Defining mechanisms underlying Listeria monocytogenes cardiac infections

定义单核细胞增生李斯特氏菌心脏感染的机制

基本信息

批准号：
8441534
负责人：
Nancy Elizabeth Freitag
金额：
$ 19.94万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8441534
关键词：
Animals Bacterial Infections Bacterial Translocation Bioluminescence Cardiac Cells Clinical Complement Data Death Rate Development Diagnostic tests Disease Disease Outbreaks Early identification Enabling Factors Endocarditis Exhibits Gastroenteritis Genetic Goals Heart Heart Diseases Human Immune Immune response Immunocompromised Host Individual Infection Infiltration Inflammatory Inflammatory Response Intestines Invaded Listeria monocytogenes Meningoencephalitis Methodology Mitral Valve Modeling Molecular Target Monitor Mus Myocarditis Pathogenesis Pathology Patients Play Population Predisposition Pregnant Women Prosthesis Proteins Publishing Relative (related person)Risk Role Septicemia Site Technology Testing Tissues Tropism abortion aortic valve cell type cellular targeting enhancing factor foodborne in vivo insight novel older patient oxidative damage pathogen research study response stillbirth tissue tropism

项目摘要

DESCRIPTION (provided by applicant): Listeria monocytogenes (Lm) is a gram-positive, food-borne facultative intracellular bacterial pathogen that infects humans and causes disease following bacterial translocation across the intestinal barrier. While healthy individuals usually exhibit mild forms of disease such as gastroenteritis, individuals who are immune-compromised as well as elderly patients often suffer more severe forms of illness that include meningoencephalitis and septicemia. A significant but much less well-documented sequelae of invasive Lm infections involve the heart; this type of infection is estimated to occur in at least % to 10% of those with invasive disease. Recently published data indicates that significant subpopulations of Lm strains have the capacity to target and invade cardiac cells; this is a new finding with important clinical implications. Experiments outlined within this proposal will test te hypothesize that cardioinvasive Lm strains have developed novel mechanisms and/or express novel or altered bacterial factors that enable them to replicate within cardiac tissues. These studies will provide a detailed understanding of the pathogenesis and maturation of myocarditis resulting from Lm infection, and will clarify bacterial factors that contribute to specific host tisue tropisms. Aim 1 will decipher the pathology of Lm cardioinvasive strains in animal infection models. Bacterial infections will be monitored in mice using in vivo bioluminescence imagining to determine the progression of cardiac infection as well as the potential for bacterial colonization at other body sites. Experiments will also include the histological examination of target tissues to characterize sites of host immune cell infiltration as well as the use of immuno-spin capture technology to definitively identify cellular damage that occurs as a result of the hos inflammatory response to Lm infection. Aim 2 will focus on the functional characterization of bacterial factors associated with invasive cardiac infections. Genetic and cellular approaches will be used to identify Lm factors that enhance cardiac invasion relative to the invasion of other cell types. The ultimate goal of these studies will be to establish and functionally characterize a cardiac model of infection for Lm and to determine the bacterial factors that contribute to the enhanced ability of selected Lm strains to invade and destroy cardiac tissue. This information will be useful for the early identification of Lm outbreak strains that pose increased risk for patient heart infections. Finally, the experiments outlined in this proposal will provide important insight into the mechanisms that establish bacterial tropism for specific host tissues and in addition will identify in vivo cellular targets of oxidative damage resulting from host inflammator responses to infection.

描述（由申请人提供）：单核细胞增生李斯特氏菌 (Lm) 是一种革兰氏阳性、食源性兼性细胞内细菌病原体，可感染人类并在细菌穿过肠道屏障后引起疾病。虽然健康个体通常表现出轻微的疾病，例如胃肠炎，但免疫功能低下的个体以及老年患者经常患有更严重的疾病，包括脑膜脑炎和败血症。侵袭性 Lm 感染的一个重要但记录较少的后遗症涉及心脏。据估计，至少 % 至 10% 的侵袭性疾病患者会发生这种类型的感染。最近发表的数据表明，Lm 菌株的重要亚群具有靶向和侵入心脏细胞的能力；这是具有重要临床意义的新发现。该提案中概述的实验将检验以下假设：侵入心脏的 Lm 菌株已开发出新的机制和/或表达新的或改变的细菌因子，使它们能够在心脏组织内复制。这些研究将详细了解 Lm 感染引起的心肌炎的发病机制和成熟过程，并将阐明导致特定宿主组织向性的细菌因素。目标 1 将破译 Lm 心脏侵袭菌株在动物感染模型中的病理学。将使用体内生物发光成像监测小鼠的细菌感染，以确定心脏感染的进展以及细菌在身体其他部位定植的可能性。实验还将包括对靶组织进行组织学检查，以表征宿主免疫细胞浸润的部位，以及使用免疫旋转捕获技术来明确识别由于宿主对 Lm 感染的炎症反应而发生的细胞损伤。目标 2 将重点关注与侵袭性心脏感染相关的细菌因子的功能特征。遗传和细胞方法将用于识别相对于其他侵袭性疾病增强心脏侵袭的 Lm 因子。细胞类型。这些研究的最终目标是建立并在功能上表征 Lm 感染的心脏模型，并确定有助于增强所选 Lm 菌株侵入和破坏心脏组织的能力的细菌因素。该信息将有助于早期识别 Lm 爆发菌株，这些菌株会增加患者心脏感染的风险。最后，本提案中概述的实验将提供重要的深入了解针对特定宿主组织建立细菌趋向性的机制，此外还将识别宿主炎症反应对感染引起的氧化损伤的体内细胞靶点。