Mechanisms underlying the pathogenic potential of cardioinvasive L. monocytogenes

侵入心脏的单核细胞增生李斯特菌潜在致病机制

• 批准号: 8121909
• 负责人: Philip D McMullen
• 金额: $ 4.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-16 至 2015-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121909
• 关键词: Animal Model; Animals; Bacterial Infections; Bacterial Proteins; Bacterial Translocation; Bioluminescence; Cardiac; Cell Line; Cells; Clinical; Comparative Genomic Analysis; Data; Diagnosis; Disease; Disease Outbreaks; Drug or chemical Tissue Distribution; Enabling Factors; Endocarditis; Epithelial; Evolution; Exhibits; Foundations; Gastroenteritis; Generations; Genetic; Genome; Genomics; Goals; Growth; Heart; Heart Diseases; Human; Image; Immune; Immunocompromised Host; Individual; Infection; Infiltration; Inflammatory Response; Invaded; Lead; Lesion; Libraries; Listeria monocytogenes; Meningoencephalitis; Methods; Mitral Valve; Modeling; Monitor; Mus; Mutagenesis; Myocarditis; Organism; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Population; Property; Prosthesis; Relative (related person); Reporter; Reporter Genes; Risk; Septicemia; Site; Source; Time; Tissues; Tropism; Ventricular septum; Virulence; aortic valve; cell type; comparative; cost effective; design; enhancing factor; foodborne; foodborne outbreak; genetic analysis; in vivo; mouse model; mutant; novel; older patient; pathogen

DESCRIPTION (provided by applicant): Invasive cardiac infections are a recognized yet poorly understood facet of Listeria monocytogenes pathogenesis. Preliminary examinations of selected L. monocytogenes isolates indicates that a sub-population of strains exhibit an enhanced ability to invade and infect cardiac tissue. It is hypothesized that these cardioinvasive strains have developed novel mechanisms and/or express novel or altered factors that enable them to replicate within cardiac tissue. The goal of this project will be to elucidate the mechanism(s) by which cardioinvasive isolates of L. monocytogenes target the heart for bacterial replication. The aims of this project are designed to elucidate the course and pathology of cardiac infection by L. monocytogenes as well as to identify bacterial factors responsible for increased cardio-tropism. Mouse models of infection will be used to define the time course and tissue distribution of cardioinvasive strains of L. monocytogenes. In vivo infections in mice will be monitored using bioluminescence imaging of L. monocytogenes strains containing lux reporter fusions, and subsequent histological examination of target tissues will be used to further elucidate pathogenesis and host inflammatory response. Comparative genomic analysis of cardioinvasive and noncardioinvasive strains will be used in combination with genetic approaches to identify bacterial factors that contribute to bacterial invasion and replication within cardiac cells. The use of transposon insertion mutagenesis in a highly cardioinvasive strain and the generation of bacterial insertion libraries will be done to enable the identification of bacterial factors that contribute to invasion and replication within cardiac cells. The libraries will be screened for mutants that lack the ability to invade and replicate within cardiac cell lines. Genetic analyses of these mutants will be used to elucidate virulence mechanisms responsible for the cardiotropism of cardioinvasive strains. The information gained from these studies may ultimately enable the identification of cardiotropic strains early in the patient infection as well as in food-borne outbreaks, so as to increase the likelihood of successful diagnosis and treatment of at-risk individuals. PUBLIC HEALTH RELEVANCE: Cardiac infections represent a significant but poorly characterized facet of Listeria monocytogenes pathogenesis. Sub-populations of clinical isolates of L. monocytogenes exhibit an enhanced ability to colonize the hearts of infected animals, and our goal is to elucidate the mechanisms responsible for this mode of infection. The outcomes of this project may lead to methods of rapidly identifying such strains early in the course of an infection or outbreak, potentially leading to better treatment methods and outcomes.

描述（由申请人提供）：侵袭性心脏感染是单核细胞增生李斯特菌发病机制的一个公认但知之甚少的方面。对所选L.单核细胞增多性分离株表明菌株的亚群表现出增强的侵入和感染心脏组织的能力。据推测，这些心脏侵入性菌株已经开发出新的机制和/或表达新的或改变的因子，使它们能够在心脏组织内复制。本项目的目标是阐明L。单核细胞增多症靶向心脏进行细菌复制。本课题旨在阐明L.单核细胞增多症以及鉴定负责增加的向心性的细菌因子。小鼠感染模型将用于确定L.单核细胞增多症。将使用L.包含lux报告基因融合体的单核细胞增多性菌株，以及随后的靶组织的组织学检查将用于进一步阐明发病机制和宿主炎症反应。心脏侵入性和非心脏侵入性菌株的比较基因组分析将与遗传方法结合使用，以确定有助于细菌入侵和复制的细菌因子。将在高度心脏侵入性菌株中使用转座子插入诱变并产生细菌插入文库，以能够鉴定有助于心脏细胞内侵入和复制的细菌因子。将筛选文库中缺乏在心脏细胞系内侵入和复制能力的突变体。这些突变体的遗传分析将被用来阐明毒力机制，负责心肌侵袭株的向心性。从这些研究中获得的信息可能最终能够在患者感染以及食源性疫情的早期识别亲心菌株，从而增加成功诊断和治疗高危人群的可能性。 公共卫生相关性：心脏感染是单核细胞增生李斯特菌发病机制的一个重要但特征不明显的方面。临床分离的L.单核细胞增多症表现出增强的能力，以殖民地的心脏感染的动物，我们的目标是阐明机制负责这种模式的感染。该项目的成果可能导致在感染或爆发过程中早期快速识别此类菌株的方法，从而可能导致更好的治疗方法和结果。