Pathogenesis of Borrelia miyamotoi infection and Lyme coinfection in mice

项目摘要 宫本疏螺旋体是一种新出现的回归热（RF）螺旋体，由硬蜱传播， 传播莱姆病病原体伯氏疏螺旋体。B。宫本最近被发现会导致人类 莱姆病流行地区的疾病。我们小组已经隔离了B。宫本井从一个人与 播散性莱姆病，表明B. miyamotoi和B. Burgdorferi正在发生。 B的全光谱。miyamotoi相关的疾病是未知的，但是其他RF疏螺旋体引起血液 疾病、多器官系统功能障碍和胎儿死亡。该项目将使用鼠标模型来 定义B。miyamotoi发病机制，宿主免疫反应和疾病的危险因素，并检查 B的影响。宫本/B。与这些病原体中的每一种相关的疾病。研究 将用我们的临床分离株I.肩胛骨承载B。来自康涅狄格州的miyamotoi和一个新的 从威斯康星州分离出蜱虫。B的蜱附着持续时间。Miyamotoi传输将是 确定以及菌血症的动力学、疾病谱和持久性位点。最伟大的B。 在来自不同硬蜱属的分离株中观察到miyamotoi多样性，我们将在 感染I.太平洋传播B.宫本分离物。在免疫缺陷小鼠和患有 由于脾切除术、免疫抑制剂和妊娠引起的免疫改变将进行， 描述更严重疾病和不良母胎结局的风险因素。根据初步 数据，我们假设，早期先天防御B。miyamotoi可能不同于其他RF疏螺旋体。我们 将采用先进的细胞因子飞行时间质谱（CyTOF）技术， 免疫表型应答细胞和它们在感染期间产生的细胞因子。我们将确定 感染引起的抗体是否可以预防初始宿主或同一宿主的攻毒感染 被蜱虫传播的螺旋体感染我们将评估B的影响。burgdorferi/B.宫本井 共感染对与这些病原体中的每一种相关的疾病表达的影响。将进行CyTOF， 表型和功能上表征了宿主对与B共感染的免疫应答。miyamotoi和B. burgdorferi，在血液和结缔组织中生长差异的病原体。这些研究的结果将 提供关于蜱传播动力学的临床有用信息，B。宫本氏组织向性和 疾病和免疫保护的相关性，以预测人类疾病和不良后果的风险因素。 !

PROJECT SUMMARY Borrelia miyamotoi is a newly emerging relapsing fever (RF) spirochete transmitted by Ixodes tick spp that also transmit the Lyme disease agent Borrelia burgdorferi. B. miyamotoi has recently been found to cause human disease in areas where Lyme disease is endemic. Our group has isolated B. miyamotoi from a person with disseminated Lyme disease, demonstrating that coinfection of B. miyamotoi and B. burgdorferi is occurring. The full spectrum of B. miyamotoi-associated disease is not known, however other RF Borrelia cause blood disorders, multiorgan system dysfunction, and fetal demise in humans. This project will use a mouse model to define B. miyamotoi pathogenesis, host immune responses and risk factors for disease, and to examine the impact of B. miyamotoi/B. burgdorferi coinfection on disease associated with each of these pathogens. Studies will be conducted with our clinical isolate of I. scapularis-borne B. miyamotoi from Connecticut and a newly generated tick isolate from Wisconsin. The duration of tick attachment for B. miyamotoi transmission will be determined as well as kinetics of bacteremia, spectrum of disease and sites of persistence. As the greatest B. miyamotoi diversity is seen among isolates from different Ixodes spp, we will evaluate disease expression after infection with an I. pacificus-borne B. miyamotoi isolate. Studies in immunodeficient mice and mice with altered immunity due to splenectomy, immunosuppressive agents, and pregnancy will be conducted to delineate risk factors for more severe disease and adverse maternal-fetal outcomes. Based on preliminary data, we hypothesize that the early innate defense against B. miyamotoi may differ from other RF Borrelia. We will employ the advanced technology of cytokine time-of-flight mass spectrometry (CyTOF) to broadly immunophenotype responding cells and the cytokines they produce during infection. We will determine whether antibodies elicited by infection can prevent challenge infection in a naïve host or in the same host challenged with tick-transmitted spirochetes. We will assess the impact of B. burgdorferi/B. miyamotoi coinfection on disease expression associated with each of these pathogens. CyTOF will be conducted to phenotypically and functionally characterize the host immune response to coinfection with B. miyamotoi and B. burgdorferi, pathogens that thrive differentially in blood and connective tissue. The results of these studies will provide clinically useful information regarding tick transmission dynamics, B. miyamotoi tissue tropism and disease, and immune correlates of protection to predict risk factors for human disease and adverse outcomes. !