Bacteriophage-resistant mutants in Yersinia pestis: identification of phage receptors and attenuation for mice.
Bacteriophage-resistant mutants in Yersinia pestis: identification of phage receptors and attenuation for mice.
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DOI：
10.1371/journal.pone.0025486
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nikolich MP
中科院分区：
文献类型：
--
作者：
Filippov AA;Sergueev KV;He Y;Huang XZ;Gnade BT;Mueller AJ;Fernandez-Prada CM;Nikolich MP
鼠疫耶尔森氏菌特异性噬菌体通常用于鼠疫诊断，并可在耐药性鼠疫的情况下替代抗生素。噬菌体治疗的一个主要问题是噬菌体抗性突变体的出现。使用噬菌体混合物可以克服这个问题，但前提是噬菌体利用不同的受体。一些噬菌体抗性突变体失去了毒力，因此不应该使噬菌体治疗复杂化。这项工作的目的是确定Y。鼠疫噬菌体受体的定点突变和反式互补，并确定潜在的衰减噬菌体抗性突变体的小鼠。在脂多糖（LPS）内外核的不同部位发现了8种受体。R噬菌体的受体位于LPS核心之外。大多数自发的和确定的抗噬菌体突变的Y。鼠疫菌被减毒，显示LD 50和死亡时间增加。不同LPS核心生物合成酶的缺失导致Y.核心截短程度与对鼠疫毒力的影响存在相关性。yrbH和waaA突变体完全失去了它们的毒力。我们确定了Y。八种噬菌体的鼠疫受体。九个字母加在一起至少使用七个不同的Y。鼠疫受体，使其中一些有希望配制鼠疫治疗鸡尾酒。大多数抗噬菌体的Y.鼠疫突变体变得减毒，因此对于鼠疫的噬菌体治疗不应构成严重问题。LPS是Y.鼠疫
Bacteriophages specific for Yersinia pestis are routinely used for plague diagnostics and could be an alternative to antibiotics in case of drug-resistant plague. A major concern of bacteriophage therapy is the emergence of phage-resistant mutants. The use of phage cocktails can overcome this problem but only if the phages exploit different receptors. Some phage-resistant mutants lose virulence and therefore should not complicate bacteriophage therapy. The purpose of this work was to identify Y. pestis phage receptors using site-directed mutagenesis and trans-complementation and to determine potential attenuation of phage-resistant mutants for mice. Six receptors for eight phages were found in different parts of the lipopolysaccharide (LPS) inner and outer core. The receptor for R phage was localized beyond the LPS core. Most spontaneous and defined phage-resistant mutants of Y. pestis were attenuated, showing increase in LD50 and time to death. The loss of different LPS core biosynthesis enzymes resulted in the reduction of Y. pestis virulence and there was a correlation between the degree of core truncation and the impact on virulence. The yrbH and waaA mutants completely lost their virulence. We identified Y. pestis receptors for eight bacteriophages. Nine phages together use at least seven different Y. pestis receptors that makes some of them promising for formulation of plague therapeutic cocktails. Most phage-resistant Y. pestis mutants become attenuated and thus should not pose a serious problem for bacteriophage therapy of plague. LPS is a critical virulence factor of Y. pestis.