Mucosal colonization and dissemination of P. aeruginosa

铜绿假单胞菌的粘膜定植和传播

• 批准号: 7595766
• 负责人: ANDREW Y KOH
• 金额: $ 3.46万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595766
• 关键词: Bacteremia; Cancer Patient; Communicable Diseases; Cyclophosphamide; Dose; Flagella; Genes; Goals; Host Defense; Immune; Immune response; Immunity; Immunocompromised Host; Infection; Integration Host Factors; Laboratories; Lead; Leukocytes; Lipopolysaccharides; Lymphocyte; Mentors; Modeling; Mucous Membrane; Mus; Mutation; Natural Immunity; Neutropenia; Pathogenesis; Pediatric Hematology/Oncology; Pilum; Play; Polysaccharides; Properdin; Pseudomonas aeruginosa; Research Personnel; Role; Scientist; Side; Specialist; Surface; Technology; Testing; Training; Virulence; Virulence Factors; base; chemotherapy; gastrointestinal; mouse model; mutant; pathogen; pill; prevent; programs; research study; tool; transposon site hybridization

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）：该项目的中心目标是更好地了解免疫功能低下患者中 LPS 平滑菌株铜绿假单胞菌菌株引起的感染的发病机制和免疫力。根据申办者实验室和合作者之前的研究，我们建立了中性粒细胞减少症期间铜绿假单胞菌胃肠道定植和全身传播的可重复小鼠模型。使用该模型的初步研究已经确定了胃肠道定植和传播所必需的几个因素。值得注意的是，不需要预期在定植中发挥重要作用的毒力因子，即丸和鞭毛，而 LPS-外核多糖和 O-侧链则需要。中性粒细胞减少症的持续时间和强度与环磷酰胺剂量相关，对于确定传播所需的毒力因子非常重要。这些初步实验得出了以下可检验的假设：铜绿假单胞菌在胃肠粘膜定植、移位和引起菌血症所需的表面因子尚不完全清楚。这些因子的鉴定可以在小鼠模型中完成，该模型将定义病原体毒力因子（定植和易位因子）和宿主免疫反应（细胞和体液免疫效应器）。这些发现可能导致找到有效破坏粘膜定植和传播并减少铜绿假单胞菌感染对免疫功能低下宿主的影响的方法。在目标1中，将通过使用微阵列和TraSH（转座子位点杂交）技术来鉴定铜绿假单胞菌建立胃肠道定植、易位和传播所需的毒力因子，并创建突变体以在定植/传播模型中进行测试。在目标 2 中，将进一步描述预防铜绿假单胞菌定植和传播所必需的宿主免疫效应器（细胞和体液先天免疫）的作用。候选人寻求密集、正式和有指导的培训，以提供必要的知识和技术工具，以实现作为科学家的独立。作为儿科血液学/肿瘤学和传染病方面的专家，他的长期目标是制定策略和潜在疗法来预防或改善铜绿假单胞菌感染的后果。