Inhibition of Tissue Matrix Metalloproteinases Interferes with Mycobacterium tuberculosis-Induced Granuloma Formation and Reduces Bacterial Load in a Human Lung Tissue Model.
Inhibition of Tissue Matrix Metalloproteinases Interferes with Mycobacterium tuberculosis-Induced Granuloma Formation and Reduces Bacterial Load in a Human Lung Tissue Model.
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DOI：
10.3389/fmicb.2017.02370
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发表时间：
2017
影响因子：
5.2
通讯作者：
Lerm M
中科院分区：
文献类型：
--
作者：
Parasa VR;Muvva JR;Rose JF;Braian C;Brighenti S;Lerm M
肉芽肿是肺结核（TB）的标志，传统上被视为宿主保护性结构。然而，最近的证据表明，结核分枝杆菌（Mtb）利用其毒力因子刺激肉芽肿的形成。在本研究中，我们研究了基质金属蛋白酶（MMPs），宿主酶，导致细胞外基质的降解，肉芽肿的形成和结核分枝杆菌感染的组织中的细菌负荷的贡献。为此，我们使用我们的肺组织模型用于TB，其基于人肺衍生的细胞和原代人单核细胞衍生的巨噬细胞。在结核分枝杆菌感染的组织模型中，MMPs的整体抑制减少了肉芽肿形成和细菌负荷。感染引起一组MMP（MMP 1，3，9和12）的上调，这一发现可以在非空洞性TB患者的肺活检中得到验证。这项研究的数据表明，MMP激活有助于早期结核肉芽肿的形成，这表明宿主导向的MMP靶向干预可以被认为是结核治疗的辅助治疗。
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.