Chemical activation of adenylyl cyclase Rv1625c inhibits growth of Mycobacterium tuberculosis on cholesterol and modulates intramacrophage signaling.
Chemical activation of adenylyl cyclase Rv1625c inhibits growth of Mycobacterium tuberculosis on cholesterol and modulates intramacrophage signaling.
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DOI：
10.1111/mmi.13701
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发表时间：
2017-07
影响因子：
3.6
通讯作者：
McDonough KA
中科院分区：
文献类型：
--
作者：
Johnson RM;Bai G;DeMott CM;Banavali NK;Montague CR;Moon C;Shekhtman A;VanderVen B;McDonough KA
结核分枝杆菌（Mycobacterium tuberculosis，Mtb）通过一个复杂的3′-5′-cyclicAMP（cAMP）信号网络来感知和响应感染过程中所遇到的环境变化，因此cAMP信号的扰动可能被用来破坏Mtb的发病机制。然而，对cAMP信号通路的理解受到至少15种不同腺苷酸环化酶（AC）的存在的阻碍。最近，小分子V-58显示出抑制巨噬细胞内的Mtb复制并刺激Mtb中的cAMP产生。在这里，我们确定V-58快速和直接激活Mtb AC Rv 1625 c以产生高水平的cAMP，而不管细菌环境或生长培养基如何。V-58的代谢抑制在Mtb中是碳源依赖性的，并且在耻垢分枝杆菌中没有发生，这表明V-58介导的生长抑制是由于干扰特定的Mtb代谢途径而不是普遍的cAMP毒性。巨噬细胞内Mtb产生cAMP的化学刺激也引起巨噬细胞产生TNF-α的下调，表明cAMP在Mtb发病机制中的复杂作用。这些研究共同描述了一种靶向刺激Mtb中cAMP产生的新方法，并提供了对Mtb中cAMP信号传导的无数作用的新见解，特别是在Mtb与巨噬细胞的相互作用期间。
Mycobacterium tuberculosis (Mtb) uses a complex 3′-5′-cyclic AMP (cAMP) signaling network to sense and respond to changing environments encountered during infection, so perturbation of cAMP signaling might be leveraged to disrupt Mtb pathogenesis. However, understanding of cAMP signaling pathways is hindered by the presence of at least 15 distinct adenylyl cyclases (ACs). Recently, the small molecule V-58 was shown to inhibit Mtb replication within macrophages and stimulate cAMP production in Mtb. Here we determined that V-58 rapidly and directly activates Mtb AC Rv1625c to produce high levels of cAMP regardless of the bacterial environment or growth medium. Metabolic inhibition by V-58 was carbon source dependent in Mtb and did not occur in Mycobacterium smegmatis, suggesting that V-58-mediated growth inhibition is due to interference with specific Mtb metabolic pathways rather than a generalized cAMP toxicity. Chemical stimulation of cAMP production by Mtb within macrophages also caused down regulation of TNF-α production by the macrophages, indicating a complex role for cAMP in Mtb pathogenesis. Together these studies describe a novel approach for targeted stimulation of cAMP production in Mtb, and provide new insights into the myriad roles of cAMP signaling in Mtb, particularly during Mtb's interactions with macrophages.