Bacterial and host factors in the pathogenesis of Lyme neuroborreliosis

莱姆病螺旋体伯氏疏螺旋体引起的感染具有不同的临床结果， 包括关节炎以及心脏和神经系统受累。莱姆神经疏螺旋体病的范围可以从 头痛和轻度脑膜炎，严重的表现包括血管炎。尽管进行了抗生素治疗， 一部分患者继续遭受包括神经影响在内的衰弱症状。的 中枢神经系统（CNS）病理学机制以及这些疾病的细菌和宿主风险因素 临床表现知之甚少，主要是由于缺乏一个易于处理的实验室模型来研究 中枢神经系统莱姆病。 以前，我们报道了Bb在晚期播散性感染期间定殖于小鼠硬脑膜的能力 这与T细胞的增加有关。我们现在显示急性和持续的血管外Bb定植 在针接种和蜱传播后，硬脑膜的表达增加， 此外，我们还观察到硬脑膜中有强烈的干扰素（IFN）反应， 与在鼠莱姆关节炎中观察到的相当。硬脑膜定植与血管周围白细胞有关 渗透和脑膜炎，第一次证明，B b感染的小鼠可以发展脑膜炎。我们也 在受感染小鼠的皮质和海马中，IFN刺激的基因增加， 脑实质中没有可检测到的螺旋体在没有Bb的情况下， 独特的脑实质，并可以提供洞察机制的炎症中枢神经系统 与这种病原体有关的病理学。 一个尚未回答的问题是，特定的细菌毒力因子如何与宿主反应相互作用 导致中枢神经系统疾病我们易于处理的模型将使我们能够直接评估导致 更严重的炎症性CNS受累，以及测试潜在的干预措施。我们的创新提案 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，特定的细菌因子参与宿主免疫 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： 表征疏螺旋体遗传学对CNS细菌负荷和宿主反应的作用。工作 假设：莱姆病疏螺旋体感染期间CNS免疫应答的严重程度由以下因素决定： 感染菌株的基因 阐明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 信号传导影响CNS中的局部炎症和细胞活化反应。 通过靶向干预调节炎症和病理学。工作假设：减少 无论螺旋体负荷如何，早期时间点的炎症都会减少脑膜炎和有害的免疫反应， 脑实质的反应。 我们的提案直接涉及NIH蜱传疾病研究战略计划，包括了解 包括蜱传病原体的基本生物学和宿主与蜱传病原体的相互作用。我们的建议还涉及 莱姆病发病机制和病理生理学小组委员会确定的悬而未决的问题， HHS蜱传疾病工作组，包括粘附素在传播特定 组织中我们强大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 这些因素将阐明治疗干预的靶向途径。重要的是，我们的工作成果 将为莱姆病及其后遗症提供更敏感、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.