Bone M Ashley, Wilk Aaron J, Perault Andrew I, Marlatt Sara A, Scheller Erich V, Anthouard Rebecca, Chen Qing, Stibitz Scott, Cotter Peggy A, Julio Steven M
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
Department of Biology, Westmont College, Santa Barbara, CA 93108.
Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1519-E1527. doi: 10.1073/pnas.1609565114. Epub 2017 Feb 6.
Bacterial pathogens coordinate virulence using two-component regulatory systems (TCS). The virulence gene (BvgAS) phosphorelay-type TCS controls expression of all known protein virulence factor-encoding genes and is considered the "master virulence regulator" in , the causal agent of pertussis, and related organisms, including the broad host range pathogen We recently discovered an additional sensor kinase, PlrS [for persistence in the lower respiratory tract (LRT) sensor], which is required for persistence in the LRT. Here, we show that PlrS is required for BvgAS to become and remain fully active in mouse lungs but not the nasal cavity, demonstrating that PlrS coordinates virulence specifically in the LRT. PlrS is required for LRT persistence even when BvgAS is rendered constitutively active, suggesting the presence of BvgAS-independent, PlrS-dependent virulence factors that are critical for bacterial survival in the LRT. We show that PlrS is also required for persistence of the human pathogen in the murine LRT and we provide evidence that PlrS most likely functions via the putative cognate response regulator PlrR. These data support a model in which PlrS senses conditions present in the LRT and activates PlrR, which controls expression of genes required for the maintenance of BvgAS activity and for essential BvgAS-independent functions. In addition to providing a major advance in our understanding of virulence regulation in , which has served as a paradigm for several decades, these results indicate the existence of previously unknown virulence factors that may serve as new vaccine components and therapeutic or diagnostic targets.
细菌病原体利用双组分调节系统（TCS）来协调毒力。毒力基因（BvgAS）磷酸化传递型TCS控制所有已知编码蛋白质毒力因子的基因的表达，被认为是百日咳病原体及其相关生物体（包括广泛宿主范围的病原体）中的“主要毒力调节因子”。我们最近发现了另一种传感激酶PlrS [用于在下呼吸道（LRT）中的持续性传感]，它是在LRT中持续性所必需的。在这里，我们表明PlrS是BvgAS在小鼠肺部而非鼻腔中变得并保持完全活性所必需的，这表明PlrS专门在LRT中协调毒力。即使BvgAS被组成性激活，PlrS对于LRT持续性也是必需的，这表明存在不依赖BvgAS、依赖PlrS的毒力因子，这些因子对于细菌在LRT中的存活至关重要。我们表明PlrS对于人类病原体在小鼠LRT中的持续性也是必需的，并且我们提供证据表明PlrS最有可能通过假定的同源反应调节因子PlrR发挥作用。这些数据支持了一个模型，其中PlrS感知LRT中存在的条件并激活PlrR，PlrR控制维持BvgAS活性和必需的不依赖BvgAS功能所需的基因的表达。除了在我们对几十年来一直作为范例的毒力调节的理解方面取得重大进展之外，这些结果还表明存在以前未知的毒力因子，这些因子可能作为新的疫苗成分以及治疗或诊断靶点。
