Mucosal colonization and dissemination of P. aeruginosa

铜绿假单胞菌的粘膜定植和传播

• 批准号: 7389572
• 负责人: ANDREW Y KOH
• 金额: $ 12.81万
• 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/7389572
• 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）：本项目的中心目标是更好地了解免疫功能低下患者中LPS-光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。基于申办方实验室和合作者的既往研究，我们建立了一种可重现的铜绿假单胞菌胃肠道定植和中性粒细胞减少症全身扩散的小鼠模型。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，预期在定殖中起重要作用的毒力因子，即pill和鞭毛，不需要，而LPS-外核多糖和O-侧链需要。中性粒细胞减少的持续时间和强度与环磷酰胺剂量有关，在确定传播所需的毒力因子方面很重要。这些初步实验导致了以下可验证的假设：铜绿假单胞菌的表面因子需要定植在胃肠道粘膜和移位，并导致菌血症是不完全知道的。这些因子的鉴定可以在鼠模型中完成，该模型将定义病原体毒力因子（定殖和易位因子）和宿主免疫应答（细胞和体液免疫效应物）。这些发现可能导致有效破坏粘膜定植和传播的方法，并减少免疫功能低下宿主中铜绿假单胞菌感染的影响。在目标1中，将通过使用微阵列和TraSH（转座子位点杂交）技术鉴定铜绿假单胞菌建立胃肠道定植、易位和播散所需的毒力因子，并将创建突变体用于定植/播散模型中的测试。在目标2中，将进一步阐明宿主免疫效应物（细胞和体液先天免疫）对预防铜绿假单胞菌定植和传播所必需的作用。候选人寻求密集，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/肿瘤学和传染病专家，他的长期目标是开发策略和潜在疗法，以预防或改善铜绿假单胞菌感染的后果。