Question
1b. What is the background for doing this experiment?
Granulomas are hallmarks of pulmonary tuberculosis (TB) and traditionally viewed as host-protective structures. However, recent evidence suggest that Mycobacterium tuberculosis (Mtb) uses its virulence factors to stimulate the formation of granuloma. In the present study, we investigated the contribution of matrix metalloproteinases (MMPs), host enzymes that cause degradation of the extracellular matrix, to granuloma formation and bacterial load in Mtb-infected tissue. To this end, we used our lung tissue model for TB, which is based on human lung-derived cells and primary human monocyte-derived macrophages. Global inhibition of MMPs in the Mtb-infected tissue model reduced both granuloma formation and bacterial load. The infection caused upregulation of a set of MMPs (MMP1, 3, 9, and 12), and this finding could be validated in lung biopsies from patients with non-cavitary TB. Data from this study indicate that MMP activation contributes to early TB granuloma formation, suggesting that host-directed, MMP-targeted intervention could be considered as adjunct therapy to TB treatment. Keywords: matrix metalloproteinases, tuberculosis, tissue inhibitor of matrix metalloproteinases, tissue models, granuloma INTRODUCTION Immune responses in human tuberculosis (TB) are mainly studied in easily accessible peripheral blood samples, while the center of attention instead is staged in Mycobacterium tuberculosis (Mtb)-infected tissues where the granulomatous inflammation occurs. Granulomas are organized clusters of immune cells considered as pathological hallmarks at the site of Mtb infection, especially in human TB. Although it was initially anticipated that the function of the granuloma was solely to wall off the infection, it has become clear that early TB granuloma formation can instead favor dissemination of the bacteria in the tissue (Davis and Ramakrishnan, 2009). Consequently, late stage necrotic granulomas are a prerequisite for effective spread of Mtb in the local tissue environment (Pagan and Ramakrishnan, 2014). We and others have previously demonstrated that the ESX-1 gene-encoded ESAT-6 protein is essential for
Explanation / Answer
The objective of this paper is to study the role of Matrix matalloproteins (MMP &TIMP) in the formation of Mycobacterium tuberculi (Mtb) induced granuloma and dessemination of infection to surrounding tissues.The paper also aims to study whether inhibition of MMP could stop the growth of Mycobacterium tuberculi and granuloma formation in human beings .Assuch an anti TB drug could be developed.
b.A number of earlier research studies have reported that levels of MMPs are elevated in Serum,sputum,and lung fluid of TB patients and when such patients are treated with anti TB drugs, MMP levels decline.Some studies also suggest that MMPs cause dispersal of infected tissue to other parts of the body.It is in the backdrop of these studies that currrent study was carried out to unravel the actual role played by the MMPs in the granuloma formation and infection dispersal of Mycobacterim tuberculi.
