199 results found
Brace PT, Tezera LB, Bielecka MK, et al., 2017, Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology, PLOS PATHOGENS, Vol: 13, ISSN: 1553-7366
Brilha S, Ong CWM, Weksler B, et al., 2017, Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis., Sci Rep, Vol: 7
Central nervous system tuberculosis (CNS TB) has a high mortality and morbidity associated with severe inflammation. The blood-brain barrier (BBB) protects the brain from inflammation but the mechanisms causing BBB damage in CNS TB are uncharacterized. We demonstrate that Mycobacterium tuberculosis (Mtb) causes breakdown of type IV collagen and decreases tight junction protein (TJP) expression in a co-culture model of the BBB. This increases permeability, surface expression of endothelial adhesion molecules and leukocyte transmigration. TJP breakdown was driven by Mtb-dependent secretion of matrix metalloproteinase (MMP)-9. TJP expression is regulated by Sonic hedgehog (Shh) through transcription factor Gli-1. In our model, the hedgehog pathway was downregulated by Mtb-stimulation, but Shh levels in astrocytes were unchanged. However, Scube2, a glycoprotein regulating astrocyte Shh release was decreased, inhibiting Shh delivery to brain endothelial cells. Activation of the hedgehog pathway by addition of a Smoothened agonist or by addition of exogenous Shh, or neutralizing MMP-9 activity, decreased permeability and increased TJP expression in the Mtb-stimulated BBB co-cultures. In summary, the BBB is disrupted by downregulation of the Shh pathway and breakdown of TJPs, secondary to increased MMP-9 activity which suggests that these pathways are potential novel targets for host directed therapy in CNS TB.
Brilha S, Sathyamoorthy T, Stuttaford LH, et al., 2017, Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 56, Pages: 223-232, ISSN: 1044-1549
Brilha S, Wysoczanski R, Whittington AM, et al., 2017, Monocyte Adhesion, Migration, and Extracellular Matrix Breakdown Are Regulated by Integrin alpha V beta 3 in Mycobacterium tuberculosis Infection, JOURNAL OF IMMUNOLOGY, Vol: 199, Pages: 982-991, ISSN: 0022-1767
Hargreaves S, Duarte R, Friedland JS, 2017, The role of pre-migration medical screening in high TB burden countries, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 21, Pages: 718-719, ISSN: 1027-3719
Hargreaves S, Lonnroth K, Nellums LB, et al., 2017, Multidrug-resistant tuberculosis and migration to Europe, CLINICAL MICROBIOLOGY AND INFECTION, Vol: 23, Pages: 141-146, ISSN: 1198-743X
Kirwan DE, Ugarte-Gil C, Gilman RH, et al., 2017, Histological Examination in Obtaining a Diagnosis in Patients with Lymphadenopathy in Lima, Peru., Am J Trop Med Hyg, Vol: 97, Pages: 1271-1276
The differential diagnosis for lymphadenopathy is wide and clinical presentations overlap, making obtaining an accurate diagnosis challenging. We sought to characterize the clinical and radiological characteristics, histological findings, and diagnoses for a cohort of patients with lymphadenopathy of unknown etiology. 121 Peruvian adults with lymphadenopathy underwent lymph node biopsy for microbiological and histopathological evaluation. Mean patient age was 41 years (Interquartile Range 26-52), 56% were males, and 39% were HIV positive. Patients reported fever (31%), weight loss (23%), and headache (22%); HIV infection was associated with fever (P < 0.05) and gastrointestinal symptoms (P < 0.05). Abnormalities were reported in 40% of chest X-rays (N = 101). Physicians suspected TB in 92 patients (76%), lymphoma in 19 patients (16%), and other malignancy in seven patients (5.8%). Histological diagnoses (N = 117) included tuberculosis (34%), hyperplasia (27%), lymphoma (13%), and nonlymphoma malignancy (14%). Hyperplasia was more common (P < 0.001) and lymphoma less common (P = 0.005) among HIV-positive than HIV-negative patients. There was a trend toward reduced frequency of caseous necrosis in samples from HIV-positive than HIV-negative TB patients (67 versus 93%, P = 0.055). The spectrum of diagnoses was broad, and clinical and radiological features correlated poorly with diagnosis. On the basis of clinical features, physicians over-diagnosed TB, and under-diagnosed malignancy. Although this may not be inappropriate in resource-limited settings where TB is the most frequent easily treatable cause of lymphadenopathy, diagnostic delays can be detrimental to patients with malignancy. It is important that patients with lymphadenopathy undergo a full diagnostic work-up including sampling for histological evaluation to obtain an accurate diagnosis.
