Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid utilization regulator.
Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid utilization regulator.
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结核分枝杆菌对胆固醇的反应通过脂质利用调节剂与环境 pH 值和钾水平相结合。
DOI：
10.1101/2023.08.22.554309
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Tan,Shumin
中科院分区：
文献类型：
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作者：
Chen,Yue;MacGilvary,NathanJ;Tan,Shumin
细菌对环境信号和营养源的反应如何整合到宿主定植中还知之甚少。利用基于细菌的筛选，我们发现结核分枝杆菌（Mtb）脂质利用调节剂的过表达改变了由低环境钾（K+）抑制的Mtb酸性pH响应。转录分析揭示了在胆固醇（感染期间Mtb的主要碳源）存在下Mtb对酸性pH的响应的扩增，反之亦然。引人注目的是，假定的脂质调节剂mce3R的缺失导致（i）在酸性pH下胆固醇响应的增强损失，以及（ii）胆固醇的低[K+]响应，对Mtb对每个信号的响应影响最小。最后，在用富含脂质的泡沫状巨噬细胞重现病变的鼠模型中，使p53 mce3R突变体的定殖减弱。这些发现揭示了细菌对环境和营养线索的反应之间的关键协调，并建立了Mce3R作为这一过程的关键整合者。
How bacterial response to environmental cues and nutritional sources may be integrated in enabling host colonization is poorly understood. Exploiting a reporter-based screen, we discovered that overexpression of Mycobacterium tuberculosis (Mtb) lipid utilization regulators altered Mtb acidic pH response dampening by low environmental potassium (K+). Transcriptional analyses unveiled amplification of Mtb response to acidic pH in the presence of cholesterol, a major carbon source for Mtb during infection, and vice versa. Strikingly, deletion of the putative lipid regulator mce3R resulted in loss of augmentation of (i) cholesterol response at acidic pH, and (ii) low [K+] response by cholesterol, with minimal effect on Mtb response to each signal individually. Finally, the ∆mce3R mutant was attenuated for colonization in a murine model that recapitulates lesions with lipid-rich foamy macrophages. These findings reveal critical coordination between bacterial response to environmental and nutritional cues, and establish Mce3R as a crucial integrator of this process.