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

项目主任/主要研究者（最后，第一，中间）：Belay，Tesfaye 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性疾病。如果放任 未经治疗的衣原体生殖器感染会导致盆腔炎、宫外孕和不孕症。人们普遍 众所周知，这种疾病的免疫病理反应，而不是感染本身，仍然是一个严重的公共卫生问题， 问题.了解压力如何影响对性行为的抵抗力或易感性是医学上的兴趣。 传播疾病许多研究者已经研究了对C.沙眼，但效果 对衣原体生殖器感染的压力尚未探讨，也不了解。我们的研究旨在了解 它们之间的关系。为了实现这一目标，我们开发了一种小鼠慢性应激模型， 每天在冷水中浸泡5分钟，持续21天。这种冷诱导应激（CIS）小鼠模型显示出增加的强度 衣原体生殖器感染，这与应激激素去甲肾上腺素的升高有关 (NE)原发性和继发性感染。我们的研究表明，CIS促进增加β 2- 肾上腺素能受体（β2-AR）在CD 4 + T细胞中的表达，以及辅助性T细胞2（Th 2）的分化，特别是通过 增加加塔-3的表达和IL-4的分泌。此外，我们还发现β1/β2-AR KO对 C.小鼠生殖道感染率高于WT C57 BL/6 J。这些观察结果促使我们使用β2-AR KO模型， 探讨生殖道衣原体感染的免疫发病机制。我们最近发现，β2-AR KO更能抵抗 C.与野生型C57 BL/6 J相比，然而，慢性CIS对感染的潜在机制和 在我们小鼠模型中免疫发病机制仍然未知。本提案的中心目标是确定 应激可能抑制免疫系统并增加生殖器C的强度的机制。穆里达鲁姆 感染及其免疫病理学。我们假设CIS产生的NE刺激了 在小鼠中，CD 34 2-AR信号通路，反过来，抑制了针对C.生殖子宫 感染为了验证这一假设，我们将进行以下三个实验作为本项目的一部分：在目标#1中，我们 将比较应激β2-AR-/-小鼠和C57 BL/6 J（β2-AR+/+）小鼠的CD 4 + T细胞亚群免疫应答。我们 预期β2-AR的缺乏增强了应激小鼠中Th 1细胞因子产生的恢复，这可能 导致C. muridarum。在目标#2中，我们将探索β2-AR的下游信号通路， 与应激的C57 BL/6 J小鼠相比，应激的KO小鼠。所获得的数据可能有助于深入了解β2-AR的参与 在cAMP-蛋白激酶A（PKA）和丝裂原活化蛋白激酶（MAPK）途径中， 系统在目标#3中，我们将评估与WT C57 BL/6 J小鼠相比应激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 β2-AR KO小鼠的输卵管病理学。拟议的实验将提供深入了解免疫抑制 衣原体免疫发病机制中内分泌和免疫系统相互作用的机制。 总之，从这些β2-AR缺陷小鼠中获得的结果，结合我们以前的发现和其他人的发现， 揭示了慢性压力对人类衣原体疾病严重程度影响的更多证据。 OMB编号0925-0001/0002（修订版03/2020批准至02/28/2023）页码继续格式页码