Moores RC, Brilha S, Schutgens F, et al., 2017, Epigenetic Regulation of Matrix Metalloproteinase-1 and-3 Expression in Mycobacterium tuberculosis Infection, FRONTIERS IN IMMUNOLOGY, Vol: 8, ISSN: 1664-3224
Ong CWM, Pabisiak PJ, Brilha S, et al., 2017, Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis, JOURNAL OF NEUROINFLAMMATION, Vol: 14, ISSN: 1742-2094
Proano A, Bravard MA, Lopez JW, et al., 2017, Dynamics of Cough Frequency in Adults Undergoing Treatment for Pulmonary Tuberculosis, CLINICAL INFECTIOUS DISEASES, Vol: 64, Pages: 1174-1181, ISSN: 1058-4838
Saunders MJ, Wingfield T, Tovar MA, et al., 2017, A score to predict and stratify risk of tuberculosis in adult contacts of tuberculosis index cases: a prospective derivation and external validation cohort study, LANCET INFECTIOUS DISEASES, Vol: 17, Pages: 1190-1199, ISSN: 1473-3099
Singh S, Maniakis-Grivas G, Singh UK, et al., 2017, Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis., J Pathol
Tuberculosis (TB) is characterised by extensive pulmonary matrix breakdown. Interleukin-17 (IL-17) is key in host defence in TB but its role in TB-driven tissue damage is unknown. We investigated the hypothesis that respiratory stromal cell matrix metalloproteinase (MMP) production in TB is regulated by T helper-17 (TH -17) cytokines. Biopsies of patients with pulmonary TB were analysed by immunohistochemistry (IHC) and patient bronchoalveolar lavage fluid (BALF) MMP and cytokine concentrations measured by Luminex assays. Primary human airway epithelial cells were stimulated with conditioned medium from human monocytes infected with Mycobacterium tuberculosis (Mtb) and TH -17 cytokines. MMP secretion, activity and gene expression were determined by ELISA, Luminex assay, zymography, RT-qPCR and dual luciferase reporter assays. Signalling pathways were examined using phospho-western analysis and siRNA. IL-17 is expressed in TB patient granulomas and MMP-3 is expressed in adjacent pulmonary epithelial cells. IL-17 had a divergent, concentration-dependent effect on MMP secretion, increasing epithelial secretion of MMP-3 (p<0.001) over 72 h whilst decreasing that of MMP-9 (p<0.0001); mRNA levels were similarly affected. Both IL-17 and Interleukin-22 (IL-22) increased fibroblast Mtb-dependent MMP-3 secretion but IL-22 did not modulate epithelial MMP-3 expression. Both IL-17 and IL-22, but not Interleukin-23 (IL-23), were significantly upregulated in BALF from TB patients. IL-17-driven MMP-3 was dependent on p38 MAP kinase and the PI 3-K p110α subunit. In summary, IL-17 drives airway stromal cell-derived MMP-3, a mediator of tissue destruction in TB, alone and with monocyte-dependent networks in TB. This is regulated by p38 MAP kinase and PI3-K pathways.
