Search

Lymph node culture-positive tuberculosis (LNTB+) is associated with increased mycobacterial antigen-induced pro-inflammatory cytokine production compared to LN culture-negative tuberculosis (LNTB-). However, the frequencies of CD4+, CD8+ T cells and NK cells expressing Th1/Tc1/Type 1 (IFNγ, TNFα, IL-2), Th17/Tc17/Type 17 (IL-17A, IL-17F, IL-22) cytokines and cytotoxic (perforin [PFN], granzyme [GZE] B, CD107a) markers in LNTB+ and LNTB- individuals are not known. Thus, we have studied the unstimulated (UNS) and mycobacterial antigen-induced frequencies of CD4+, CD8+ T and NK cells expressing Th1, Th17 cytokines and cytotoxic markers using flow cytometry. The frequencies of CD4+, CD8+ T and NK cells expressing cytokines and cytotoxic markers were not significantly different between LNTB+ and LNTB- individuals in UNS condition. In contrast, upon Mtb antigen stimulation, LNTB+ individuals are associated with significantly increased frequencies of CD4+ T cells (PPD [IFNγ, TNFα], ESAT-6 PP [IFNγ, TNFα], CFP-10 PP [IFNγ, TNFα, IL-2]), CD8+ T cells (PPD [IFNγ], ESAT-6 PP [IFNγ], CFP-10 PP [TNFα]) and NK cells (PPD [IFNγ, TNFα], ESAT-6 PP [IFNγ, TNFα], CFP-10 PP [TNFα]) expressing Th1/Tc1/Type 1, but not Th17/Tc17/Type 17 cytokines and cytotoxic markers compared to LNTB- individuals. LNTB+ individuals did not show any significant alterations in the frequencies of CD4+, CD8+ T cells and NK cells expressing cytokines and cytotoxic markers compared to LNTB- individuals upon HIV Gag PP and P/I antigen stimulation. Increased frequencies of CD4+, CD8+ T and NK cells expressing Th1/Tc1/Type 1 cytokines among the LNTB+ group indicates that the presence of mycobacteria plays a dominant role in the activation of key correlates of immune protection or induces higher immunopathology. [ABSTRACT FROM AUTHOR]

Background: Diagnosing tuberculosis (TB) in children is challenging due to paucibacillary disease, and lack of ability for microbiologic confirmation. Hence, we measured the plasma chemokines as biomarkers for diagnosis of pediatric tuberculosis.Methods: We conducted a prospective case control study using children with confirmed, unconfirmed and unlikely TB. Multiplex assay was performed to examine the plasma CC and CXC levels of chemokines.Results: Baseline levels of CCL1, CCL3, CXCL1, CXCL2 and CXCL10 were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics curve analysis revealed that CCL1, CXCL1 and CXCL10 could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 80%. In addition, combiROC exhibited more than 90% sensitivity and specificity in distinguishing confirmed and unconfirmed TB from unlikely TB. Finally, classification and regression tree models also offered more than 90% sensitivity and specificity for CCL1 with a cutoff value of 28 pg/ml, which clearly classify active TB from unlikely TB. The levels of CCL1, CXCL1, CXCL2 and CXCL10 exhibited a significant reduction following anti-TB treatment.Conclusion: Thus, a baseline chemokine signature of CCL1/CXCL1/CXCL10 could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are crucial for tissue remodeling and repair and are expressed in diverse infections, whereas tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of MMPs. However, the interaction of MMPs and TIMPs in tuberculous lymphadenitis (TBL), an extra-pulmonary form of tuberculosis (EPTB) and helminth (Hel+) coinfection is not known. Therefore, this present study investigates the levels of circulating MMPs (1, 2, 3, 7, 8, 9, 12, 13) and TIMPs (1, 2, 3, 4) in TBL individuals with helminth (Strongyloides stercoralis [Ss], hereafter Hel+) coinfection and without helminth coinfection (hereafter, Hel-). In addition, we have also carried out the regression analysis and calculated the MMP/TIMP ratios between the two study groups. We describe that the circulating levels of MMPs (except MMP-8 and MMP-12) were elevated in TBL-Hel+ coinfected individuals compared to TBL-Hel- individuals. Similarly, the systemic levels of TIMPs (1, 2, 3, 4) were increased in TBL-Hel+ compared to TBL-Hel- groups indicating that it is a feature of helminth coinfection per se. Finally, our multivariate analysis data also revealed that the changes in MMPs and TIMPs were independent of age, sex, and culture status between TBL-Hel+ and TBL-Hel- individuals. We show that the MMP-2 ratio with all TIMPs were significantly associated with TBL-helminth coinfection. Thus, our results describe how helminth infection has a profound effect on the pathogenesis of TBL and that both MMPs and TIMPs could dampen the immunity against the TBL-Hel+ coinfected individuals. [ABSTRACT FROM AUTHOR]

