Negative regulation of Salmonella pathogenicity island 2 is required for contextual control of virulence during typhoid
Negative regulation of Salmonella pathogenicity island 2 is required for contextual control of virulence during typhoid
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DOI：
10.1073/pnas.0505401102
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发表时间：
2005-11-29
影响因子：
11.1
通讯作者：
Finlay, BB
中科院分区：
文献类型：
--
作者：
Coombes, BK;Wickham, ME;Finlay, BB
伤寒期间，肠沙门氏菌依靠沙门氏菌致病性岛-2 （SPI-2）编码的III型分泌系统在巨噬细胞内存活和复制。SPI-2毒力在进入巨噬细胞后被诱导，但SPI-2基因在体内的控制机制尚不清楚，特别是关于控制SPI-2上下文激活的负调节因子。在这里，我们确定并表征了YdgT作为SPI-2致病性岛的负调节因子，并确定这种负调节对全身发病至关重要，因为过度表达伤寒毒力基因的YdgT突变体在感染过程中最终被减弱。在体内竞争性感染期间，ydgT突变体表现出双相毒力表型，包括依赖于SPI-2激活的早期“毒力获得”，随后在感染后期减弱，这表明ydgT对SPI-2的适当上下文调节是系统定植过程中完全毒力的必要条件。这些数据表明，毒力相关的III型分泌基因的过表达可能对细菌在体内的发病机制产生不利影响。
Salmonella enterica relies on a type III secretion system encoded in Salmonella pathogenicity island-2 (SPI-2) to survive and replicate within macrophages at systemic sites during typhoid. SPI-2 virulence is induced upon entry into macrophages, but the mechanisms of SPI-2 gene control in vivo remain unclear, particularly with regard to negative regulators that control the contextual activation of SPI-2. Here, we identified and characterized YdgT as a negative modulator of the SPI-2 pathogenicity island and established that this negative regulation is central to systemic pathogenesis because ydgT mutants overexpressing typhoid virulence genes were ultimately attenuated during infection. ydgT mutants displayed a biphasic virulence phenotype during in vivo competitive infections that consisted of an early "gain-of-virulence" dependent on SPI-2 activation, followed by attenuation later in infection indicating that proper contextual regulation of SPI-2 by YdgT is necessary for full virulence during systemic colonization. These data suggest that overexpression of virulence-associated type III secretion genes can have an adverse effect on bacterial pathogenesis in vivo.