Listeria monocytogenes Strain-Specific Impairment of the TetR Regulator Underlies the Drastic Increase in Cyclic di-AMP Secretion and Beta Interferon-Inducing Ability
Listeria monocytogenes Strain-Specific Impairment of the TetR Regulator Underlies the Drastic Increase in Cyclic di-AMP Secretion and Beta Interferon-Inducing Ability
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DOI：
10.1128/iai.06162-11
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发表时间：
2012-07-01
影响因子：
3.1
通讯作者：
Kawamura, Ikuo
中科院分区：
文献类型：
--
作者：
Yamamoto, Takeshi;Hara, Hideki;Kawamura, Ikuo
在实验感染中使用的许多单核细胞增生李斯特菌实验室菌株中，菌株L0 28高度能够在感染的巨噬细胞中诱导稳健的β干扰素（IFN-β）产生。在这项研究中，我们研究了IFN-β诱导能力的分子机制，通过比较它与菌株EGD，一个低IFN-β诱导菌株。结果发现，LO 28分泌大量的IFN-β诱导因子，其被证明是环二AMP。环二AMP的分泌依赖于多药耐药转运蛋白MdrT，并且LO 28表现出非常高的mdrT表达水平。向mdrT中引入无效突变消除了L028诱导IFN-β产生的能力。对负责调节mdrT表达的基因的检查揭示了LO 28的tetR中自发的188-bp缺失。通过构建LO 28和EGD的重组菌株，其中来自每个菌株的tetR被替换，证实LO 28的独特能力主要归因于tetR突变。我们的结论是，强大的IFN-β诱导能力的LO 28是由于tetR的基因缺陷，导致mdrT的过度表达和伴随的增加，通过MdrT的分泌环二AMP。
Among a number of laboratory strains of Listeria monocytogenes used in experimental infection, strain LO28 is highly capable of inducing robust beta interferon (IFN-beta) production in infected macrophages. In this study, we investigated the molecular mechanism of the IFN-beta-inducing ability of LO28 by comparing it with that of strain EGD, a low-IFN-beta-inducing strain. It was found that LO28 secretes a large amount of IFN-beta-inducing factor, which turned out to be cyclic di-AMP. The secretion of cyclic di-AMP was dependent on MdrT, a multidrug resistance transporter, and LO28 exhibited a very high level of mdrT expression. The introduction of a null mutation into mdrT abolished the ability of LO28 to induce IFN-beta production. Examination of genes responsible for the regulation of mdrT expression revealed a spontaneous 188-bp deletion in tetR of LO28. By constructing recombinant strains of LO28 and EGD in which tetR from each strain was replaced, it was confirmed that the distinct ability of LO28 is attributable mostly to tetR mutation. We concluded that the strong IFN-beta-inducing ability of LO28 is due to a genetic defect in tetR resulting in the overexpression of mdrT and a concomitant increase in the secretion of cyclic di-AMP through MdrT.