Bacterial and host factors in the pathogenesis of Lyme neuroborreliosis

莱姆病伯氏疏螺旋体引起的感染具有不同的临床结果，可以 包括关节炎以及心脏和神经受累。莱姆氏神经疏螺旋体病的范围从 头痛和轻微的脑膜炎到更严重的表现，包括脉管炎。尽管接受了抗生素治疗， 一部分患者继续遭受包括神经影响在内的衰弱症状的折磨。这个 中枢神经系统(CNS)病理机制以及细菌和宿主的危险因素 对表现形式的理解很少，这主要是由于缺乏可处理的实验室模型来研究 中枢神经系统的莱姆病。 在此之前，我们报道了在晚期播散性感染过程中，BB在小鼠硬脑膜中定植的能力。 这与T细胞的增加有关。我们现在显示了急性和持续性的血管外BB定植 硬脑膜在针接种和壁虱传播后，伴随着表达增加 炎性细胞因子；此外，我们观察到在硬脑膜中有很强的干扰素反应。 与小鼠莱姆关节炎时的情况相当。硬脑膜定植与血管周围白细胞相关 第一次证明了BB感染的小鼠会患上脑膜炎。我们也 在感染小鼠的大脑皮质和海马区显示干扰素刺激基因的增加，尽管 脑实质中缺乏可检测到的螺旋体。在没有BB的情况下，无菌的干扰素反应是 脑实质独有的，可提供对炎症中枢神经系统的机制的洞察 与这种病原体有关的病理学。 一个悬而未决的问题是，特定的细菌毒力因子是如何与宿主的反应相结合的 导致中枢神经系统疾病。我们的易处理模型将使我们能够直接评估导致 更严重的炎症性中枢神经系统参与，以及测试潜在的干预措施。我们的创新方案 挑战现有模式，利用最先进的技术，解决莱姆的关键障碍 神经疏螺旋体病研究。我们的中心假设是特定的细菌因子引起宿主免疫 以有害的方式回应。我们将通过以下具体目标来解决我们的中心假设： 描述疏螺旋体遗传学在中枢神经系统细菌负荷和宿主反应中的作用。劳作 假设：感染莱姆病螺旋体期间中枢神经系统免疫反应的严重程度由 具有感染力的分离株的遗传学。 描述免疫信号和其他宿主反应在中枢神经系统中的作用。工作假设：干扰素 信号转导影响中枢神经系统的局部炎症和细胞激活反应。 通过有针对性的干预调节炎症和病理。工作假设：递减 在早期时间点发炎，无论螺旋体的负担如何，都会减少脑膜炎和有害免疫。 脑实质中的反应。 我们的建议直接涉及美国国立卫生研究院壁虱传播疾病研究战略计划，包括了解 壁虱传播病原体的基础生物学和宿主相互作用。我们的建议还解决了 莱姆病发病机制和病理生理学小组委员会确定的突出问题 卫生与公众服务部壁虱传播疾病工作组，包括粘附素在传播到特定疾病中的作用 纸巾。我们健壮的小动物模型将使我们能够充分表征中枢神经系统对BB的免疫反应 感染，并机械地定义导致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，我们的工作成果 将为莱姆氏脑疏螺旋体病及其后遗症提供更敏感和特异的诊断标准。

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.