Bile, Biofilms and Salmonella Gallbladder Carriage

描述（由申请方提供）：伤寒沙门氏菌感染可导致人胆囊慢性、相对无症状感染。S.伤寒带菌者是伤寒在人与人之间传播的主要原因。胆囊是胆汁的储存场所，胆汁是一种具有洗涤剂性质的抗菌物质。我们已经表明，胆汁影响许多沙门氏菌蛋白质的表达，包括参与与毒力相关的几种表型（例如上皮细胞侵袭、运动性、抗菌剂/胆汁抗性）的蛋白质。因此，感知和响应胆汁的能力可能是沙门氏菌建立慢性携带者状态所必需的重要属性。此外，人类胆囊异常（特别是胆结石）与沙门氏菌携带状态的发展之间存在高度相关性。我们以前已经证明，沙门氏菌在体外人胆结石表面形成生物膜，并表征了参与这一过程的许多微生物因素。在目标1中，最近确定的胆汁调节基因，包括那些参与宿主细胞侵袭和抗微生物/胆汁抗性的基因，将用于揭示独特的胆汁响应性感觉/调节途径。在目标2中，我们将通过研究在鲑鱼和胆结石的独特关系中发挥作用的微生物因子（细胞外基质）和胆结石因子，进一步表征胆囊承载的建立。我们还将探讨的假设，除了胆结石生物膜，胆囊上皮细胞的侵袭和生物膜的形成在载体的发展中发挥了作用。最后，我们将检验我们的假设和体外研究通过检查胆结石，胆囊组织和胆汁从人类载体。目的1和2的结果将提供关于细菌与胆囊环境（胆汁和胆结石）在建立这种慢性感染时的相互作用的信息。所获得的知识可能建议治疗或预防方法来干扰胆汁抵抗，胆汁感应或生物膜形成，这可以消除胆结石携带并显着限制这种生物体的传播。 公众描述：伤寒可导致沙门氏菌的无症状携带和脱落。携带的主要位置是胆囊，但很少有人知道沙门氏菌是如何引起这个器官的慢性感染的。我们假设，胆汁盐信号的细菌，使其适应胆囊中的生活，包括增强的殖民/生物膜的能力和降低的侵袭性的表型变化。我们打算研究沙门氏菌胆汁信号，以及胆汁对胆结石生物膜和胆囊上皮细胞体外侵袭力的影响。计划中的实验还包括研究我们对人类携带者的假设的实验。

DESCRIPTION (provided by applicant): Infection with Salmonella typhi can cause a chronic, relatively asymptomatic infection of the human gallbladder. S. typhi carriers are responsible for much of the human-to-human spread of typhoid fever. The gallbladder is the storage site for bile, an antimicrobial substance with detergent-like properties. We have shown that bile affects the expression of a number of Salmonella proteins including those involved in several phenotypes associated with virulence (e.g. epithelial cell invasion, motility, antimicrobial/bile resistance). Therefore, the ability to sense and respond to bile is likely an important attribute of Salmonella necessary to establish a chronic carrier state. In addition, a high correlation exists between human gallbladder abnormalities (especially gallstones) and the development of the Salmonella carrier state. We have previously demonstrated that salmonellae form a biofilm on the surface of human gallstones in vitro, and have characterized numerous microbial factors involved in this process. In Aim 1, recently identified bile-regulated genes, including those involved in host cell invasion and antimicrobial/bile resistance will be used to uncover unique bile-responsive sensory/regulatory pathways. In Aim 2, we will further characterize the establishment of gallbladder carriage with the study of microbial factors (extracellular matrix) and gallstone factors that play a role in the unique relationship of salmonellae and gallstones. We will also explore the hypothesis that, in addition to gallstone biofilms, invasion of and biofilm formation on the gallbladder epithelium plays a role in carrier development. Finally, we will test our hypotheses and in vitro studies by examining gallstones, gallbladder tissue and bile from human carriers. The results from Aims 1 and 2 will provide information concerning the interplay of the bacterium with the gallbladder environment (bile and gallstones) on the establishment of this chronic infection. The knowledge gained may suggest therapeutic or preventative approaches to interfere with bile resistance, bile sensing, or biofilm formation, which could eliminate gallstone carriage and dramatically limit the spread of this organism. Public description: Typhoid fever can result in the asymptomatic carriage and shedding of Salmonella. The primary location of carriage is the gallbladder, but little is known about how Salmonella can cause chronic infection of this organ. We hypothesize that bile salts signal phenotypic changes in the bacterium that adapt it to life in the gallbladder, including enhanced colonization/biofilm capabilities and reduced invasiveness. We intend to study bile signaling in Salmonella, as well as the effect of bile on gallstone biofilms and gallbladder epithelial cell invasiveness in vitro. Planned experiments also include those to study our hypotheses in human carriers.