Biozentrum der Universität Basel, Basel, Switzerland.
PLoS One. 2010 Dec 8;5(12):e15159. doi: 10.1371/journal.pone.0015159.
Yersinia adhesin A (YadA) is an essential virulence factor for the food-borne pathogens Yersinia enterocolitica and Yersinia pseudotuberculosis. Surprisingly, it is a pseudogene in Yersinia pestis. Even more intriguing, the introduction of a functional yadA gene in Y. pestis EV76 was shown to correlate with a decrease in virulence in a mouse model. Here, we report that wild type (wt) Y. enterocolitica E40, as well as YadA-deprived E40 induced the synthesis of neutrophil extracellular traps (NETs) upon contact with neutrophils, but only YadA-expressing Y. enterocolitica adhered to NETs and were killed. As binding seemed to be a prerequisite for killing, we searched for YadA-binding substrates and detected the presence of collagen within NETs. E40 bacteria expressing V98D,N99A mutant YadA with a severely reduced ability to bind collagen were found to be more resistant to killing, suggesting that collagen binding contributes significantly to sensitivity to NETs. Wt Y. pestis EV76 were resistant to killing by NETs, while recombinant EV76 expressing YadA from either Y. pseudotuberculosis or Y. enterocolitica were sensitive to killing by NETs, outlining the importance of YadA for susceptibility to NET-dependent killing. Recombinant EV76 endowed with YadA from Y. enterocolitica were also less virulent for the mouse than wt EV76, as shown before. In addition, EV76 carrying wt YadA were less virulent for the mouse than EV76 expressing YadA(V₉₈D,N₉₉A). The observation that YadA makes Yersinia sensitive to NETs provides an explanation as for why evolution selected for the inactivation of yadA in the flea-borne Y. pestis and clarifies an old enigma. Since YadA imposes the same cost to the food-borne Yersinia but was nevertheless conserved by evolution, this observation also illustrates the duality of some virulence functions.
耶尔森氏菌黏附素 A (YadA) 是食源性病原体小肠结肠炎耶尔森氏菌和假结核耶尔森氏菌的必需毒力因子。令人惊讶的是，它是鼠疫耶尔森氏菌中的一个假基因。更有趣的是，在鼠疫耶尔森氏菌 EV76 中引入功能性 yadA 基因与在小鼠模型中降低毒力相关。在这里，我们报告野生型 (wt) 小肠结肠炎耶尔森氏菌 E40 以及缺乏 YadA 的 E40 在与中性粒细胞接触时会诱导中性粒细胞胞外陷阱 (NETs) 的合成，但只有表达 YadA 的小肠结肠炎耶尔森氏菌会附着在 NETs 上并被杀死。由于结合似乎是杀伤的先决条件，我们寻找 YadA 结合的底物，并在 NETs 中检测到胶原蛋白的存在。表达 V98D,N99A 突变 YadA 的 E40 细菌，其结合胶原蛋白的能力严重降低，发现对杀伤的抵抗力更强，表明胶原蛋白结合对 NETs 的敏感性有重要贡献。wt 鼠疫耶尔森氏菌 EV76 对 NETs 的杀伤具有抗性，而表达来自假结核耶尔森氏菌或小肠结肠炎耶尔森氏菌的 YadA 的重组 EV76 对 NETs 的杀伤敏感，这突显了 YadA 对 NET 依赖性杀伤的敏感性的重要性。正如之前所示，赋予源自小肠结肠炎耶尔森氏菌的 YadA 的重组 EV76 对小鼠的毒力也低于 wt EV76。此外，携带 wt YadA 的 EV76 对小鼠的毒力低于表达 YadA(V₉₈D,N₉₉A)的 EV76。YadA 使耶尔森氏菌易受 NETs 杀伤的观察结果为为什么进化选择在跳蚤传播的鼠疫耶尔森氏菌中使 yadA 失活提供了一个解释，并阐明了一个古老的谜团。由于 YadA 对食源性病原体耶尔森氏菌造成相同的代价，但仍被进化所保留，这一观察结果也说明了一些毒力功能的双重性。