Walker NF, Wilkinson KA, Meintjes G, et al., 2017, Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study, CLINICAL INFECTIOUS DISEASES, Vol: 65, Pages: 121-132, ISSN: 1058-4838
Dudley MZ, Sheen P, Gilman RH, et al., 2016, Detecting Mutations in the Mycobacterium tuberculosis Pyrazinamidase Gene pncA to Improve Infection Control and Decrease Drug Resistance Rates in Human Immunodeficiency Virus Coinfection, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, Vol: 95, Pages: 1239-1246
Hargreaves S, Nellums L, Friedland JS, 2016, Time to rethink approaches to migrant health screening, LANCET, Vol: 388, Pages: 2456-2457, ISSN: 0140-6736
Hargreaves S, Nellums L, Friedland JS, et al., 2016, Extending migrant charging into emergency services, BMJ-BRITISH MEDICAL JOURNAL, Vol: 352, ISSN: 1756-1833
Kubler A, Larsson C, Luna B, et al., 2016, Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis, JOURNAL OF INFECTIOUS DISEASES, Vol: 213, Pages: 618-627, ISSN: 0022-1899
Martin LJ, Roper MH, Grandjean L, et al., 2016, Rationing tests for drug-resistant tuberculosis - who are we prepared to miss?, BMC MEDICINE, Vol: 14, ISSN: 1741-7015
Proano A, Bravard MA, Tracey BH, et al., 2016, Protocol for studying cough frequency in people with pulmonary tuberculosis, BMJ OPEN, Vol: 6, ISSN: 2044-6055
Al Shammari B, Shiomi T, Tezera L, et al., 2015, The Extracellular Matrix Regulates Granuloma Necrosis in Tuberculosis, JOURNAL OF INFECTIOUS DISEASES, Vol: 212, Pages: 463-473, ISSN: 0022-1899
Elkington PT, Friedland JS, 2015, Permutations of time and place in tuberculosis, LANCET INFECTIOUS DISEASES, Vol: 15, Pages: 1357-1360, ISSN: 1473-3099
Kirwan D, Ugarte-Gil C, Gilman RH, et al., 2015, Microscopic Observation Drug Susceptibility Assay for Rapid Diagnosis of Lymph Node Tuberculosis and Detection of Drug Resistance, Journal of Clinical Microbiology, Vol: 54, Pages: 185-189, ISSN: 1098-660X
In the study, 132 patients with lymphadenopathy were investigated. 52 (39.4%) were diagnosed with TB. MODS provided rapid (13 days), accurate diagnosis (sensitivity 65.4%), and reliable DST. Despite lower sensitivity than other methods, faster results and simultaneous DST are advantageous in resource-poor settings, supporting incorporation of MODS into diagnostic algorithms for extrapulmonary TB.
Kuebler A, Luna B, Larsson C, et al., 2015, Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation, JOURNAL OF PATHOLOGY, Vol: 235, Pages: 431-444, ISSN: 0022-3417
Nathavitharana RR, Friedland JS, 2015, A tale of two global emergencies: tuberculosis control efforts can learn from the Ebola outbreak, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 293-296, ISSN: 0903-1936
Ong CWM, Elkington PT, Brilha S, et al., 2015, Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis, PLOS PATHOGENS, Vol: 11, ISSN: 1553-7366
Sathyamoorthy T, Sandhu G, Tezera LB, et al., 2015, Gender-Dependent Differences in Plasma Matrix Metalloproteinase-8 Elevated in Pulmonary Tuberculosis, PLOS ONE, Vol: 10, ISSN: 1932-6203
Sathyamoorthy T, Tezera LB, Walker NF, et al., 2015, Membrane Type 1 Matrix Metalloproteinase Regulates Monocyte Migration and Collagen Destruction in Tuberculosis, JOURNAL OF IMMUNOLOGY, Vol: 195, Pages: 882-891, ISSN: 0022-1767
Ugarte-Gil C, Elkington PT, Gotuzzo E, et al., 2015, Induced Sputum Is Safe and Well-Tolerated for TB Diagnosis in a Resource-Poor Primary Healthcare Setting, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, Vol: 92, Pages: 633-635, ISSN: 0002-9637
Brilha S, Ong CWM, Friedland JS, 2014, Matrix metalloproteinases cause blood-brain barrier disruption in central nervous system tuberculosis, 12th International Congress of Neuroimmunology (ISNI), Publisher: ELSEVIER SCIENCE BV, Pages: 27-27, ISSN: 0165-5728
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