Immunity and Latency to Chlamydial Infections

衣原体感染的免疫和潜伏期

基本信息

批准号：
7589660
负责人：
Gerald Irwin Byrne
金额：
$ 47.97万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-08-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7589660
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Address Anabolism Anatomic Sites Animal Model Animals Antibiotic Resistance Antibiotic Therapy Biological Cavia Cell Culture System Cell Culture Techniques Cell Line Cells Chlamydia Chlamydia Infections Chlamydia trachomatis Chronic Chronic Disease Data Development Diagnosis Disease Environment Enzyme Induction Enzymes Epithelial Fibroblasts Gene Expression Genes Genetic Transcription Genital system Genitourinary system Goals Growth Health Human Immune Immune response Immunity Individual Infection Interferon Type II Investigation Knockout Mice Knowledge Link Mediating Methodology Modeling Molecular Mus NOS2A gene Nutrient Pathogenesis Pathologic Pattern Recognition Research Personnel Resistance Risk Site System Techniques Tissue-Specific Gene Expression Treatment Protocols Tryptophan Tryptophan 2,3 Dioxygenase Vaccine Design Vaccines Woman Work antimicrobial arginase base cell type cytokine design functional genomics human AKAP13 protein improved in vivo macrophage monocyte pathogen prevent programs response transmission process vaccine development

项目摘要

Investigation of immunity and latency to chlamydial infection links host immune responses with chlamydial growth modulation. The concept that chlamydial infections progress to chronic disease has been acknowledged for decades in animals, but is supported by only meager data in humans. Cell culture models do provide proof of principle for the chronic infection (latency) hypothesis. The most compelling mechanistic model is referred to as chlamydial persistence and involves induction of non-productive, but reversible, intracellular chlamydial growth elicited by Th1 immune regulated cytokines (e.g. gamma interferon; IFN-g) on chlamydial host cells. This model has been developed in a variety of human cell culture systems and is based on the induction of an enzyme (indoleamine 2,3-dioxygenase, IDO) that decyclizes tryptophan, creating a nutrient deficient intracellular environment to restrict intracellular chlamydial growth. Study of persistence has, however, been hampered in vivo because appropriate animal models are not available. A major reason for this deficit is that although the mouse is a convenient model for C. trachomatis genital tract disease, murine IFN-g-mediated responses are different from responses observed in humans. Murine immune responses to chlamydiae in wild type animals are likely to result in eradicative immunity rather than persistence, although the full repertoire of lethal and static mouse responses are not yet fully elucidated. Therefore, to gain a better appreciation of requirements for development of chronic chlamydial infections in mice the murine antimicrobial activities elicited by IFN-g will be systematically classified in cell culture (e.g. iNOS, arginase, p47, phox, IDO) using several cell types and primary cells from conventional and knock out mice. Cell culture results will be exploited to study mice that are genetically manipulated or chemically treated to elicit responses that provide an environment conducive to development of chronic chlamydial genital tract infection. Results will provide an improved tractable model of chlamydial persistence, furnish a way to understand more completely the pathogenesis of chronic chlamydial infections, and help define requirements for efficacious vaccine design.

对衣原体感染的免疫和潜伏期的研究将宿主免疫反应与衣原体联系起来生长调节。衣原体感染进展为慢性疾病的概念一直被认为是几十年来，这一观点在动物身上得到了认可，但在人类身上却只有很少的数据支持。细胞培养模型确实为慢性感染（潜伏期）假设提供了原理证明。最引人注目的机制模型被称为衣原体持久性并涉及非生产性的诱导，但是由 Th1 免疫调节细胞因子（例如 γ 干扰素； IFN-g）对衣原体宿主细胞的影响。该模型已在多种人体细胞中开发培养系统，基于酶（吲哚胺 2,3-双加氧酶，IDO）的诱导，使色氨酸脱环，创造营养缺乏的细胞内环境以限制细胞内衣原体生长。然而，体内持久性研究受到了阻碍，因为适当的动物型号不可用。造成这种缺陷的一个主要原因是，尽管鼠标是一种方便的模型对于沙眼衣原体生殖道疾病，小鼠 IFN-g 介导的反应与反应不同在人类中观察到。野生型动物对衣原体的小鼠免疫反应可能会导致根除性免疫而不是持久性，尽管致命和静态小鼠的全部技能回应尚未完全阐明。因此，为了更好地了解需求小鼠慢性衣原体感染的发展，IFN-g 引起的小鼠抗菌活性将使用多种细胞类型对细胞培养物（例如 iNOS、精氨酸酶、p47、phox、IDO）进行系统分类，并且来自传统小鼠和基因敲除小鼠的原代细胞。细胞培养结果将用于研究小鼠经过基因操纵或化学处理以引发反应，提供有利的环境慢性衣原体生殖道感染的发展。结果将提供改进的易于处理的衣原体持久性模型，提供了一种更全面地了解慢性衣原体发病机制的方法衣原体感染，并帮助确定有效疫苗设计的要求。