Bacterial and host factors in the pathogenesis of Lyme neuroborreliosis

莱姆神经疏螺旋体病发病机制中的细菌和宿主因素

• 批准号: 10443463
• 负责人: Catherine Ayn Brissette
• 金额: $ 42.3万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-23 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443463
• 关键词: Acute; Address; Affect; Animal Model; Anti-Inflammatory Agents; Antibiotic Therapy; Arthritis; Asia; Bacterial Adhesins; Biology; Blood Vessels; Borrelia; Borrelia burgdorferi; Brain; CD8-Positive T-Lymphocytes; Cardiac; Cells; Central Nervous System Diseases; Cephalic; Clinical; Clinical Research; Disease; Dura Mater; Encephalitis; Europe; Functional disorder; Genes; Genetic; Genotype; Headache; Heart; Hippocampus (Brain); Immune; Immune response; Immune signaling; Infection; Infiltration; Inflammation; Inflammatory; Integration Host Factors; Interferon Type II; Interferons; Intervention; Joints; Laboratories; Lead; Leukocytes; Lyme Arthritis; Lyme Disease; Lyme Neuroborreliosis; Lymphocyte; Macaca; Meningeal; Meninges; Meningitis; Modeling; Mus; Needles; Nervous system structure; Neuraxis; Neuritis; Neurologic; Neurologic Effect; Order Spirochaetales; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Rattus; Reporting; Research; Research Support; Risk Factors; Role; Severities; Short-Term Memory; Signal Transduction; Sterility; Strategic Planning; Study models; T-Lymphocyte; Technology; Testing; Therapeutic Intervention; Tick-Borne Diseases; Time; Tissues; United States; United States National Institutes of Health; Vasculitis; Vector-transmitted infectious disease; Virulence Factors; Work; brain parenchyma; cytokine; density; diagnostic criteria; disabling symptom; experience; innovation; insight; lyme pathogenesis; lymphatic drainage; neuroinflammation; nonhuman primate; pathogen; pathogenic bacteria; response; targeted treatment; tick transmission; tick-borne pathogen; working group

The Lyme disease spirochete Borrelia burgdorferi causes an infection with diverse clinical outcomes, which can include arthritis as well as cardiac and neurological involvement. Lyme neuroborreliosis can range from headaches and mild meningitis to more serious manifestations including vasculitis. Despite antibiotic treatment, a proportion of patients continue to suffer from debilitating symptoms including neurological effects. The mechanisms of central nervous system (CNS) pathology as well as bacterial and host risk factors for these manifestations are poorly understood, largely due to the lack of a tractable laboratory model for the study of Lyme disease in the CNS. Previously, we reported the ability of Bb to colonize the dura mater of mice during late disseminated infection that was associated with an increase in T cells. We now show acute and persistent extravascular Bb colonization of the dura mater after both needle inoculation and tick transmission, accompanied by increases in expression of inflammatory cytokines; in addition, we observe a robust interferon (IFN) response in the dura mater comparable to that seen during murine Lyme arthritis. Dura colonization is associated with perivascular leukocyte infiltration and meningitis, demonstrating for the first time that Bb-infected mice can develop meningitis. We also demonstrate an increase in IFN-stimulated genes in both the cortex and hippocampus of infected mice, despite a lack of detectable spirochetes in the brain parenchyma. A sterile IFN response in the absence of Bb is unique to the brain parenchyma and could provide insights into the mechanism of inflammatory CNS pathology associated with this pathogen. An unanswered question is how specific bacterial virulence factors, in concert with the host response, intersect to cause CNS disease. Our tractable model will allow us to directly assess bacterial and host factors leading to more severe inflammatory CNS involvement, as well as test potential interventions. Our innovative proposal challenges existing paradigms, utilizes state-of-the-art technologies, and addresses critical barriers to Lyme neuroborreliosis research. Our central hypothesis is that specific bacterial factors engage the host immune response in a deleterious manner. We will address our central hypothesis with the following Specific Aims: Characterize the role of Borrelia genetics on CNS bacterial burden and host response. Working hypothesis: the severity of the CNS immune response during infection with Lyme disease Borrelia is dictated by the genetics of the infecting isolate. Delineate the role of immune signaling and other host responses in the CNS. Working hypothesis: IFN signaling affects the local inflammatory and cellular activation responses in the CNS. Modulate inflammation and pathology through targeted intervention. Working hypothesis: Decreasing inflammation at early time points, regardless of spirochete burden, will reduce meningitis and deleterious immune responses in the brain parenchyma. Our proposal directly addresses the NIH Strategic Plan for Tickborne Disease Research, including understanding both the fundamental biology of, and host interactions with, tickborne pathogens. Our proposal also addresses outstanding questions identified by the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee of the HHS Tick Borne Disease Working Group, including what is the role of adhesins in dissemination to specific tissues. Our robust small animal model will allow us to fully characterize the CNS immune response to Bb infection, and to mechanistically define factors that contribute to neuroinflammation and disease. Identifying these factors will elucidate pathways to target for therapeutic intervention. Importantly, the results of our work will provide more sensitive and specific diagnostic criteria for Lyme neuroborreliosis and its sequalae.

