Mucosal colonization and dissemination of P. aeruginosa

铜绿假单胞菌的粘膜定植和传播

• 批准号: 6856404
• 负责人: ANDREW Y KOH
• 金额: $ 11.73万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856404
• 关键词: Pseudomonas aeruginosa; bacteria infection mechanism; enteric bacteria; gastrointestinal epithelium; host organism interaction; immune response; laboratory mouse; lipopolysaccharides; microarray technology; mucosal immunity; neutropenia; virulence

DESCRIPTION (provided by applicant): The central goal of this project is to gain a better understanding of the pathogenesis of and immunity to infections caused by LPS-smooth strains P. aeruginosa strains in immunocompromised patients. Based on previous studies by the sponsor's laboratory and collaborators, we have established a reproducible mouse model of P. aeruginosa gastrointestinal-colonization and systemic spread during neutropenia. Preliminary studies using this model have identified several factors that are necessary for gastrointestinal colonization and dissemination. Of note, virulence factors expected to play an important role in colonization, namely pill and flagella, were not needed whereas LPS-outer core polysaccharide and O-side chains were. The duration and intensity of neutropenia, related to cyclophosphamide dose, was important in identifying virulence factors needed for dissemination. These preliminary experiments have led to the following testable hypothesis: Surface factors of P. aeruginosa needed to colonize the gastrointestinal mucosa and to translocate and cause bacteremia are not fully known. Identification of such factors can be accomplished in a murine model that will define both pathogen virulence factors (colonization and translocation factors) and host immune responses (cellular and humoral immune effectors). The findings could lead to means to effectively disrupt mucosal colonization and dissemination and diminish the impact of P. aeruginosa infection in immunocompromised hosts. In Aim 1, virulence factors needed by P. aeruginosa to establish gastrointestinal colonization, translocation, and dissemination will be identified by use of microarray and TraSH (transposon site hybridization) technology, and mutants will be created for testing in the colonization/dissemination model. In Aim 2, the role of host immune effectors (cellular and humoral innate immunity) that are necessary for preventing P. aeruginosa colonization and dissemination will be further delineated. The candidate seeks an intensive, formal, and mentored training to provide the necessary intellectual and technical tools to achieve independence as a scientist. As a specialist in pediatric hematology/oncology and infectious diseases, his long-term goal is to develop strategies and potential therapies to prevent or ameliorate the consequences of P. aeruginosa infections.

描述（由申请人提供）：该项目的核心目的是更好地了解免疫功能低下患者中由LPS平滑菌株P.铜绿假单胞菌菌株引起的感染的发病机理和免疫力。根据赞助商的实验室和合作者的先前研究，我们在中性粒细胞减少期间建立了一种可再现的小鼠铜绿假单胞菌胃肠道殖民化和全身扩散的小鼠模型。使用该模型的初步研究确定了胃肠道定殖和传播所必需的几个因素。值得注意的是，预期在定植中发挥重要作用的毒力因素不需要药丸和鞭毛，而LPS-outer核心多糖和O侧链则是。与环磷酰胺剂量有关的中性粒细胞减少症的持续时间和强度对于鉴定传播所需的毒力因子很重要。这些初步的实验导致了以下可检验的假设：在胃肠道粘膜定居并易位并引起菌血症所需的铜绿假单胞菌的表面因子尚不完全清楚。可以在鼠模型中识别此类因素，该模型将定义病原体毒力因子（定殖和易位因子）和宿主免疫反应（细胞和体液免疫效应子）。这些发现可能导致有效破坏粘膜定殖和传播的手段，并减少铜绿假单胞菌感染对免疫功能低下的宿主的影响。在AIM 1中，铜绿假单胞菌所需的毒力因素将通过使用微阵列和垃圾（Transposon位点杂交）技术来确定胃肠道定植，易位和传播，并将创建突变体以在定殖/传播模型中进行测试。在AIM 2中，将进一步描述宿主免疫效应子（细胞和体液先天免疫）的作用（细胞和体液先天免疫），这些作用将进一步描述。候选人寻求深入，正式和指导的培训，以提供必要的知识和技术工具，以实现作为科学家的独立性。作为儿科血液学/肿瘤学和传染病的专家，他的长期目标是制定策略和潜在的疗法，以预防或改善铜绿假单胞菌感染的后果。