Effects and mechanisms of cold-induced stress on the development of chlamydia genital infection in a mouse model

 描述(申请人提供)：沙眼衣原体生殖器感染是全球最常见的细菌性性病(STD)。如果不治疗，衣原体生殖器感染会导致盆腔炎、宫外孕和不孕症等并发症。人们越来越有兴趣了解压力如何影响对包括性传播疾病在内的多种疾病的抵抗力或易感性。许多研究人员已经研究了沙眼衣原体的免疫反应，但压力的影响尚未被探索。我们已经证明，小鼠长期暴露在冷水中会导致衣原体生殖器感染强度增加，但其机制(S)尚不清楚。衣原体免疫主要由CD4+T细胞介导，针对T细胞分化和树突状细胞等主要抗原提呈细胞激活的应激源可能会影响对衣原体感染的免疫反应。这项建议的中心目标是确定应激可能抑制免疫系统、增加小鼠生殖器沙眼衣原体感染强度和免疫病理的机制(S)。我们的假设是，冷水应激导致去甲肾上腺素(NE)通过刺激β2肾上腺素能受体(β2AR)的表达来调节对疾病后遗症的免疫反应。目前，我们正在通过增加免疫致病细胞因子的产生来对抗沙眼衣原体生殖道感染，这些细胞因子的产生导致在体外检测合成的NE对包括T细胞在内的不同小鼠免疫细胞增殖的影响，通过细胞因子的产生来衡量。在拟议项目的目标1中，将确定CD4+T细胞上的β肾上腺素能受体亚型的基因表达。目的2分析比较β-2AR基因缺陷小鼠和野生型小鼠成熟感染过程中细胞因子的动态变化。由此获得的结果，骨髓来源的树突状细胞暴露于NE将被分析。在目标3中，清除沙眼衣原体生殖器应激研究将为免疫系统和内分泌系统之间的相互作用提供重要的新信息，这可能导致未来开发控制衣原体生殖器感染和人类受试者病理的对策和干预措施。

 DESCRIPTION (provided by applicant): Genital infection by Chlamydia trachomatis is the most common bacterial sexually transmitted disease (STD) worldwide. If left untreated, chlamydia genital infection leads to complications such as pelvic inflammatory disease, ectopic pregnancy, and infertility. There is an increasing interest in understanding how stress may impact resistance or susceptibility to a number of diseases, including sexually transmitted disease. Many investigators have examined the immune response to C. trachomatis but the effect of stress has not yet been explored. We have demonstrated that prolonged exposure of mice to cold water results in increased intensity of chlamydia genital infection, but the mechanism(s) are not known. Chlamydial immunity is predominantly CD4+ T cell-mediated, and stressors that target T cell differentiation and activation by primary antigen- presenting cells such as dendritic cells are likely to affect immune response against chlamydia infection. The central objective of this proposal is to define the mechanism(s) by which stress may suppress the immune system and increase the intensity of genital C. trachomatis infection and immunopathologies in mice. Our hypothesis is that cold water-induced stress leads to norepinephrine (NE) modulation of immune response to disease sequelae by stimulation of beta-2 adrenergic receptor (β2AR) expression. At present we are against C. trachomatis genital infection by enhancing the production of immunopathogenic cytokines that lead examining in vitro the effect of synthetic NE on the proliferation of different mouse immune cells, including T cells, as measured by cytokine production. In Aim 1 of the proposed project, gene expression of beta adrenergic receptor subtypes on CD4+ T cells will be determined. In Aim 2 the kinetics of cytokines in maturing infection in β2AR-deficient and wild-type mice will be analyzed and compared. Results obtained from this of marrow-derived dendritic cells exposed to NE will be analyzed. In Aim 3, clearance of C. trachomatis genital stress study in mice will provide important new information on the interaction between the immune system and the endocrine system, which could lead to future development of countermeasures and interventions to control chlamydia genital infection and pathologies in human subjects.