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: 7494234
• 负责人: Henry H. Wortis
• 金额: $ 3万
• 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/7494234
• 关键词: Age; Animal Model; Antigen-Presenting Cells; B-Lymphocytes; Babesia microti; Babesiosis; Borrelia microti; C57BL/6 Mouse; Candidate Disease Gene; Cells; Chromosome Mapping; Complement; DBA/2 Mouse; Data; Disease; Effector Cell; Erythrocytes; Frequencies; Gene Expression; Genetic; Immunity; Inbred BALB C Mice; Individual; Infection; Laboratories; Lymphocyte; Lymphoid; Maps; Mediating; Modeling; Mouse Strains; Mus; Natural Immunity; Numbers; Organism; Parasitemia; Parasites; Phenotype; Population; Predisposition; Purpose; Reagent; Recombinant Inbred Strain; Recombinants; Resistance; Resistance to infection; SCID Mice; Spleen; Splenocyte; System; Systems Analysis; T-Lymphocyte; TLR2 gene; Testing; Time; Toll-like receptors; Variant; age effect; age related; aged; base; genetic analysis; immunosenescence; pathogen; prevent; programs

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 frequentlyproduces 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. microti increases with age.Specifically,we have shown that as DBA/2 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 DBA/2 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.

虽然老年人对各种微生物感染的易感性增加已被广泛记录，但其 机械原理还不太清楚。我们不知道有任何成熟的实验系统来分析 这种现象。我们相信我们可以为此目的开发一种独特的动物模型。我们提出的有机体 要研究的是病原体巴贝氏田鼠，一种原生动物血寄生虫， 50岁及以上的健康人士。我们实验室生成的数据首次证明， 小鼠对B的易感性。具体地说，我们已经证明，当DBA/2小鼠从2岁开始衰老时， 到6个月、12个月和18个月，寄生虫感染的红细胞的频率和持续性增加。 我们还证明，与年龄相关的易感性存在明显的菌株差异，如2、6、12 18个月大的BALB/c和C57 BL/6小鼠表现出明显的抗感染能力。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的持续寄生虫血症。 我们有额外的数据表明，SCID BALB/c小鼠维持长期的高寄生虫血症。转移幼稚 BALB/c脾细胞到SCID小鼠防止了这种持续的寄生虫血症，表明细胞转移系统可以被用于治疗寄生虫病。 用于识别效应细胞。重要的是，存在与年龄相关的可转移保护性免疫的丧失， DBA/2和BALB/c脾细胞。由于年龄相关的DBA/2脾细胞转移能力的差异， 抗性仅在较低的寄生虫负荷下显示，我们得出结论，BALB/c脾细胞赋予更大的保护作用 DBA/2细胞我们现在提出检验在特定人群中存在功能差异的假设 淋巴细胞和/或抗原提呈细胞，负责与年龄相关的抵抗力丧失。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 更高数量的B。先天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，利用重组近交和经典交配， 绘制与年龄相关的抗B能力下降的关键基因。显微镜我们将尝试找出候选人 基因的协调遗传分析和转录谱（微阵列）研究。