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: 10303049
• 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/10303049
• 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. !

项目摘要 Miyamotoi Borrelia是由Ixodes Tick SPP传播的新兴接力发烧（RF）螺旋体 传输莱姆病代理Borrelia burgdorferi。 B. Miyamotoi最近被发现引起人类 莱姆病是内在疾病的地区。我们的小组已将B. Miyamotoi与患有 传播的莱姆病表明，发生了宫林芽孢杆菌和B. burgdorferi的共同感染。 宫类芽孢杆菌相关疾病的全部光谱尚不清楚，但是其他RF伯氏引起血液 人类的疾病，多器官系统功能障碍和胎儿灭亡。该项目将使用鼠标模型 定义B.宫类芽孢杆菌发病机理，宿主免疫反应和疾病风险因素，并检查 B.宫本B./b的影响。与这些病原体相关的有关疾病的伯格多菲利（Burgdorferi）。研究 将与我们的临床分离株进行。 从威斯康星州产生的tick分离。 B. Miyamotoi传输的刻度附件持续时间将是 确定细菌的动力学，疾病谱和持久部位。作为最伟大的B。 在不同ixodes spp的分离株中，观察到的宫类多样性，我们将评估疾病的表达 i。pacificus-borne B.宫类分离株感染。对免疫缺陷的小鼠和小鼠的研究 由于脾切除术，免疫抑制剂和妊娠而改变的免疫学改变了 描述更严重疾病和不良母亲结局的风险因素。基于初步 数据，我们假设针对宫山芽孢杆菌的早期天生防御可能与其他RF Borrelia有所不同。我们 将采用飞机飞行时间质谱（CYTOF）的先进技术 免疫表型反应细胞及其在感染过程中产生的细胞因子。我们将确定 感染引起的抗体是否可以防止幼稚宿主或同一宿主中的挑战感染 受到tick传输的螺旋体的挑战。我们将评估B. burgdorferi/b的影响。 Miyamotoi 与这些病原体相关的疾病表达的共同感染。将进行cytof 表型和功能上表征了宿主对与宫类芽孢杆菌和B.共感染的免疫反应。 Burgdorferi，在血液和连接的组织中繁殖的病原体。这些研究的结果将 提供有关tick传输动态，宫山芽孢杆菌的临床有用信息 疾病和保护症状的免疫接地液可预测人类疾病和不良后果的危险因素。 呢