Bile, Biofilms and Salmonella Gallbladder Carriage

胆汁、生物膜和沙门氏菌胆囊运输

• 批准号: 7758847
• 负责人: JOHN S GUNN
• 金额: $ 36.42万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758847
• 关键词: Affect; Area; Bacteria; Bile fluid; Binding; Carrier State; Cells; Cholelithiasis; Chronic; Cities; Data; Detergents; Development; Digestion; Environment; Epithelial Cells; Epithelium; Eukaryotic Cell; Extracellular Matrix; Gallbladder; Gene Expression Alteration; Genes; Genetic Transcription; Goals; Human; In Vitro; Individual; Infection; Invaded; Knowledge; Life; Lipids; Location; Maintenance; Mediating; Mexico; Microbial Biofilms; Modeling; Molecular; Organ; Organism; Pathogenesis; Phenotype; Play; Population; Process; Property; Proteins; Regulatory Pathway; Reporter; Resistance; Risk; Role; Salmonella; Salmonella typhi; Sensory; Signal Transduction; Site; Surface; Testing; Therapeutic; Tissues; Translating; Typhoid Fever; Virulence; Work; antimicrobial; base; bile salts; cell motility; interest; killings; microbial; mutant; prevent; research study; response; sensory mechanism; sensory system; transmission process

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.

描述（由申请人提供）：伤寒沙门氏菌感染可引起人类胆囊的慢性、相对无症状的感染。伤寒沙门氏菌携带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，胆汁是一种具有类似清洁剂特性的抗菌物质。我们已经证明，胆汁影响许多沙门氏菌蛋白的表达，包括那些与毒力相关的几种表型（例如上皮细胞侵袭、运动、抗菌/胆汁耐药性）相关的蛋白。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状态所必需的一个重要属性。此外，人类胆囊异常（尤其是胆结石）与沙门氏菌携带状态的发展之间存在高度相关性。我们之前已经证明沙门氏菌在体外在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，最近发现的胆汁调节基因，包括那些参与宿主细胞侵袭和抗菌/胆汁耐药性的基因，将用于揭示独特的胆汁反应感觉/调节途径。在目标 2 中，我们将通过研究在沙门氏菌和胆结石的独特关系中发挥作用的微生物因素（细胞外基质）和胆结石因素，进一步表征胆囊运输的建立。我们还将探讨这样的假设：除了胆结石生物膜之外，胆囊上皮的侵袭和生物膜的形成在载体发育中也发挥着作用。最后，我们将通过检查人类携带者的胆结石、胆囊组织和胆汁来检验我们的假设和体外研究。目标 1 和 2 的结果将提供有关细菌与胆囊环境（胆汁和胆结石）相互作用对这种慢性感染的影响的信息。获得的知识可能会提出干扰胆汁抵抗、胆汁感应或生物膜形成的治疗或预防方法，这可以消除胆结石携带并极大地限制这种生物体的传播。 公开描述：伤寒可导致沙门氏菌无症状携带和传播。携带的主要位置是胆囊，但人们对沙门氏菌如何引起该器官的慢性感染知之甚少。我们假设胆汁盐标志着细菌的表型变化，使其适应胆囊中的生活，包括增强的定植/生物膜能力和减少的侵袭性。我们打算在体外研究沙门氏菌中的胆汁信号传导，以及胆汁对胆结石生物膜和胆囊上皮细胞侵袭性的影响。计划中的实验还包括在人类携带者身上研究我们的假设的实验。