Effect of standard tuberculosis treatment on naive, memory and regulatory T-cell homeostasis in tuberculosis-diabetes co-morbidity

Perturbations in CD4(+) and CD8(+) T‐cell phenotype and function are hallmarks of tuberculosis–diabetes co‐morbidity. However, their contribution to the pathogenesis of this co‐morbidity and the effect of anti‐tuberculosis treatment on the phenotype of the T‐cell subsets is poorly understood. In this study, we examined the frequency of different T‐cell subsets in individuals with pulmonary tuberculosis (PTB) with diabetes mellitus (DM) or without coincident diabetes mellitus (NDM) before, during and after completion of anti‐tuberculosis chemotherapy. PTB‐DM is characterized by heightened frequencies of central memory CD4(+) and CD8(+) T cells and diminished frequencies of naive, effector memory and/or effector CD4(+) and CD8(+) T cells at baseline and after 2 months of treatment but not following treatment completion in comparison with PTB‐NDM. Central memory CD4(+) and CD8(+) T‐cell frequencies exhibited a positive correlation with fasting blood glucose and glycated haemoglobin A1c levels, whereas the frequencies of naive and effector memory or effector CD4(+) and CD8(+) T cells exhibited a negative correlation. However, the frequencies of CD4(+) and CD8(+) T‐cell subsets in individuals with PTB exhibited no significant relationship with bacterial burdens. Finally, although minor alterations in the T‐cell subset compartment were observed at 2 months of treatment, significantly decreased frequencies of central memory and significantly enhanced frequencies of naive CD4(+) and CD8(+) T cells were observed at the completion of treatment. Our data reveal a profound effect of coexistent diabetes on the altered frequencies of central memory, effector memory and naive T cells and its normalization following therapy

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

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

Plasma chemokines are biomarkers of disease severity, higher bacterial burden and delayed sputum culture conversion in pulmonary tuberculosis

Plasma cytokines are biomarkers of disease extent and mycobacterial burden in pulmonary tuberculosis (PTB). Whether chemokines can perform the same role in PTB is not known. We examined the plasma levels of chemokines in individuals with PTB, latent TB (LTB) or healthy controls (HC) and their association with disease severity and mycobacterial burdens in PTB. We also examined the chemokines in PTB individuals at the end of anti-tuberculous chemotherapy (ATT). PTB individuals exhibited significantly higher levels of CCL1, CCL3, CXCL1, CXCL2, CXCL9 and CXCL10 in comparison to LTB and/or HC individuals. PTB individuals with bilateral or cavitary disease displayed significantly elevated levels of CCL1, CCL3, CXCL1, CXCL10 and CXCL11 compared to those with unilateral or non-cavitary disease and also exhibited a significant positive relationship with bacterial burdens. In addition, PTB individuals with slower culture conversion displayed significantly elevated levels of CCL1, CCL3, CXCL1 and CXCL9 at the time of PTB diagnosis and prior to ATT. Finally, the chemokines were significantly reduced following successful ATT. Our data demonstrate that PTB is associated with elevated levels of chemokines, which are partially reversed followed chemotherapy. Our data demonstrate that chemokines are markers of disease severity, predicting increased bacterial burden and delayed culture conversion in PTB

Type 2 diabetes mellitus is associated with altered CD8+T and natural killer cell function in pulmonary tuberculosis

Type 2 diabetes mellitus (DM) is associated with expanded frequencies of mycobacterial antigen-specific CD4(+) T helper type 1 (Th1) and Th17 cells in individuals with active pulmonary tuberculosis (TB). No data are available on the role of CD8(+) T and natural killer (NK) cells in TB with coincident DM. To identify the role of CD8(+) T and NK cells in pulmonary TB with diabetes, we examined mycobacteria-specific immune responses in the whole blood of individuals with TB and DM (TB-DM) and compared them with those without DM (TB-NDM). We found that TB-DM is characterized by elevated frequencies of mycobacterial antigen-stimulated CD8(+) T cells expressing type 1 [interferon-γ and interleukin-2 (IL-2)] and type 17 (IL-17F) cytokines. We also found that TB-DM is characterized by expanded frequencies of TB antigen-stimulated NK cells expressing type 1 (tumour necrosis factor-α) and type 17 (IL-17A and IL-17F) cytokines. In contrast, CD8(+) T cells were associated with significantly diminished expression of the cytotoxic markers perforin, granzyme B and CD107a both at baseline and following antigen or anti-CD3 stimulation, while NK cells were associated with significantly decreased antigen-stimulated expression of CD107a only. This was not associated with alterations in CD8(+) T-cell or NK cell numbers or subset distribution. Therefore, our data suggest that pulmonary TB complicated with type 2 DM is associated with an altered repertoire of cytokine-producing and cytotoxic molecule-expressing CD8(+) T and NK cells, possibly contributing to increased pathology

IL‐27 and TGFβ mediated expansion of Th1 and adaptive regulatory T cells expressing IL‐10 correlates with bacterial burden and disease severity in pulmonary tuberculosis

