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Early evolutionary loss of the lipid A modifying enzyme PagP resulting in innate immune evasion in Yersinia pestis.
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-09-15 , DOI: 10.1073/pnas.1917504117
Courtney E Chandler 1 , Erin M Harberts 1 , Mark R Pelletier 1 , Iyarit Thaipisuttikul 2 , Jace W Jones 3 , Adeline M Hajjar 4 , Jason W Sahl 5 , David R Goodlett 1, 6 , Aaron C Pride 7 , David A Rasko 8 , M Stephen Trent 9 , Russell E Bishop 10 , Robert K Ernst 11
Affiliation  

Immune evasion through membrane remodeling is a hallmark of Yersinia pestis pathogenesis. Yersinia remodels its membrane during its life cycle as it alternates between mammalian hosts (37 °C) and ambient (21 °C to 26 °C) temperatures of the arthropod transmission vector or external environment. This shift in growth temperature induces changes in number and length of acyl groups on the lipid A portion of lipopolysaccharide (LPS) for the enteric pathogens Yersinia pseudotuberculosis (Ypt) and Yersinia enterocolitica (Ye), as well as the causative agent of plague, Yersinia pestis (Yp). Addition of a C16 fatty acid (palmitate) to lipid A by the outer membrane acyltransferase enzyme PagP occurs in immunostimulatory Ypt and Ye strains, but not in immune-evasive Yp. Analysis of Yp pagP gene sequences identified a single-nucleotide polymorphism that results in a premature stop in translation, yielding a truncated, nonfunctional enzyme. Upon repair of this polymorphism to the sequence present in Ypt and Ye, lipid A isolated from a Yp pagP+ strain synthesized two structures with the C16 fatty acids located in acyloxyacyl linkage at the 2′ and 3′ positions of the diglucosamine backbone. Structural modifications were confirmed by mass spectrometry and gas chromatography. With the genotypic restoration of PagP enzymatic activity in Yp, a significant increase in lipid A endotoxicity mediated through the MyD88 and TRIF/TRAM arms of the TLR4-signaling pathway was observed. Discovery and repair of an evolutionarily lost lipid A modifying enzyme provides evidence of lipid A as a crucial determinant in Yp infectivity, pathogenesis, and host innate immune evasion.



中文翻译:

脂质A修饰酶PagP的早期进化损失导致鼠疫耶尔森氏菌先天免疫逃避。

通过膜重塑进行免疫逃逸是鼠疫耶尔森氏菌发病机理的标志。细菌在节肢动物传播媒介或外部环境的哺乳动物宿主(37°C)和环境温度(21°C至26°C)之间交替变化时,耶尔森氏菌会在其生命周期内重塑其膜。这种转变在上为肠病原体的脂多糖的脂质A部分(LPS)的酰基的数量和长度生长温度诱导的变化假结核耶尔森菌YPT)和小肠结肠炎耶尔森菌),以及鼠疫,的病原体耶尔森氏菌鼠疫YP)。外膜酰基转移酶PagP将C16脂肪酸(棕榈酸酯)加到脂质A中,发生在免疫刺激的YptYe菌株中,而发生在免疫逃逸的Yp中。对Yp pagP基因序列的分析确定了单核苷酸多态性,该多态性导致翻译的过早终止,产生了截短的无功能的酶。将此多态性修复为YptYe中存在的序列后,从Yp pagP +该菌株合成了两个结构,其中C16脂肪酸位于二葡糖胺骨架的2'和3'位置的酰氧基酰基键中。通过质谱和气相色谱法确认了结构修饰。随着Yp中PagP酶活性的基因型恢复,通过TLR4信号通路的MyD88和TRIF / TRAM臂介导的脂质A内毒素的显着增加。发现和修复进化上丢失的脂质A修饰酶可提供脂质A作为Yp感染性,发病机制和宿主先天性免疫逃避的关键决定因素的证据。

更新日期:2020-09-16
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