当前位置:科学网首页 > 小柯机器人 >详情
mTOR调控的线粒体代谢限制分枝杆菌诱导的细胞毒性
作者:小柯机器人 发布时间:2022/9/18 16:46:31

英国剑桥大学Lalita Ramakrishnan、Antonio J. Pagán等研究人员合作发现,mTOR调控的线粒体代谢限制分枝杆菌诱导的细胞毒性。该研究于2022年9月13日在线发表于国际一流学术期刊《细胞》。

通过斑马鱼的正向遗传筛选,研究人员发现mTOR激酶,一个代谢的主调控器,是结核病的早期宿主抵抗因素。研究人员发现,mTOR复合体1通过使感染诱导的线粒体能量代谢增加,并以糖酵解为燃料,保护巨噬细胞免受分枝杆菌诱导的死亡。这些代谢适应性是防止线粒体损伤和由分泌的分枝杆菌毒力决定因子ESAT-6引起的死亡所需的。因此,宿主只需通过调节能量代谢就可以有效地对抗这种早期关键的分枝杆菌毒力机制,从而使病原体特异性免疫机制有时间发展。这些发现可能解释了为什么结核分枝杆菌尽管是人类最致命的病原体,但只在少数感染者中致病。

据介绍,肉芽肿中巨噬细胞的坏死,是结核病的标志性免疫结构,也是增加宿主易感性的一个主要致病事件。

附:英文原文

Title: mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity

Author: Antonio J. Pagán, Lauren J. Lee, Joy Edwards-Hicks, Cecilia B. Moens, David M. Tobin, Elisabeth M. Busch-Nentwich, Erika L. Pearce, Lalita Ramakrishnan

Issue&Volume: 2022-09-13

Abstract: Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity’s most lethal pathogen, is successful in only a minority of infected individuals.

DOI: 10.1016/j.cell.2022.08.018

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01112-6

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/