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: 7121706
• 负责人: Henry H. Wortis
• 金额: $ 6.07万
• 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/7121706
• 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）：虽然增加的敏感性 老年人被多种生物体感染的情况已被广泛记录，其 其机制基础知之甚少。我们不知道有任何成熟的 分析这一现象的实验系统。我们相信我们可以 为此目的开发独特的动物模型。我们建议的有机体 研究的病原体是田鼠巴贝斯虫，一种原生动物血寄生虫， 50 岁以下健康人士经常会患上严重疾病 多于。我们实验室生成的数据首次证明 小鼠对微小芽孢杆菌的易感性随着年龄的增长而增加。具体来说，我们有 结果表明，随着 DBAI2 小鼠年龄从 2 个月到 6 个月、12 个月和 18 个月， 寄生虫感染红细胞的频率和持久性增加。我们 还证明了存在显着的应变变化 与年龄相关的易感性，如 2、6、12 和 18 个月大的 BALB/c 和 C57BL/6小鼠表现出明显的抗感染能力。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，但从未表现出来 可检测到的持续性寄生虫血症。我们有额外的数据证明 SCID BALB/c 小鼠长期维持高寄生虫血症。转移幼稚 BALB/c SCID 小鼠的脾细胞可以预防这种持续的寄生虫血症，这表明 细胞转移系统可用于鉴定效应细胞。重要的是，有 是 DBA/2 与年龄相关的可转移保护性免疫力的丧失，并且 BALB/c 脾细胞。由于年龄相关的能力差异 DBA/2 脾细胞对转移的抗性仅在较低级寄生虫中显示 负载，我们得出结论，BALB/c 脾细胞比 DBAJ2 细胞。我们现在建议检验以下假设：存在功能性 特定淋巴细胞群和/或抗原呈递的差异 负责与年龄相关的抵抗力丧失的细胞。我们将 在 SCID 小鼠中使用我们的适应性转移系统来定义这些细胞群。 由于 SCID 小鼠不会死于大量田鼠芽孢杆菌，因此先天免疫 可能有助于抵抗。我们将使用遗传方法来测试这一点 假设。我们进一步建议使用正式的遗传分析 重组近交和经典交配来绘制对此至关重要的基因 年龄相关的田鼠芽孢杆菌抵抗力下降。我们将尝试识别 通过协调遗传分析和转录谱分析候选基因 （微阵列）研究。