Pathogenesis of Borrelia miyamotoi infection and Lyme coinfection in mice

小鼠宫本疏螺旋体感染和莱姆病合并感染的发病机制

• 批准号: 10059164
• 负责人: Linda K. Bockenstedt
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059164
• 关键词: Acute; Antibodies; Area; B-Lymphocyte Subsets; Bacteremia; Black-legged Tick; Blood; Borrelia; Borrelia burgdorferi; Borrelia miyamotoi; Cells; Characteristics; Chronic; Clinical; Complement; Connecticut; Connective Tissue; Data; Disease; Disease Outcome; Elderly; Event; Functional disorder; Gait abnormality; Goals; Health; Hematological Disease; Host resistance; Human; Immune; Immune Sera; Immune response; Immunity; Immunocompromised Host; Immunodeficient Mouse; Immunophenotyping; Immunosuppressive Agents; Impaired cognition; Inbred Strains Mice; Infection; Interleukin-10; Ixodes; Ixodidae; Japan; Kinetics; Lyme Disease; Meningoencephalitis; Modeling; Mouse Strains; Mus; Mutant Strains Mice; Natural Immunity; Order Spirochaetales; Organ; Ornithodoros; Outcome; Pathogenesis; Pathology; Patients; Peromyscus; Persons; Phenotype; Predisposition; Pregnancy; Pregnant Women; Public Health; Relapse; Relapsing Fever; Reporting; Resolution; Risk; Risk Factors; Russia; Severity of illness; Site; Source; Specificity; Splenectomy; Splenocyte; Syndrome; System; T-Lymphocyte; Technology; Ticks; Time; Tissues; Tropism; United States; Viral; Vulnerable Populations; Wisconsin; Work; adaptive immunity; adverse outcome; base; co-infection; cytokine; epidemiologic data; fetal; human disease; human pathogen; infection rate; innate immune mechanisms; motor disorder; mouse model; pathogen; prevent; relapsing fever borrelia; response; tick transmission; time of flight mass spectrometry; tissue tropism; transmission process; vector

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. !

项目总结 宫本疏螺旋体是一种新出现的复发热(RF)螺旋体，由硬蜱传播，也是一种 传播莱姆病病原体伯氏疏螺旋体。宫本杆菌最近被发现会导致人类 莱姆病流行地区的疾病。我们小组从一名患有B型流感的人身上分离出宫本杆菌 播散性莱姆病，表明宫本芽胞杆菌和伯氏杆菌混合感染正在发生。 宫本杆菌相关疾病的全谱尚不清楚，但其他rf疏螺旋体可引起血液。 人类的疾病、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 确定宫本杆菌的致病机制、宿主免疫反应和疾病的危险因素，并检查 宫本杆菌/伯氏杆菌混合感染对与这些病原体相关的疾病的影响。研究 将与我们来自康涅狄格州的临床分离的肩周炎传播的宫本杆菌和一种新的 产生了威斯康星州的壁虱分离株。宫本氏杆菌传播的壁虱持续时间为 确定以及菌血症、疾病谱和持续部位的动力学。作为最伟大的B。 从不同的硬体动物分离到不同的Miyamotoi多样性，我们将在 感染由太平洋乳杆菌携带的宫本杆菌分离株。免疫缺陷小鼠和免疫缺陷小鼠的研究 因脾切除、免疫抑制剂和怀孕而改变的免疫力将被用于 描述更严重疾病和不良母婴结局的危险因素。基于初步的 数据，我们推测对宫本螺旋体的早期先天防御可能与其他RF疏螺旋体不同。我们 将应用先进的细胞因子飞行时间质谱仪(CyTOF)技术来广泛 免疫表型反应细胞及其在感染过程中产生的细胞因子。我们将决定 感染引发的抗体是否能防止幼稚宿主或同一宿主中的挑战感染 受到壁虱传播的螺旋体的挑战。我们将评估Burgdorferi/B.Miyamotoi的影响 混合感染对疾病表达的影响与这些病原体中的每一种都有关。将进行细胞TOF以 从表型和功能上描述了宿主对宫本芽胞杆菌和芽胞杆菌混合感染的免疫反应。 伯氏杆菌是一种在血液和结缔组织中以不同方式繁殖的病原体。这些研究的结果将 提供有关蜱类传播动态、宫本杆菌组织嗜性和 疾病和免疫保护的相关性，以预测人类疾病的风险因素和不良后果。 好了！