Singh Vishal, Yeoh Beng San, Xiao Xia, Kumar Manish, Bachman Michael, Borregaard Niels, Joe Bina, Vijay-Kumar Matam
Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109-5602, USA.
Nat Commun. 2015 May 12;6:7113. doi: 10.1038/ncomms8113.
During an inflammatory response in the gut, some commensal bacteria such as E. coli can thrive and contribute to disease. Here we demonstrate that enterobactin (Ent), a catecholate siderophore released by E. coli, is a potent inhibitor of myeloperoxidase (MPO), a bactericidal enzyme of the host. Glycosylated Ent (salmochelin) and non-catecholate siderophores (yersiniabactin and ferrichrome) fail to inhibit MPO activity. An E. coli mutant (ΔfepA) that overproduces Ent, but not an Ent-deficient double mutant (ΔaroB/ΔfepA), inhibits MPO activity and exhibits enhanced survival in inflamed guts. This survival advantage is counter-regulated by lipocalin 2, a siderophore-binding host protein, which rescues MPO from Ent-mediated inhibition. Spectral analysis reveals that Ent interferes with compound I [oxoiron, Fe(IV)=O] and reverts the enzyme back to its native ferric [Fe(III)] state. These findings define a fundamental mechanism by which E. coli surpasses the host innate immune responses during inflammatory gut diseases and gains a distinct survival advantage.
在肠道的炎症反应过程中，一些共生细菌，如大肠杆菌，能够大量繁殖并引发疾病。在此我们证明，大肠杆菌释放的儿茶酚盐铁载体肠杆菌素（Ent）是宿主杀菌酶髓过氧化物酶（MPO）的强效抑制剂。糖基化的Ent（沙门菌素）和非儿茶酚盐铁载体（耶尔森菌素和铁色素）无法抑制MPO活性。过量产生Ent的大肠杆菌突变体（ΔfepA），而非Ent缺陷型双突变体（ΔaroB/ΔfepA），能够抑制MPO活性，并在发炎的肠道中表现出更强的生存能力。这种生存优势受到铁载体结合宿主蛋白lipocalin 2的反向调节，lipocalin 2能够使MPO免受Ent介导的抑制。光谱分析表明，Ent会干扰化合物I [氧代铁，Fe(IV)=O]，并使该酶恢复到天然的三价铁[Fe(III)]状态。这些发现确定了一种基本机制，通过该机制大肠杆菌在炎症性肠道疾病期间超越宿主先天免疫反应并获得独特的生存优势。
