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

寒冷应激对鼠衣原体生殖道感染小鼠模型的影响及机制

• 批准号: 10730819
• 负责人: Tesfaye Belay
• 金额: $ 44.4万
• 依托单位: BLUEFIELD STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730819
• 关键词: Acute; Adrenergic Receptor; Affect; African American population; Animal Model; Bacterial Sexually Transmitted Diseases; Binding; Bone Marrow; CD4 Positive T Lymphocytes; Catecholamines; Cell physiology; Cell surface; Cells; Centers for Disease Control and Prevention (U.S.); Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Chronic; Chronic stress; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dendritic Cells; Development; Disease; Ectopic Pregnancy; Endocrine system; Enzyme-Linked Immunosorbent Assay; Epinephrine; Fibrosis; Flow Cytometry; Future; Gene Expression; Genital; Genitalia; Histopathology; Hormone Receptor; Hormones; Human; IL17 gene; Immune; Immune response; Immune system; Immunity; Immunosuppression; Impairment; Infection; Infertility; Inflammation; Interferon Type II; Interleukin-10; Interleukin-12; Interleukin-4; Intervention; Knock-out; Knockout Mice; Left; Link; Literature; Lymphocyte; Mammalian Oviducts; Mediating; Medical; Methods; Mitogen-Activated Protein Kinases; Modeling; Mus; NF-kappa B; Neurons; Norepinephrine; Norepinephrine Receptors; Norepinephrine Secretion Induction; Pathologic; Pathology; Pathway interactions; Pelvic Inflammatory Disease; Plasma Cells; Population; Predisposition; Primary Infection; Principal Investigator; Production; Proteins; Public Health; Reaction; Reporting; Research; Research Personnel; Resistance; Role; Severities; Sexually Transmitted Diseases; Signal Pathway; Signal Transduction; Stress; System; T-Lymphocyte Subsets; TNF gene; Testing; Time; United States; Water; Wild Type Mouse; World Health Organization; biological adaptation to stress; comparison control; cytokine; experimental study; genital infection; human model; human subject; immune function; immunopathology; insight; interest; interleukin-23; low socioeconomic status; lymphoid organ; mouse model; neutrophil; pathogen; programs; psychological stressor; restoration; secondary infection; transcription factor

Program Director/Principal Investigator (Last, First, Middle): Belay, Tesfaye Project Summary Chlamydia trachomatis genital infection is the most common sexually-transmitted bacterial disease in the world. If left untreated, chlamydia genital infection leads to pelvic inflammatory disease, ectopic pregnancy, and infertility. It is widely known that the immunopathological reactions to this disease, rather than the infection itself, remain a serious public health problem. There is medical interest in understanding how stress may impact resistance or susceptibility to sexually transmitted diseases. Many investigators have examined the immunological responses to C. trachomatis, but the effect of stress on chlamydia genital infection has not yet been explored and is not understood. Our research seeks to understand the relationship between them. To accomplish this, we have developed a chronic-stress model in mice by daily immersing mice in cold water for five minutes daily for 21 days. This cold-induced stress (CIS) mouse model shows the increased intensity of Chlamydia muridarum genital infection, which is associated with the elevation of the stress hormone norepinephrine (NE) during both primary and secondary infections. Our research has demonstrated that CIS promotes increased beta2- adrenergic receptor (β2-AR) expression in CD4 + T cells, as well as T helper 2 (Th2) differentiation, specifically by increasing the expression of GATA-3 and IL-4 secretion. Moreover, we showed that β1/β2-AR KO are less susceptible to C. muridarum genital infection than the WT C57BL/6J. Those observations prompted us to use a β2-AR KO model and explore the immunopathogenesis of chlamydia genital infection. We recently found that the β2-AR KO is more resistant to C. muridarum than the WT C57BL/6J. However, the underlying mechanisms of chronic CIS on the infection and the immunopathogenesis in our mouse model remain unknown. 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. muridarum infection and its immunopathologies in mice. We hypothesize that the NE produced by CIS leads to stimulation of the 𝛽𝛽2-AR signaling pathway in mice which, in turn, suppresses the protective immune response against C. muridarum genital infection. To test this hypothesis, we will conduct the following three experiments as part of this project: In Aim #1, we will compare the CD4+ T cell subset immune responses of stressed β2-AR-/- mice and C57BL/6J (β2-AR+/+) mice. We anticipate that the deficiency of β2-AR enhances the restoration of Th1 cytokine production in stressed mice, which may result in the clearance of C. muridarum. In Aim #2, we will explore the downstream signaling pathways from the β2-AR of stressed KO mice compared to stressed C57BL/6J mice. Data obtained may provide insight into the involvement of β2-AR in cAMP-protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) pathways in suppressing the immune system. In Aim#3, we will assess the histopathological changes of stressed β2-AR KO as compared to WT C57BL/6J mice, and we will then evaluate the contributions of cytokines to pathology. Data from this method will demonstrate a reduced oviductal pathology in β2-AR KO mice. The proposed experiments will provide insight into the immunosuppression mechanisms resulting from the interactions of the endocrine and immune systems in the immunopathogenesis of chlamydia. Overall, results obtained from these β2-AR deficient mice, combined with our previous findings and those of others, could reveal more evidence of the effects of chronic stress on the severity of chlamydial disease in humans. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

