Babesiosis as a model of age-related immunosenescence

巴贝虫病作为年龄相关免疫衰老的模型

• 批准号: 6891809
• 负责人: Henry H. Wortis
• 金额: $ 46.91万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891809
• 关键词: B lymphocyte; Babesia; Coccidia; SCID mouse; T lymphocyte; age difference; antigen presenting cell; babesiosis; cellular immunity; genetic mapping; genetic strain; genetic susceptibility; immunosenescence; inbreeding; laboratory mouse; microarray technology; microorganism immunology; passive immunization; toll like receptor

DESCRIPTION (provided by the applicant): While the increased susceptibility of the aged to infection by a variety of organisms is widely documented, its mechanistic basis is little understood. We are not aware of any well-developed experimental system for analysis of this phenomenon. We believe that we can exploit a unique animal model for this purpose. The organism we propose to study is the pathogen Babesia microti, a protozoan hemoparasite that most frequently produces severe disease in otherwise healthy individuals aged 50 and above. Data generated in our laboratory demonstrate for the first time that susceptibility of mice to B. microtiincreases with age. Specifically, we have shown that as DBAI2 mice age from two to six, twelve and 18 months there is an increase in the frequency and persistence of parasite infected erythrocytes. We have also demonstrated that there is a marked strain variation in age-associated susceptibility, as two, six, twelve and 18-month-old BALB/c and C57BL/6 mice show marked resistance to infection. Nonetheless, older BALB/c and C57BL/6 mice display a modest increase in early parasitemia but never manifest detectable persistent parasitemia. We have additional data demonstrating that SCID BALB/c mice sustain prolonged high parasitemia. Transfer of naive BALB/c splenocytes to SCID mice prevents such persistent parasitemia, showing that a cell transfer system can be used to identify effector cells. Importantly, there is an age-associated loss of transferable protective immunity by DBA/2 and BALB/c spleen cells. Since the age-associated differences in the ability of DBA/2 spleen cells to transfer resistance is only revealed at a lower parasite load, we conclude that BALB/c spleen cells confer a greater protection than DBAJ2 cells. We now propose to test the hypothesis that there are functional differences in specific populations of lymphocytes and/or antigen presenting cells that are responsible for the age-associated loss of resistance. We will use our adaptive transfer system in SCID mice to define these cell populations. Since SCID mice do not succumb to high numbers of B. microti, innate immunity may contribute to resistance. We will use a genetic approach to test this hypothesis. We further propose to use formal genetic analysis utilizing recombinant inbred and classic matings to map genes critical for this age-associated decline in resistance to B. microti. We will attempt to identify candidate genes by coordinated genetic analysis and transcriptional profiling (microarray) studies.

描述(由申请人提供)：虽然增加的易感性 老年人受到各种微生物感染的情况被广泛记录在案，其 人们对机制基础知之甚少。我们不知道有没有任何发达的 用于分析这一现象的实验系统。我们相信我们可以 为此，开发一种独特的动物模型。我们提议的生物体 研究的病原体是微小巴贝斯虫，一种原生动物血寄生虫 通常在50岁和其他健康的人中产生严重的疾病 上面。我们实验室产生的数据第一次证明 小鼠对微滴虫的敏感性随着年龄的增长而增加。具体来说，我们有 结果表明，当DBAI2小鼠从2岁到6岁、12个月和18个月时，有一个 寄生虫感染红细胞的频率和持久性增加。我们 也证明了有一个显著的菌株变异 年龄相关性易感性，如2、6、12和18个月龄的BALB/c和 C57BL/6小鼠对感染表现出明显的抵抗力。尽管如此，较旧的BALB/c和 C57BL/6小鼠早期寄生虫血症略有增加，但从未出现过 可检测到的持续性寄生虫血症。我们有更多的数据表明 SCID BALB/c小鼠长期存在高寄生虫血症。朴素的BALB/c的转移 脾细胞给SCID小鼠预防这种持续性寄生虫血症，表明一种 细胞转移系统可用于识别效应细胞。重要的是，在那里 是DBA/2与年龄相关的可转移保护性免疫的丧失 Balb/c脾细胞。由于年龄相关的能力差异 DBA/2脾细胞对转移的抵抗力只表现在较低的寄生虫 负载，我们得出结论，BALB/c脾细胞比 DBAJ2细胞。我们现在建议检验这样一个假设，即有功能的 淋巴细胞和/或抗原呈递的特定群体的差异 负责与年龄相关的抵抗力丧失的细胞。我们会 使用我们在SCID小鼠中的适应性转移系统来定义这些细胞群。 由于SCID小鼠不会死于大量的微小芽孢杆菌，因此先天免疫 可能会导致抵抗。我们将使用遗传方法来测试这一点 假设。我们还建议使用正式的遗传分析方法 重组自交系和经典配对定位对此至关重要的基因 对微小芽孢杆菌的抵抗力随年龄增长而下降。我们会尝试找出 协同遗传分析和转录谱分析的候选基因 (微阵列)研究。