Background: Neutrophils are important for host innate immune defense and mediate inflammatory responses. Pulmonary tuberculosis (PTB) is associated with increased neutrophil granular protein (NGP) levels in the circulation. However, the systemic levels of neutrophil granular proteins were not examined in tuberculous lymphadenitis (TBL) disease. Methods: We measured the systemic levels of NGP (myeloperoxidase [MPO], elastase and proteinase 3 [PRTN3]) in TBL and compared them to latent tuberculosis (LTB) and healthy control (HC) individuals. We also measured the pre-treatment (Pre-T) and post-treatment (Post-T) systemic levels of neutrophil granular proteins in TBL individuals upon anti-tuberculosis treatment (ATT) completion. In addition, we studied the correlation and discriminatory ability of NGPs using receiver operating characteristic (ROC) analysis. Results: Our data suggests that systemic levels of NGPs (MPO, PRTN3, elastase) were significantly reduced in TBL individuals compared to LTB and HC individuals. Similarly, after ATT, the plasma levels of MPO and elastase but not PRTN3 were significantly elevated compared to pre-treatment levels. NGPs (except PRTN3) were positively correlated with absolute neutrophil count of TBL, LTB and HC individuals. Further, NGPs were able to significantly discriminate TBL from LTB and HC individuals. Conclusion: Hence, we conclude reduced neutrophil granular protein levels might be associated with disease pathogenesis in TBL. [ABSTRACT FROM AUTHOR]

Pediatric TB poses challenge in diagnosis due to the paucibacillary nature of the disease. We conducted a prospective diagnostic study to identify immune biomarkers of pediatric TB and controls (discovery cohort) and obtained a separate "validation" cohort of confirmed cases of pediatric TB and controls. Multiplex ELISA was performed to examine the plasma levels of cytokines. Discovery and validation cohorts revealed that baseline plasma levels of IFNγ, TNFα, IL-2, and IL-17A were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics (ROC) curve analysis revealed that IFNγ, IL-2, TNFα, and IL-17A (in the discovery cohort) and TNFα and IL-17A (in the validation cohort) could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 90%. In the discovery cohort, cytokines levels were significantly diminished following anti-tuberculosis treatment. In both the cohorts, combiROC models offered 100% sensitivity and 98% to 100% specificity for a three-cytokine signature of TNFα, IL-2, and IL-17A, which can distinguish confirmed or unconfirmed TB children from unlikely TB. Thus, a baseline cytokine signature of TNFα, IL-2, and IL-17A could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Pulmonary tuberculosis (PTB) is characterized by elevated levels of acute phase proteins (APPs), but their association with tuberculous lymphadenitis (TBL) is poorly studied. Methods: We examined the systemic levels of APPs (alpha-2-macroglobulin [⍺-2MG], serum amyloid A [SAA], C-reactive protein [CRP] and haptoglobin [Hp]) in TBL, PTB, latent tuberculosis (LTB) and healthy controls (HC) at baseline and in TBL after the completion of anti-tuberculosis treatment (ATT). We have also examined the association of these proteins with lymph node (LN) size, culture grade and multiple versus single LN involvement. Results: TBL individuals exhibited increased systemic levels of ⍺-2MG, SAA, CRP and Hp in comparison to HCs and increased CRP levels in comparison to LTB individuals. TBL individuals also exhibited decreased systemic levels of Hp compared to PTB individuals. APPs were not significantly associated with LN size, LN involvement and culture grade, indicating a lack of association with disease severity. Following ATT, post-treatment levels of ⍺-2MG, CRP and Hp were significantly diminished compared to pre-treatment levels. Conclusion: TBL disease is characterized by altered levels of APPs at baseline and modulated following treatment, indicating the presence of systemic inflammation. [ABSTRACT FROM AUTHOR]

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Author summary: Strongyloides stercoralis (Ss) infects about 30–100 million people worldwide and it is the main causative agent of strongyloidiasis, a chronic parasitic infection. Similarly, tuberculosis (TB) affects nearly 2 billion people and both Ss and TB are co-endemic as well as share a major global disease burden. Earlier studies have revealed that helminth co-infection can modify the effect produced by the host immunity against Mycobacterium tuberculosis. However, no studies have examined the association of helminth co-infection with extra-pulmonary TB, especially in tuberculous lymphadenitis (TBL). In the present study, we have addressed this gap by measuring the cytokine profile in co-infected helminth-TBL individuals. Our study first shows that TBL-Ss+ co-infection is associated with "higher bacterial burden" in the affected lymph nodes. Our study also shows that co-infection is associated with alterations in plasma cytokines, specifically Type 2, regulatory and Type 17 cytokines were elevated and pro-inflammatory cytokines were reduced. Our study demonstrates significantly diminished unstimulated or TB—antigen stimulated levels of Type 1, Type 17 or IL-1 family of cytokines in TBL-Ss+ coinfected individuals. Hence, we conclude that helminth coinfection can possibly skew the protective immunity in TBL disease or infection. [ABSTRACT FROM AUTHOR]