莱姆病螺旋菌伯氏伯氏菌引起感染，具有多种临床结果，可以 包括关节炎以及心脏和神经系统受累。莱姆神经红细胞增多的范围从 头痛和轻度脑膜炎，包括血管炎，包括血管炎。尽管抗生素治疗 一部分患者继续患有令人衰弱的症状，包括神经系统作用。这 中枢神经系统（CNS）病理学以及细菌和宿主风险因素的机制 表现的理解很少，这主要是由于缺乏研究的实验室模型来研究 中枢神经系统中的莱姆病。 以前，我们报告了BB在晚期传播感染期间殖民小鼠的硬脑膜母乳的能力 这与T细胞的增加有关。现在，我们显示出急性和持续的血管外BB定殖 针接种和tick传输后，硬脑膜的伴随着表达的增加 炎症细胞因子；此外，我们观察到硬脑膜的强大干扰素（IFN）反应 与鼠莱姆关节炎期间看到的相当。硬脑膜定植与血管周白细胞有关 浸润和脑膜炎，首次证明了BB感染的小鼠可以发展脑膜炎。我们也是 尽管有感染小鼠的皮质和海马中的IFN刺激基因的增加，尽管 大脑实质缺乏可检测的螺旋体。在没有BB的情况下，无菌IFN响应是 大脑实质独有的，可以提供有关炎症性中枢神经系统机制的见解 与这种病原体相关的病理学。 一个未解决的问题是特定细菌毒力因素如何与宿主反应一致 引起中枢神经系统疾病。我们的可处理模型将使我们能够直接评估细菌和宿主因素，导致 更严重的炎症中枢神经系统参与以及测试潜在干预措施。我们的创新建议 挑战现有范式，利用最先进的技术，并解决莱姆的关键障碍 神经红细胞增多研究。我们的核心假设是特定的细菌因素使宿主免疫接触 以有害的方式做出回应。我们将以以下具体目的解决我们的中心假设： 表征疏螺旋体遗传学在中枢神经系统细菌负担和宿主反应中的作用。在职的 假设：莱姆病渗透症感染期间中枢神经系统免疫反应的严重程度取决于 感染分离物的遗传学。 描述了中枢神经系统中免疫信号传导和其他宿主反应的作用。工作假设：IFN 信号传导会影响中枢神经系统中局部炎症和细胞活化反应。 通过靶向干预来调节炎症和病理。工作假设：减少 早期炎症，无论螺旋体负担如何，都会减少脑膜炎和有害免疫力 大脑实质中的反应。 我们的建议直接解决了NIH的tick疾病研究战略计划，包括理解 两者的基本生物学和与tick虫病原体的相互作用和托管相互作用。我们的建议也解决了 莱姆病小组委员会的发病机理和病理生理学确定的杰出问题 HHS tick虫疾病工作组，包括粘附蛋白在传播特定方面的作用是什么 组织。我们强大的小动物模型将使我们能够充分表征CNS免疫反应对BB 感染，并从机械上定义有助于神经炎症和疾病的因素。识别 这些因素将阐明靶向治疗干预的途径。重要的是，我们工作的结果 将为莱姆神经红细胞增多及其序列化提供更灵敏和特定的诊断标准。