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: 7069621
• 负责人: Henry H. Wortis
• 金额: $ 45.11万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069621
• 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， 老年人感染各种生物体是广泛记载的，其 机械原理还不太清楚。我们不知道任何发达的 实验系统分析这一现象。我们相信我们可以 为此目的开发了一种独特的动物模型。我们提出的生物体 研究的是病原体小Babelioti，一种原生动物血寄生虫， 在50岁的健康个体中经常产生严重的疾病， 以上我们实验室生成的数据首次证明， 小鼠对B的易感性。微滴随年龄增长而增加。具体来说，我们有 显示当DBAI 2小鼠年龄从2到6个月、12个月和18个月时， 寄生虫感染红细胞的频率和持续性增加。我们 也证明了，有一个显着的应变变化， 年龄相关的易感性，如2、6、12和18月龄BALB/c， C57 BL/6小鼠显示出显著的抗感染性。尽管如此，年龄较大的BALB/c和 C57 BL/6小鼠显示早期寄生虫血症适度增加，但从未表现出 可检测到的持续寄生虫血症我们有额外的数据表明， SCID BALB/c小鼠持续长时间的高寄生虫血症。未处理BALB/c的转移 脾细胞对SCID小鼠预防这种持续的寄生虫血症，表明 细胞转移系统可用于鉴定效应细胞。重要的是 是年龄相关的DBA/2可转移保护性免疫力丧失， BALB/c脾细胞。由于年龄相关的能力差异， DBA/2脾细胞对转移抗性仅在较低寄生虫时显示 负荷，我们得出结论，BALB/c脾细胞提供更大的保护比 DBAJ 2细胞。我们现在提出测试的假设，有功能 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小鼠不会屈服于大量的B.先天性免疫 可能有助于抵抗。我们将使用遗传学方法来测试这一点 假说.我们进一步建议使用正式的遗传分析， 重组近交系和经典交配，以绘制对此至关重要的基因 与年龄相关的对B的抗性下降。显微镜我们会尝试找出 候选基因的协调遗传分析和转录谱 （微阵列）研究。