Decoration of the enterococcal polysaccharide antigen EPA is essential for virulence, cell surface charge and interaction with effectors of the innate immune system
Decoration of the enterococcal polysaccharide antigen EPA is essential for virulence, cell surface charge and interaction with effectors of the innate immune system
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DOI：
10.1371/journal.ppat.1007730
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发表时间：
2019-05-01
期刊：
影响因子：
6.7
通讯作者：
Mesnage, Stephane
中科院分区：
文献类型：
--
作者：
Smith, Robert E.;Salamaga, Bartlomiej;Mesnage, Stephane
粪肠球菌是一种机会致病菌，对先天免疫系统的关键效应物溶菌酶具有固有的高抗性。这种高水平的抗性需要转录调节因子和几个基因（oatA、pgdA、dltA和sigV）的复杂网络协同作用以抑制溶菌酶的酶促和阳离子抗微生物肽活性。我们试图确定新的基因调节E。粪菌对溶菌酶的抗性。随机转座子诱变中进行的四倍oatA/pgdA/dltA/sigV突变体导致几个独立的插入染色体上聚类的鉴定。这些突变位于被称为肠球菌多糖抗原（EPA）可变区的基因座中，所述可变区位于高度保守的epaA-epaR基因的下游，所述epaA-epaR基因被提议编码核心合成机制。EPA可变区以前被认为是负责EPA装饰，但这个位点的作用仍然在很大程度上未知。在这里，我们表明，EPA装饰有助于抵抗带电的抗菌剂，并通过赋予抵抗吞噬作用来支持斑马鱼感染模型中的毒力。总的来说，我们的结果表明EPA鼠李糖多糖骨架的产生不足以促进E。粪便感染，并揭示了这种表面聚合物的修饰对肠球菌发病机制的重要作用。
Enterococcus faecalis is an opportunistic pathogen with an intrinsically high resistance to lysozyme, a key effector of the innate immune system. This high level of resistance requires a complex network of transcriptional regulators and several genes (oatA, pgdA, dltA and sigV) acting synergistically to inhibit both the enzymatic and cationic antimicrobial peptide activities of lysozyme. We sought to identify novel genes modulating E. faecalis resistance to lysozyme. Random transposon mutagenesis carried out in the quadruple oatA/pgdA/dltA/sigV mutant led to the identification of several independent insertions clustered on the chromosome. These mutations were located in a locus referred to as the enterococcal polysaccharide antigen (EPA) variable region located downstream of the highly conserved epaA-epaR genes proposed to encode a core synthetic machinery. The epa variable region was previously proposed to be responsible for EPA decorations, but the role of this locus remains largely unknown. Here, we show that EPA decoration contributes to resistance towards charged antimicrobials and underpins virulence in the zebrafish model of infection by conferring resistance to phagocytosis. Collectively, our results indicate that the production of the EPA rhamnopolysaccharide backbone is not sufficient to promote E. faecalis infections and reveal an essential role of the modification of this surface polymer for enterococcal pathogenesis.