Scientists claim the collagenase enzyme matrix metalloproteinase 1 (MMP-1) plays a key role in the immunmopathology of tuberculosis (TB). A team led by researchers at Imperial College London found increased levels of MMP-1 in the lungs of TB patients.
They further demonstrated that M. tuberculosis infection selectively upregulates MMP-1 gene expression and secretion in primary human monocytes. Moreover, Ro32-3555, a selective collagenase inhibitor that has been tested in human Phase III trials for a different disease, completely inhibited the activity of MMP-1 activity secreted by M. tuberculosis-infected primary human macrophages.
Their results are published in the Journal of Clinical Investigation in a paper titled “MMP-1 drives immunopathology in human tuberculosis and transgenic mice.”
Although the mechanisms by which M. tuberculosis evades the host immune response are becoming increasingly well understood, those by which the bacterium engages the immune response to drive tissue destruction and hence transmission are relatively poorly characterized, explain Paul Elkington, Ph.D., at Imperial’s department of infectious diseases and immunity, and colleagues.
To determine whether MMPs play a role in the immunopathology of TB, the scientists profiled MMPs and their natural tissue inhibitor of metalloproteinases (TIMPs) in sputum and bronchoalveolar lavage fluid from patients with TB and symptomatic controls. MMP-1 concentrations were significantly increased in both HIV-negative and HIV-positive patients with TB, while TIMP concentrations were lower in the same groups. Interestingly, there were no differences in the concentrations of TNF-α, IFN-γ, and IL-1b, which are key cytokines in the immune response, the researchers note.
In primary human monocytes, M. tuberculosis infection selectively upregulated MMP-1 gene expression and secretion. Significantly, Ro32-3555, a compound that has been used in Phase III clinical trials for arthritis, effectively suppressed M. tuberculosis-driven MMP-1 activity in infected primary human macrophages.
To test the effects of MMP-1 in vivo, the researchers used a mouse model. Mice do not naturally express the murine equivalent of MMP-1 in the lung, and mice infected with M. tuberculosis do not develop tissue destruction equivalent to that in infected humans. Dr. Elkington’s team therefore infected transgenic mice expressing human MMP-1 with M. tuberculosis to investigate whether MMP-1 caused lung immunopathology. They found that in the transgenic mice M. tuberculosis infection increased MMP-1 expression, and the alveolar walls were destroyed in areas of infection.
“Our data using what we believe to be a novel murine model of TB demonstrates a functional role for MMP-1 driving extracellular matrix remodeling in TB,” the authors conclude. “Targeting MMP-1 activity may reduce the pathology that results in the morbidity and mortality of TB.”