A Mammalian Cellular Niche for Chronic Bacteria

慢性细菌的哺乳动物细胞生态位

基本信息

批准号：
7535604
负责人：
Corrella S Detweiler
金额：
$ 18.56万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-15 至 2010-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Despite great strides in understanding the mechanisms of acute bacterial disease, the mechanisms involved in chronic disease - persistence in an otherwise healthy host - are far less known. Chronic bacterial infections are a major public health problem because infected individuals appear healthy, but often shed bacteria, causing outbreaks or epidemics of acute infection. Using a mouse model of chronic bacterial infection, we have discovered that salmonellae reside within a particular kind of macrophage, cytophagocytic macrophages, that have ingested live white blood cells. These are similar to macrophages that can harbor salmonellae in humans with typhoid fever and that are referred to as "typhoidal cells". We now want to identify the molecular mechanisms that enable the bacteria to survive within cytophagocytic macrophages. To this end, we developed a tissue culture model of our in vivo observations which recapitulates the replication of bacteria inside of macrophages that have ingested live, but not dead, white blood cells grown in the laboratory. In this highly focused proposal we outline 3 questions with which we will exploit this model to identify the molecular mechanisms of persistent infection. 1.) Are bacteria vacuolar or cytosolic when they replicate within macrophages that have ingested live white blood cells? 2.) What contributions do the live white blood cells and/or S. typhimurium make that allow the bacteria to replicate? 3.) Is the activation state of macrophages altered by the ingestion of live white blood cells and/or bacteria to allow for bacterial replication? These studies will lay the foundation for molecular analyses of the signaling pathways that allow for bacterial replication in cytophagocytic macrophages. This proposal is relevant to public health because it addresses a poorly understood issue of major medical importance: how and where do bacteria survive during chronic infection. Once these questions have been addressed, therapeutics that clear chronic bacterial infections can be developed, reducing the frequency/severity of epidemics of acute bacterial infection.

描述（由申请人提供）：尽管在理解急性细菌疾病的机制方面取得了长足的进步，但与慢性疾病有关的机制 - 在原本健康的宿主中的持久性 - 鲜为人知。慢性细菌感染是一个主要的公共卫生问题，因为受感染的人看起来很健康，但通常会散发细菌，导致急性感染的爆发或流行病。使用慢性细菌感染的小鼠模型，我们发现沙门氏菌居住在特定种类的巨噬细胞，细胞巨噬细胞中，这些巨噬细胞摄入了活血细胞。这些类似于可以在伤寒的人类中含有沙门氏菌的巨噬细胞，被称为“伤寒细胞”。现在，我们想确定使细菌在细胞巨噬细胞中生存的分子机制。为此，我们开发了一种组织培养模型的体内观测模型，该模型概括了在实验室中生长的巨噬细胞内部细菌的复制。在这个高度重点的建议中，我们概述了3个问题，我们将利用该模型来确定持续感染的分子机制。 1.）细菌在摄入活白细胞的巨噬细胞中复制时是液泡或胞质的吗？ 2.）活的白细胞和/或鼠伤寒链球菌使细菌复制有何贡献？ 3.）巨噬细胞的激活状态是否因摄入活血细胞和/或细菌而改变以允许细菌复制？这些研究将奠定对信号通路的分子分析的基础，这些途径允许细菌复制中的细菌复制。该提议与公共卫生有关，因为它解决了一个鲜为人知的主要医学重要性问题：在慢性感染期间细菌如何以及在哪里生存。解决这些问题后，可以开发出明显的慢性细菌感染的治疗方法，从而降低了急性细菌感染的流行病的频率/严重程度。