibit significantly diminished unstimulated or mycobacterial—antigen stimulated levels of Type 1, Type 17 or IL-1 family cytokines in comparison to TBL-Ss- individuals but no differences in mitogen stimulated cytokine levels. Conclusion Therefore, our data reveal a profound influence of Ss infection on the bacteriological profile of TBL and suggesting that the underlying modulation of cytokine responses might be a mechanism by which this helminth infection could impart a detrimental effect on the pathogenesis of TBL disease.

Background Helminths and tuberculosis (TB) largely overlap at the population level. Whether helminth infections influence disease severity and bacterial burdens in TB is not well understood. Methods This study was conducted to examine the disease severity in a cohort of pulmonary TB (PTB) individuals with (Ss+) or without (Ss−) seropositivity for Strongyloides stercoralis infection. Results Ss+ was associated with increased risk of cavitation (odds ratio [OR], 4.54; 95% confidence interval [CI], 2.33–9.04; P < .0001) and bilateral lung involvement (OR, 5.97; 95% CI, 3.03–12.09; P < .0001) in PTB individuals. Ss+ was also associated with higher bacterial burdens (OR, 7.57; 95% CI, 4.18–14.05; P < .0001) in PTB individuals. After multivariate analysis adjusting for covariates, Ss+ was still associated with greater risk of cavitation (adjusted OR [aOR], 3.99; 95% CI, 1.73–9.19; P = .0014), bilateral lung involvement (aOR, 4.09; 95% CI, 1.78–9.41; P = .0011), and higher bacterial burden (aOR, 9.32; 95% CI, 6.30–13.96; P < .0001). Finally, Ss+ was also associated with higher plasma levels of matrix metalloproteinases ([MMP]-1, -2, -7, -8, and -9) in PTB individuals. Conclusions Therefore, our data demonstrate that coexistent Ss infection is associated with greater disease severity and higher bacterial burden in PTB. Our data also demonstrate enhanced plasma levels of MMPs in coinfected individuals, suggesting a plausible biological mechanism for these effects.

Lymph node tuberculosis (LNTB) is characterized by the enhanced baseline and antigen-specific production of type 1/17 cytokines and reduced baseline and antigen-specific production of interleukin (IL)-1β and IL-18 at the site of infection when compared with peripheral blood. However, the cytokine profile in the lymph nodes (LNs) of Mycobacterium tuberculosis culture-positive LNTB (LNTB+) and negative LNTB (LNTB−) has not been examined. To address this, we have examined the baseline and mycobacterial antigen-stimulated cytokine levels of type 1 (interferon gamma [IFNγ], tumor necrosis factor alpha [TNFα], IL-2), type 2 (IL-4, IL-5, and IL-13), type 17 (IL-17A, IL-17F, and IL-22), pro-inflammatory (IL-1α, IL-1β, IL-18, and granulocyte macrophage colony-stimulating factor [GM-CSF]), and regulatory cytokines (IL-10, transforming growth factor beta [TGF-β]) cytokines in the LN culture supernatants of LNTB+ and LNTB− individuals. We have observed significantly enhanced baseline levels of IL-13 and IL-10 and significantly reduced baseline levels of IL-4 and GM-CSF in LNTB+ individuals compared with LNTB− individuals. By contrast, we have observed significantly enhanced levels of type 1 (IFNγ, TNFα, and IL-2), type 17 (IL-17F and IL-22), and pro-inflammatory (IL-1α and GM-CSF) cytokines and significantly reduced levels of TGFβ in response to purified protein derivative, early secreted antigen-6, and culture filtrate protein-10 antigens in LNTB+ compared with LNTB− individuals. On phorbol 12-myristate 13-acetate/ionomycin stimulation, no significant difference was observed for any of the cytokines examined. Thus, our study revealed several interesting differences in the cytokine profiles of mycobacterial antigen-stimulated LN cultures in LNTB+ and LNTB− individuals. Therefore, we suggest the presence of mycobacteria plays a significant role in driving the cytokine response at the site of infection in LNTB.