B cell activating factor/a proliferation-inducing ligand (BAFF/APRIL) are members of the tumor necrosis factor alpha (TNF) α family of ligands, which are essential for B cell survival, development, and modulation of the immune system. To examine the association of circulating levels of BAFF and APRIL with pulmonary tuberculosis (PTB) and tuberculous lymphadenitis (TBL), we measured the systemic levels of APRIL and BAFF in individuals with PTB, TBL, latent tuberculosis (LTB) and healthy controls (HC). Further, we also examined the pre and post-treatment plasma levels of above-mentioned parameters in PTB and TBL individuals upon completion of anti-TB chemotherapy. Next, the association of these cytokines either with extent of disease, disease severity, bacterial burden in PTB and lymph node culture grade or the lymph node size in TBL was also assessed. Finally, ROC analysis was performed to examine the discrimination capacity of APRIL and BAFF between PTB or TBL with LTB. Our study revealed significantly diminished plasma levels of APRIL in PTB and higher plasma levels of BAFF in both PTB and TBL individuals compared to LTB and HC. Furthermore, we observed a significant increase in APRIL levels in TBL and significantly decreased plasma levels of BAFF in both PTB and TBL after the completion of successful anti-TB treatment. There was no statistically positive relationship between BAFF and APRIL levels and the extent of disease, disease severity and bacterial burden in PTB. In TBL, there was a significant correlation between APRIL (but not BAFF) levels with lymph node culture grades. In contrast, APRIL in PTB and BAFF in TBL were able to clearly discriminate from LTB in ROC analysis. In summary, our results showed altered levels of BAFF/APRIL and their modulation upon chemotherapy, suggesting that these cytokines might be involved in the immune-modulation of TB infection. [ABSTRACT FROM AUTHOR]

Background: Shortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India. Methods: Newly diagnosed, sputum-positive HIV-negative pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The Data and Safety Monitoring Board recommended termination of the trial due to high TB recurrence rates in the G and M regimens. Results: Of 416 patients in intent-to-treat analysis, 6 (5%) of 124, 2 (2%) of 110 and 2 (2%) of 137 patients with drug-susceptible TB in the G, M and C arms respectively had unfavorable response at the end of treatment; during the next 24 months, 17 (15%) of 115, 11 (11%) of 104 and 8 (6%) of 132 patients respectively, had TB recurrence. Of 38 drug-resistant patients 1 of 8 and 3 of 26 in the G and C arms respectively had unfavourable response at the end of treatment; and TB recurrence occurred in 2 of 7 and 2 of 23 patients, respectively. The differences in TB recurrence rates between the G and C arms was statistically significant (p = 0.02). Gastro-intestinal symptoms occurred in 23%, 22% and 9% of patients in the G, M and C arms respectively, but most reactions were mild and manageable with symptomatic measures; 1% required regimen modification. Conclusions: 4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampicin and pyrazinamide, were inferior to standard 6-month treatment, in patients with newly diagnosed sputum positive pulmonary TB. Trial Registration: Clinical Trials Registry of India CTRI/2012/10/003060 [ABSTRACT FROM AUTHOR]

The major human pathogen Mycobacterium tuberculosis is rarely reported to cause disease in other animals. Cases in livestock are thought to occur through contact with infected handlers, but previous studies evaluating putative livestock-human transmission used typing techniques with limited resolution. Here, we undertook cross-sectional surveillance for tuberculosis in 271 livestock handlers and 167 cattle on three farms in Chennai, India and defined the relatedness of cultured isolates using whole genome sequencing. Humans and livestock were screened for active mycobacterial infection, and opportunistic post-mortem examination was performed on comparative intradermal test-positive cattle that died. Four cattle and 6 handlers on two farms were culture-positive for M. tuberculosis; M. bovis was not isolated. All 10 isolates (one from each case) belonged to Lineage 1. Pairwise genome comparisons of single nucleotide polymorphism (SNP) differences ranged from 1 to 600 SNPs, but 3 isolate pairs were less than 5 SNPs different. Two pairs were from handlers and the third pair were from two cattle on the same farm. The minimum pairwise SNP difference between a cattle and human isolate was >250 SNPs. Our study confirms the presence of M. tuberculosis infection in cattle in India, sequencing of which characterised relatedness between human and cattle-derived isolates. [ABSTRACT FROM AUTHOR]