项目总监/首席研究员（最后，第一，中间）：贝莱，特斯法伊 项目摘要 沙眼衣原体生殖器感染是世界上最常见的性传播细菌疾病。如果离开 未经治疗的衣原体生殖器感染会导致骨盆炎症性疾病，异位妊娠和不育。它是广泛的 知道对这种疾病而不是感染本身的免疫病理反应仍然是严重的公共卫生 问题。了解压力如何影响抵抗力或对性的易感性有医疗兴趣 传播疾病。许多研究人员检查了对沙眼梭菌的免疫学反应，但 尚未探索对衣原体生殖器感染的压力，尚未被理解。我们的研究试图了解 他们之间的关系。为了实现这一目标，我们通过每天浸入小鼠在小鼠中开发了一种慢性压力模型 在冷水中每天五分钟持续21天。这种冷诱导的应力（CIS）小鼠模型显示了强度的增加 衣原体的穆拉达果生殖器感染，这与压力马龙肾上腺素的升高有关 （NE）在原发性和继发感染期间。我们的研究表明，CIS促进了Beta2-的增加 CD4 + T细胞中的肾上腺素受体（β2-AR）表达以及T辅助2（Th2）分化，特别是由 增加GATA-3和IL-4分泌的表达。此外，我们表明β1/β2-ar ko不太容易受到 C. muridarum生殖器感染比WT C57BL/6J。这些观察结果促使我们使用β2-AR KO模型，并且 探索衣原体生殖器感染的免疫发作。我们最近发现β2-ar KO对 C. muridarum比WT C57BL/6J。然而，慢性单牙的潜在机制在感染和 我们的小鼠模型中的免疫致病发生仍然未知。该提议的核心目的是定义 压力可以抑制免疫系统并增加生殖器孢子虫的强度的机制 感染及其在小鼠中的免疫病理学。我们假设顺式产生的NE导致刺激 小鼠中的𝛽𝛽2-ar信号通路，反过来抑制了针对Muridarum C. c. c. gunital的受保护的免疫反应 感染。为了检验这一假设，我们将进行以下三个实验作为该项目的一部分：在AIM＃1中，我们 将比较应力的β2-AR - / - 小鼠和C57BL/6J（β2-AR+/+）小鼠的CD4+T细胞子集免疫反应。我们 预计β2-AR的缺乏会增强胁迫小鼠中Th1细胞因子产生的恢复，这可能 导致穆里达鲁姆梭菌的清除。在AIM＃2中，我们将探索从β2-AR的下游信号通路 与压力的C57BL/6J小鼠相比，应力的KO小鼠。获得的数据可能会深入了解β2-AR的参与 在camp蛋白激酶A（PKA）和有丝分裂原激活的蛋白激酶（MAPK）途径中抑制免疫 系统。在AIM＃3中，我们将评估与WT C57BL/6J小鼠相比，应力的β2-AR KO的组织病理学变化， 然后，我们将评估细胞因子对病理学的贡献。该方法的数据将证明减少 β2-AR KO小鼠中的卵形病理学。提出的实验将提供有关免疫抑制的洞察力 内分泌和免疫系统在衣原体的免疫病作用中的相互作用引起的机制。 总体而言，从这些β2-ar不足小鼠获得的结果，加上我们以前的发现和其他发现，可以 揭示了更多证据表明慢性应激对人类疾病严重程度的影响。 OMB No. 0925-0001/0002（Rev. 03/2020通过02/28/2023批准）页面延续格式页面