Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.
Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.
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DOI：
10.1002/path.4432
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发表时间：
2015-02
影响因子：
7.3
通讯作者：
Bishai, William R.
中科院分区：
文献类型：
--
作者：
Kuebler, Andre;Luna, Brian;Larsson, Christer;Ammerman, Nicole C.;Andrade, Bruno B.;Orandle, Marlene;Bock, Kevin W.;Xu, Ziyue;Bagci, Ulas;Molura, Daniel J.;Marshall, John;Burns, Jay;Winglee, Kathryn;Ahidjo, Bintou Ahmadou;Cheung, Laurene S.;Klunk, Mariah;Jain, Sanjay K.;Kumar, Nathella Pavan;Babu, Subash;Sher, Alan;Friedland, Jon S.;Elkington, Paul T. G.;Bishai, William R.
活动性肺结核（TB）通常表现为晚期肺部疾病，包括不可逆的肺损伤和空洞。空洞性病变导致抗生素失效、传播、发病率和死亡率。基质金属蛋白酶（MMP），特别是MMP-1与TB发病机制有关。我们探讨了MMP/TIMP失衡与空洞形成的机制，在一个改进的兔模型空洞结核。我们的模型导致了一致的实变进展为类人腔（到第28天为100%），所产生的细菌负荷（>107 CFU/g）远远大于在匹配的肉芽肿组织中发现的那些（105 CFU/g）。使用一种新的，屏气计算机断层扫描和图像分析协议。我们发现，空洞发展迅速，从地区的密集巩固的组织。放射学变化与功能性肺组织减少相关，如通过控制肺扩张期间肺密度的变化所估计的（R2=0.6356，p<0.0001）。我们发现间质胶原酶（MMP-1）的表达在空洞性病变中比肉芽肿性病变中更高（p<0.01），而TIMP-3在空洞表面显著降低。我们的研究结果表明，MMP-1/TIMP失衡与合并区域向含有非常高的细菌负荷的空腔的进展有关。我们的模型提供了机制的见解，与人类疾病在病理学，微生物学和分子水平，。它还提供了一种策略，以研究在复杂的结核病病理学的背景下的治疗。我们使用这些发现来预测活动性TB中的MMP/TIMP平衡;并在人血浆中证实了这一点，揭示了MMP/TIMP水平作为旨在区分活动性TB和潜伏性TB的诊断矩阵的关键组分的潜力（PPV=92.9%; 95%CI 66.1- 99.8%，NPV=85.6%; 95%CI 77.0-91.9%）。
Active tuberculosis (TB) often presents with advanced pulmonary disease, including irreversible lung damage and cavities. Cavitary pathology contributes to antibiotic failure, transmission, morbidity and mortality. Matrix metalloproteinases (MMPs), in particular MMP-1 are implicated in TB pathogenesis. We explored the mechanisms relating MMP/TIMP imbalance to cavity formation in a modified rabbit model of cavitary TB. Our model results in consistent progression of consolidation to human-like cavities (100% by day 28) with resultant bacillary burdens (>107 CFU/g) far greater than those found in matched granulomatous tissue (105 CFU/g). Using a novel, breath-hold computerized tomography scanning and image analysis protocol. We show that cavities develop rapidly from areas of densely consolidated tissue. Radiological change correlated with a decrease in functional lung tissue as estimated by changes in lung density during controlled pulmonary expansion (R2=0.6356, p<0.0001). We demonstrated that the expression of interstitial collagenase (MMP-1) is specifically greater in cavitary compared to granulomatous lesions (p<0.01), and that TIMP-3 significantly decreases at the cavity surface. Our findings demonstrate that an MMP-1/TIMP imbalance, is associated with the progression of consolidated regions to cavities containing very high bacterial burdens. Our model provided mechanistic insight, correlating with human disease at the pathological, microbiological and molecular levels,. It also provides a strategy to investigate therapeutics in the context of complex TB pathology. We used these findings to predict a MMP/TIMP balance in active TB; and confirmed this in human plasma, revealing the potential of MMP/TIMP levels as key components of a diagnostic matrix aimed at distinguishing active from latent TB (PPV=92.9%; 95%CI 66.1–99.8%, NPV=85.6%; 95%CI 77.0–91.9%).
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影响因子：
4.2
作者：
Jassal MS;Nedeltchev GG;Osborne J;Bishai WR
通讯作者：
Bishai WR
影响因子：
3.2
作者：
Hunter, Robert L.;Jagannath, Chinnaswamy;Actor, Jeffrey K.
通讯作者：
Actor, Jeffrey K.
影响因子：
15.9
作者：
Elkington, Paul;Shiomi, Takayuki;Friedland, Jon S.
通讯作者：
Friedland, Jon S.
影响因子：
4.8
作者：
Cha J;Lee HY;Lee KS;Koh WJ;Kwon OJ;Yi CA;Kim TS;Chung MJ
通讯作者：
Chung MJ
影响因子：
6.4
作者：
Kunnath-Velayudhan, Shajo;Davidow, Amy L.;Gennaro, Maria L.
通讯作者：
Gennaro, Maria L.