CD4(+) T cell expression of IL-10 is an important mechanism controlling immunity to tuberculosis (TB). To identify the CD4(+) T cell subsets producing IL-10 in human TB, we enumerated the frequencies of IL-10 expressing CD4(+) T cell subsets following TB—antigen stimulation of cells from individuals with pulmonary (PTB) and latent TB (LTB). We first demonstrate that TB antigens induce an expansion of IL-10 expressing Th1 (IL-10(+), IFNγ(+), T-bet(+)), Th2 (IL-10(+), IL-4(+), GATA-3(+)), Th9 (IL-10(+), IL-9(+), IL-4(−)), Th17 (IL-10(+), IL-17(+), IFNγ(−)), and natural and adaptive regulatory T cells [nTregs; IL-10(+), CD4(+), CD25(+), Foxp3(+) and aTregs; IL-10 single(+), CD4(+), CD25(−), Foxp3(−)] in PTB and LTB individuals, with frequencies being significantly higher in the former. However, only Th1 cells and adaptive Tregs expressing IL-10 exhibit a positive relationship with bacterial burdens and extent of disease in PTB. Finally, we show that IL-27 and TGFβ play an important role in the regulation of IL-10(+) Th cell subsets. Thus, active PTB is characterized by an IL-27 and TGFβ mediated expansion of IL-10 expressing CD4(+) T cell subsets, with IL-10(+) Th1 and IL-10(+) aTreg cells playing a potentially pivotal role in the pathogenesis of active disease

Type 2 Diabetes Mellitus Coincident with Pulmonary Tuberculosis Is Associated with Heightened Systemic Type 1, Type 17, and Other Proinflammatory Cytokines

Rationale: Type 2 diabetes mellitus is a major risk factor for the development of active tuberculosis, although the biological basis underlying this susceptibility remains poorly characterized. Objectives and Methods: To identify the influence of coincident diabetes mellitus on cytokine levels in pulmonary tuberculosis, we examined circulating levels of a panel of cytokines and chemokines in the plasma of individuals with tuberculosis with diabetes and compared them with those of individuals without diabetes. Measurements and Main Results: Tuberculosis with diabetes is characterized by elevated circulating levels of type 1 (IFN-γ, tumor necrosis factor-α, and IL-2), type 2 (IL-5), and type 17 (IL-17A) cytokines but decreased circulating levels of IL-22. This was associated with increased systemic levels of other proinflammatory cytokines (IL-1β, IL-6, and IL-18) and an antiinflammatory cytokine (IL-10) but not type 1 IFNs. Moreover, tuberculosis antigen–stimulated whole blood also showed increased levels of proinflammatory cytokines. Finally, type 1 and type 17 cytokines in plasma exhibit a significant positive correlation with hemoglobin A1C levels, indicating that impaired control of diabetes is associated with this proinflammatory milieu. Multivariate analysis revealed that the association of proinflammatory cytokines with diabetes mellitus was not influenced by age, sex, or other metabolic parameters. Conclusions: Our data reveal that tuberculosis with diabetes is characterized by heightened cytokine responsiveness, indicating that chronic inflammation underlying type 2 diabetes potentially contributes to increased immune pathology and poor control in tuberculosis infection

Strongyloides stercoralis Coinfection Is Associated With Greater Disease Severity, Higher Bacterial Burden, and Elevated Plasma Matrix Metalloproteinases in Pulmonary Tuberculosis

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

Prime-Boost Vaccination With Covaxin/BBV152 Induces Heightened Systemic Cytokine and Chemokine Responses

Covaxin/BBV152 is a whole virion inactivated SARS-CoV-2 vaccine. The effect of prime-boost vaccination with Covaxin on systemic immune responses is not known. We investigated the effect of Covaxin on the plasma levels of a wide panel of cytokines and chemokines at baseline (M0) and at months 1 (M1), 2 (M2) and 3 (M3) following prime-boost vaccination in healthy volunteers. Our results demonstrate that Covaxin induces enhanced plasma levels of Type 1 cytokines (IFNγ, IL-2, TNFα), Type 2/regulatory cytokines (IL-4, IL-5, IL-10 and IL-13), Type 17 cytokine (IL-17A), other pro-inflammatory cytokines (IL-6, IL-12, IL-1α, IL-1β) and other cytokines (IL-3 and IL-7) but diminished plasma levels of IL-25, IL-33, GM-CSF and Type 1 IFNs. Covaxin also induced enhanced plasma levels of CC chemokine (CCL4) and CXC chemokines (CXCL1, CXCL2 and CX3CL1) but diminished levels of CXCL10. Covaxin vaccination induces enhanced cytokine and chemokine responses as early as month 1, following prime-boost vaccination, indicating robust activation of innate and adaptive immune responses in vaccine recipients

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

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

Inactivated COVID-19 vaccines: durability of Covaxin/BBV152 induced immunity against variants of concern

BACKGROUND: Covaxin/BBV152 is one of the most widely used vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and one of the few vaccines used extensively in low- and middle-income countries (LMIC). METHODS: We investigated the effect of Covaxin on the SARS-CoV-2 specific IgG and IgA and neutralizing antibody (NAb) levels at baseline (M0) and at Months 1 (M1), 2 (M2), 3 (M3), 4 (M4), 6 (M6) and 12 (M12) following vaccination in healthcare workers. In addition, we also examined the NAb levels against variant lineages of B.1.617.2 (Delta, India), B.1.617.2.1 (Delta Plus, India), B.1.351 (Beta, SA), B.1.1.7 (Alpha, UK) and B.1.1.529 (Omicron). RESULTS: Covaxin induces enhanced SARS-CoV-2 binding antibodies of IgG and IgA responses against both spike (S) and nucleocapsid (N) antigens at M1, M2, M3, M4, M6 and M12 in comparison with M0. Our data also reveal that NAb levels against the ancestral strain (Wuhan, wild type) are elevated and sustained at M1, M2, M3, M4, M6 and M12 in comparison with M0 and against variant lineages of B.1.617.2 (Delta, India), B.1.617.2.1 (Delta Plus, India), B.1.351 (Beta, SA) and B.1.1.7 (Alpha, UK) are elevated at M3, M6 and M12 in comparison with M0. However, NAb levels against B.1.1.529 (Omicron) was consistently below the limit of detection except at M12. CONCLUSION: Thus, Covaxin induces an enhanced humoral immune response, with persistence till at least 12 months post-vaccination against most SARS-CoV-2 variants