FasR Regulates Fatty Acid Biosynthesis and Is Essential for Virulence of Mycobacterium tuberculosis.
FasR Regulates Fatty Acid Biosynthesis and Is Essential for Virulence of Mycobacterium tuberculosis.
复制标题
DOI：
10.3389/fmicb.2020.586285
复制
发表时间：
2020
影响因子：
5.2
通讯作者：
Gago G
中科院分区：
文献类型：
--
作者：
Mondino S;Vázquez CL;Cabruja M;Sala C;Cazenave-Gassiot A;Blanco FC;Wenk MR;Bigi F;Cole ST;Gramajo H;Gago G
结核分枝杆菌是人类结核病的病原，是世界上导致传染病死亡的主要原因。这种病原体的主要特征之一是细胞包膜的复杂和动态的脂质组成，它通过积极地与免疫反应相互作用和调节来适应多变的宿主环境，并决定感染的命运。然而，尽管我们已经了解了许多脂质途径的酶，但对于结核分枝杆菌感染期间调节脂质代谢的蛋白质和代谢信号知之甚少。在这项工作中，我们构建并表征了结核分枝杆菌中FasR缺陷突变体，并证明FasR正调控fas和acpS的表达。野生型和突变株的脂质组学分析显示，细胞包膜的大多数脂质成分完全重排，磷脂、霉菌酸、亚脂和硫代酚二真菌酸酯的相对丰度严重改变。结果，突变株在巨噬细胞中的复制受损，导致小鼠感染模型中的毒力降低。此外，我们发现fasR突变存在于酸化的细胞室中，这表明由突变引起的脂质扰动阻止了结核分枝杆菌对吞噬溶酶体成熟的抑制。本研究发现FasR是一个参与分枝杆菌毒力调节的新因子，并为脂质稳态调节在结核分枝杆菌感染结果中的重要作用提供了证据。
Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the world’s leading cause of death from an infectious disease. One of the main features of this pathogen is the complex and dynamic lipid composition of the cell envelope, which adapts to the variable host environment and defines the fate of infection by actively interacting with and modulating immune responses. However, while much has been learned about the enzymes of the numerous lipid pathways, little knowledge is available regarding the proteins and metabolic signals regulating lipid metabolism during M. tuberculosis infection. In this work, we constructed and characterized a FasR-deficient mutant in M. tuberculosis and demonstrated that FasR positively regulates fas and acpS expression. Lipidomic analysis of the wild type and mutant strains revealed complete rearrangement of most lipid components of the cell envelope, with phospholipids, mycolic acids, sulfolipids, and phthiocerol dimycocerosates relative abundance severely altered. As a consequence, replication of the mutant strain was impaired in macrophages leading to reduced virulence in a mouse model of infection. Moreover, we show that the fasR mutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation prevented M. tuberculosis inhibition of phagolysosome maturation. This study identified FasR as a novel factor involved in regulation of mycobacterial virulence and provides evidence for the essential role that modulation of lipid homeostasis plays in the outcome of M. tuberculosis infection.
登录
查看更多内容
影响因子：
6.7
作者：
Astarie-Dequeker C;Le Guyader L;Malaga W;Seaphanh FK;Chalut C;Lopez A;Guilhot C
通讯作者：
Guilhot C
影响因子：
6.4
作者：
DeJesus MA;Gerrick ER;Xu W;Park SW;Long JE;Boutte CC;Rubin EJ;Schnappinger D;Ehrt S;Fortune SM;Sassetti CM;Ioerger TR
通讯作者：
Ioerger TR
影响因子：
3.6
作者：
Kolly, Gaelle S.;Boldrin, Francesca;Cole, Stewart T.
通讯作者：
Cole, Stewart T.
DOI：
10.1073/pnas.1707840114
发表时间：
2017-10-17
影响因子：
11.1
作者：
Blanc, Landry;Gilleron, Martine;Nigou, Jerome
通讯作者：
Nigou, Jerome
用于结核分枝杆菌化学分类学分析的比较脂质组学平台。
影响因子：
--
作者：
Layre E;Sweet L;Hong S;Madigan CA;Desjardins D;Young DC;Cheng TY;Annand JW;Kim K;Shamputa IC;McConnell MJ;Debono CA;Behar SM;Minnaard AJ;Murray M;Barry CE 3rd;Matsunaga I;Moody DB
通讯作者：
Moody DB