Mondino Sonia, Vázquez Cristina L, Cabruja Matías, Sala Claudia, Cazenave-Gassiot Amaury, Blanco Federico C, Wenk Markus R, Bigi Fabiana, Cole Stewart T, Gramajo Hugo, Gago Gabriela
Laboratory of Physiology and Genetics of Actinomycetes, Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET), Universidad Nacional de Rosario, Rosario, Argentina.
Instituto de Biotecnología-IABIMO (INTA-CONICET), Hurlingham, Argentina.
Front Microbiol. 2020 Oct 27;11:586285. doi: 10.3389/fmicb.2020.586285. eCollection 2020.
, 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 infection. In this work, we constructed and characterized a FasR-deficient mutant in and demonstrated that FasR positively regulates and 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 mutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation prevented 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 infection.
人类结核病的病原体结核分枝杆菌是全球因传染病导致死亡的主要原因。这种病原体的主要特征之一是细胞包膜复杂且动态的脂质组成，它能适应多变的宿主环境，并通过与免疫反应积极相互作用和调节来决定感染的结局。然而，尽管我们对众多脂质途径中的酶已有很多了解，但对于感染期间调节脂质代谢的蛋白质和代谢信号却知之甚少。在这项研究中，我们构建并鉴定了结核分枝杆菌中FasR缺陷型突变体，并证明FasR正向调节[具体基因1]和[具体基因2]的表达。对野生型和突变株的脂质组分析显示，细胞包膜的大多数脂质成分发生了完全重排，磷脂、分枝菌酸、硫脂和结核菌醇二霉菌酸酯的相对丰度严重改变。因此，突变株在巨噬细胞中的复制受到损害，导致感染小鼠模型中的毒力降低。此外，我们发现突变株存在于酸化的细胞区室中，这表明突变引起的脂质紊乱阻止了结核分枝杆菌对吞噬溶酶体成熟的抑制。本研究确定FasR是参与调节结核分枝杆菌毒力的一个新因子，并为脂质稳态调节在结核分枝杆菌感染结局中所起的关键作用提供了证据。
