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：
7212112
负责人：
Gerald Irwin Byrne
金额：
$ 35.13万
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/7212112
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 Line Cells Chlamydia Chlamydia Infections Chlamydia trachomatis Chronic Chronic Disease Condition Cultured Cells Data Development Diagnosis Disease Environment Enzyme Induction Enzymes Epithelial Fibroblasts Gene Expression 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 Numbers Nutrient Pathogenesis Pathologic Pattern Recognition Rate 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 concept cytokine design functional genomics human AKAP13 protein human NOS2A protein improved in vivo knockout gene macrophage monocyte pathogen prevent programs response transmission process vaccine development

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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生长调节联系起来。衣原体感染会发展为慢性疾病的概念在动物中已被认可数十年，但在人类中仅得到微薄的数据支持。细胞培养模型确实为慢性感染（潜伏期）假说提供了原理证明。最引人注目的机制模型被称为衣原体持久性，涉及由衣原体宿主细胞上的 Th1 免疫调节细胞因子（例如 γ 干扰素；IFN-g）诱导非生产性但可逆的细胞内衣原体生长。该模型已在多种人类细胞培养系统中开发，基于对色氨酸脱环的酶（吲哚胺 2,3-双加氧酶，IDO）的诱导，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，由于没有合适的动物模型，体内持久性研究受到了阻碍。造成这种缺陷的主要原因是，尽管小鼠是沙眼衣原体生殖道疾病的方便模型，但小鼠 IFN-g 介导的反应与在人类中观察到的反应不同。尽管致死性和静态小鼠反应的全部内容尚未完全阐明，但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。因此，为了更好地了解小鼠慢性衣原体感染发展的要求，将使用几种细胞类型和细胞培养物（例如 iNOS、精氨酸酶、p47、phox、IDO）对 IFN-g 引发的小鼠抗菌活性进行系统分类。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经过基因操纵或化学处理的小鼠，以引发反应，从而提供有利于慢性衣原体生殖道感染发展的环境。结果将提供一个改进的、易于处理的衣原体持久性模型，提供一种更全面地了解慢性衣原体感染发病机制的方法，并帮助确定有效疫苗设计的要求。