Slow growth of Mycobacterium tuberculosis at acidic pH is regulated by phoPR and host-associated carbon sources.
Slow growth of Mycobacterium tuberculosis at acidic pH is regulated by phoPR and host-associated carbon sources.
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DOI：
10.1111/mmi.12688
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发表时间：
2014-10
影响因子：
3.6
通讯作者：
Abramovitch RB
中科院分区：
文献类型：
--
作者：
Baker JJ;Johnson BK;Abramovitch RB
在发病过程中，结核分枝杆菌 (Mtb) 定植于酸性且富含胆固醇和脂肪酸的环境中，例如巨噬细胞或坏死肉芽肿。本研究的目的是研究酸性 pH 值和可用碳源如何相互作用来调节结核分枝杆菌生理机能。在这里，我们报道了 Mtb 在酸性 pH 下的生长需要宿主相关的碳源，这些碳源在糖酵解和 TCA 循环的交叉点发挥作用，例如丙酮酸、乙酸盐、草酰乙酸和胆固醇。相比之下，在其他测试的碳源中，Mtb 在酸性 pH 值下完全抑制其生长，并建立非复制持久性状态。通过添加丙酮酸可以使生长停滞的结核分枝杆菌恢复活力，这表明生长停滞是由于代谢中 pH 依赖性检查点造成的。此外，我们证明 phoPR 双组分调节系统是在酸性 pH 下减缓 Mtb 生长所必需的，并具有维持氧化还原稳态的功能。转录谱和功能代谢研究表明，来自酸性 pH 值和碳源的信号被整合以重塑与回补中枢代谢、脂质合成代谢和氧化辅因子再生相关的途径。由于 phoPR 是 Mtb 在动物中的毒力所必需的，因此我们认为 pH 驱动的适应可能对 Mtb 发病机制至关重要。
During pathogenesis, Mycobacterium tuberculosis (Mtb) colonizes environments, such as the macrophage or necrotic granuloma, that are acidic and rich in cholesterol and fatty acids. The goal of this study was to examine how acidic pH and available carbon sources interact to regulate Mtb physiology. Here we report that Mtb growth at acidic pH requires host-associated carbon sources that function at the intersection of glycolysis and the TCA cycle, such as pyruvate, acetate, oxaloacetate and cholesterol. In contrast, in other tested carbon sources, Mtb fully arrests its growth at acidic pH and establishes a state of non-replicating persistence. Growth-arrested Mtb is resuscitated by the addition of pyruvate suggesting that growth arrest is due to a pH-dependent checkpoint on metabolism. Additionally, we demonstrate that the phoPR two-component regulatory system is required to slow Mtb growth at acidic pH and functions to maintain redox homeostasis. Transcriptional profiling and functional metabolic studies demonstrate that signals from acidic pH and carbon source are integrated to remodel pathways associated with anaplerotic central metabolism, lipid anabolism and the regeneration of oxidized cofactors. Because phoPR is required for Mtb virulence in animals, we suggest that pH-driven adaptation may be critical to Mtb pathogenesis.
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影响因子：
--
作者：
Beste DJ;Nöh K;Niedenführ S;Mendum TA;Hawkins ND;Ward JL;Beale MH;Wiechert W;McFadden J
通讯作者：
McFadden J
影响因子：
3.2
作者：
Fisher, MA;Plikaytis, BB;Shinnick, TM
通讯作者：
Shinnick, TM
DOI：
10.1073/pnas.0610634104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Jain, Madhulika;Petzold, Christopher J.;Cox, Jeffery S.
通讯作者：
Cox, Jeffery S.
影响因子：
3.2
作者：
Chang, Jennifer C.;Miner, Maurine D.;Sherman, David R.
通讯作者：
Sherman, David R.
APRABC：结核分枝杆菌的复杂特异性基因座，可调节pH驱动的巨噬细胞吞噬体。
影响因子：
3.6
作者：
Abramovitch RB;Rohde KH;Hsu FF;Russell DG
通讯作者：
Russell DG