Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity.
Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity.
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结核分枝杆菌是一种主要的人类病原体和结核病的病原体。M.结核病能够在宿主衍生的抗微生物分子一氧化氮（NO）和铜（Cu）的作用下持续存在。然而，M。具有缺陷蛋白酶体活性的结核病对NO和Cu高度敏感，使得蛋白酶体成为药物开发的有吸引力的靶点。先前的工作将NO敏感性与M中对羟基苯甲醛（pHBA）的积累联系起来。蛋白酶体降解缺陷的结核病突变体。在这项研究中，我们发现，pHBA的积累也负责在这些菌株中的铜敏感性。我们发现，外源添加pHBA到野生型M。结核培养物使细菌对Cu敏感到与蛋白酶体降解突变体相似的程度。我们确定pHBA减少了铜抑制子（RicR）调节子中关键铜抗性蛋白的产生和功能。此外，我们将这些Cu增敏效应扩展到M。肺结核可能面临的巨噬细胞内。总的来说，这项研究是第一个机械地提出醛如何使M。结核病易受现有宿主防御的影响，并可能支持醛在控制M.肺结核感染。M.结核病是单一传染性病原体造成的主要死亡原因，每年造成150万人死亡。一种有效的M.目前缺乏结核病感染，并且先前的感染通常不能提供对随后感染的强大免疫力。尽管如此，有免疫能力的人可以控制M。结核病感染几十年。由于这些原因，有必要清楚地了解哺乳动物免疫如何抑制分枝杆菌的生长。在这项研究中，我们发现醛可以增加M。结核杆菌对铜的敏感性，铜是免疫细胞用来控制结核杆菌的一种确定的抗菌金属。结核病和其他微生物。鉴于活化的巨噬细胞在感染过程中产生更多的醛，我们建议宿主衍生的醛可能有助于控制细菌感染，使醛成为以前不受重视的抗菌防御。
Mycobacterium tuberculosis is a major human pathogen and the causative agent of tuberculosis disease. M. tuberculosis is able to persist in the face of host-derived antimicrobial molecules nitric oxide (NO) and copper (Cu). However, M. tuberculosis with defective proteasome activity is highly sensitive to NO and Cu, making the proteasome an attractive target for drug development. Previous work linked NO susceptibility with the accumulation of para-hydroxybenzaldehyde (pHBA) in M. tuberculosis mutants with defective proteasomal degradation. In this study, we found that pHBA accumulation was also responsible for Cu sensitivity in these strains. We showed that exogenous addition of pHBA to wild-type M. tuberculosis cultures sensitized bacteria to Cu to a degree similar to that of a proteasomal degradation mutant. We determined that pHBA reduced the production and function of critical Cu resistance proteins of the regulated in copper repressor (RicR) regulon. Furthermore, we extended these Cu-sensitizing effects to an aldehyde that M. tuberculosis may face within the macrophage. Collectively, this study is the first to mechanistically propose how aldehydes can render M. tuberculosis susceptible to an existing host defense and could support a broader role for aldehydes in controlling M. tuberculosis infections. M. tuberculosis is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for M. tuberculosis infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control M. tuberculosis infections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increase M. tuberculosis susceptibility to copper, an established antibacterial metal used by immune cells to control M. tuberculosis and other microbes. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes may help control bacterial infections, making aldehydes a previously unappreciated antimicrobial defense.
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影响因子：
3.6
作者：
Chawla M;Parikh P;Saxena A;Munshi M;Mehta M;Mai D;Srivastava AK;Narasimhulu KV;Redding KE;Vashi N;Kumar D;Steyn AJ;Singh A
通讯作者：
Singh A
DOI：
10.1073/pnas.1423319112
发表时间：
2015-04-07
影响因子：
11.1
作者：
Jastrab, Jordan B.;Wang, Tong;Darwin, K. Heran
通讯作者：
Darwin, K. Heran
影响因子：
56.9
作者：
Darwin, KH;Ehrt, S;Nathan, CF
通讯作者：
Nathan, CF
影响因子：
2.8
作者：
Bardarov, S;Bardarov, S;Jacobs, WR
通讯作者：
Jacobs, WR
影响因子：
6.4
作者：
通讯作者：
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