Elevated plasma matrix metalloproteinases associate with Mycobacterium tuberculosis blood stream infection and mortality in HIV-associated tuberculosis.

Mortality from HIV-associated tuberculosis (HIV-TB) is high, particularly among hospitalised patients. In 433 people living with HIV admitted to hospital with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality and Mycobacterium tuberculosis (Mtb) blood stream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10 and procollagen III N-terminal propeptide (PIIINP) associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.

Elevated Plasma Matrix Metalloproteinase 8 Associates With Sputum Culture Positivity in Pulmonary Tuberculosis.

Current methods for tuberculosis treatment monitoring are suboptimal. We evaluated plasma matrix metalloproteinase (MMP) and procollagen III N-terminal propeptide concentrations before and during tuberculosis treatment as biomarkers. Plasma MMP-1, MMP-8, and MMP-10 concentrations significantly decreased during treatment. Plasma MMP-8 was increased in sputum Mycobacterium tuberculosis culture-positive relative to culture-negative participants, before (median, 4993 pg/mL [interquartile range, 2542-9188] vs 698 [218-4060] pg/mL, respectively; P = .004) and after (3650 [1214-3888] vs 720 [551-1321] pg/mL; P = .008) 6 months of tuberculosis treatment. Consequently, plasma MMP-8 is a potential biomarker to enhance tuberculosis treatment monitoring and screen for possible culture positivity.

Matrix metalloproteinases in tuberculosis.

Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB.

Filter sterilization of highly infectious samples to prevent false negative analysis of matrix metalloproteinase activity.

Matrix metalloproteinases (MMPs) are implicated in the immunopathology of numerous infectious diseases. High risk samples such as those generated after infection with Mycobacterium tuberculosis require filter sterilization for safe analysis of MMP concentrations. Here, we report that commercial filter membranes may cause artefacts by binding MMPs. Anopore 0.2 microM membrane filtration reduced MMP-1 concentrations to undetectable levels by zymography and Western blotting. Polypropylene 0.45 microM filtration removed some MMP-1, while Polysulphone, Durapore and Bio-inert 0.2 microM membranes did not remove MMP-1. Anopore filtration also removed all MMP-7 and -9 activity, suggesting that the conserved MMP catalytic domain binds the membrane. This study demonstrates the importance of selecting the appropriate filter in MMP analysis to avoid incorrectly excluding MMP involvement in infection-related immunopathology.

Matrix metalloproteinases in destructive pulmonary pathology.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that have a number of important physiological roles including remodelling of the extracellular matrix, facilitating cell migration, cleaving cytokines, and activating defensins. However, excess MMP activity may lead to tissue destruction. The biology of MMP and the role of these proteases in normal pulmonary immunity are reviewed, and evidence that implicates excess MMP activity in causing matrix breakdown in chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), sarcoidosis, and tuberculosis is discussed. Evidence from both clinical studies and animal models showing that stromal and inflammatory cell MMP expression leads to immunopathology is examined, and the mechanisms by which excess MMP activity may be targeted to improve clinical outcomes are discussed.

The paradox of matrix metalloproteinases in infectious disease.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that perform multiple roles in the normal immune response to infection. MMPs facilitate leucocyte recruitment, cytokine and chemokine processing, defensin activation and matrix remodelling. However, excess MMP activity following infection may lead to immunopathology that causes host morbidity or mortality and favours pathogen dissemination or persistence. Here, we review the normal functions of MMPs in immunity and then discuss viral and bacterial infections where excess MMP activity has been implicated in pathology, specifically examining HIV, HTLV-1, hepatitis B, endotoxin shock, Helicobacter pylori and Mycobacterium tuberculosis. Tissue destruction may be exacerbated further by bacterial-derived enzymes which activate the host pro-MMPs. Finally, the potential for therapeutic targeting of excess MMP activity in infection is considered.

The effect of electromagnetic stimulation of the posterior parietal cortex on eye movements.

The posterior parietal cortex probably plays a central role in the sensorimotor transformations needed to make an accurate saccadic eye movement to a visual target. In an attempt to disrupt the normal programming of saccades, we magnetically stimulated the posterior parietal cortex in human volunteers, 80 ms after a small target moved 5 degrees horizontally from the centre of a VDU screen. Saccadic eye movements were recorded and experimental trials were compared with control, unstimulated trials. Magnetic stimulation was triggered in 70% of the trials selected randomly. The main effects of stimulation were: increased divergence of the eyes before each saccade, greater latency of saccade onset, and a tendency to undershoot the target. These results support the hypothesis that the posterior parietal cortex is involved in the programming of accurate saccades to visual targets.