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: 7995053
• 负责人: Edouard G Vannier
• 金额: $ 1.91万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995053
• 关键词: Acute; Affect; Age; Age-Months; Alleles; Babesia microti; Babesiosis; Backcrossings; Bioinformatics; Borrelia microti; CD8B1 gene; Candidate Disease Gene; Cell physiology; Cells; Chromosomes; Chronic; Complex; Congenic Mice; Consomic Strain; DBA/2 Mouse; Data; Dendritic Cells; Elderly; Erythrocytes; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Transcription; Goals; Human; Immune; Immune response; Inbred BALB C Mice; Individual; Infection; Maps; Modeling; Molecular Profiling; Monitor; Morbidity - disease rate; Mus; Parasitemia; Phagocytosis; Phase; Phenotype; Population; Predisposition; Production; Quantitative Trait Loci; Resistance; Spleen; T-Lymphocyte; Testing; Validation; Western World; Work; age related; aged; base; cohort; cytokine; defined contribution; experience; genetic analysis; immune resistance; immunosenescence; interest; macrophage; mouse model; positional cloning; public health relevance; research study; resistance allele; response; trait

DESCRIPTION (provided by applicant): As people age, a greater number becomes susceptible to infections. Because the aged represent an ever-growing segment of the populations in the western world, morbidities due to infection are significant. We are interested in identifying alleles that underlie this age-acquired susceptibility. We developed a mouse model of human babesiosis due Babesia microti, an emerging infection particularly severe in the aged. We observed that young DBA/2 mice experience significant parasitemia but young C57BL/6, B10.D2 and BALB/c mice do not. In DBA/2 mice an early phase characterized by an intense and transient parasitemia is followed by a late phase of low grade, but persistent parasitemia. As age advances, both acute and chronic parasitemia become greater in DBA/2, but not in C57BL/6, B10.D2 or BALB/c mice. Using B10.D2 x DBA/2 (BXD) and BALB/c x DBA/2 (CXD) crosses as well as chromosome substitution mice, we have established that i) resistance is a complex trait in young and old mice, and ii) acute resistance in young mice maps to QTL that differ from those of old mice. We conclude that the greater susceptibility of old DBA/2 mice maps to age-restricted QTL. We now propose to identify resistance and susceptibility alleles and to uncover how they modulate the response to B. microti infection. In Aim#1, we will identify the major genetic determinants of acute resistance in old mice of the BXD cross. In Aim#2, we will identify the major genetic determinants of acute resistance in old mice of the CXD cross. Both aims combine a positional cloning approach with bioinformatic analyses and gene expression studies. In Aim#3, we will identify the cells that contribute to resistance and are affected by the polymorphisms underlying the major QTL. Strain differences in cell function will be studied and used to guide the genetic analysis. We are hopeful that the identification of age-sensitive polymorphisms that modulate immune resistance of old mice to babesiosis may inform the search of alleles that predispose aged individuals to infection. PUBLIC HEALTH RELEVANCE: As they age, many people become more susceptible to infection. The reasons are poorly understood. We are exploring the genes that render aged mice susceptible to infection. Because there is great similarity between the genes of mice and humans we believe our discoveries in mice will aid work to understand the genetic basis of age-related susceptibility to infection in humans.

描述（由申请人提供）：随着人们年龄的增长，越来越多的人变得容易受到感染。由于老年人在西方世界人口中所占比例不断增长，因此感染引起的发病率很高。我们有兴趣识别导致这种年龄获得性易感性的等位基因。我们开发了一种由微小巴贝斯虫引起的人类巴贝斯虫病小鼠模型，这是一种新出现的感染，在老年人中尤其严重。我们观察到年轻的 DBA/2 小鼠会出现明显的寄生虫血症，但年轻的 C57BL/6、B10.D2 和 BALB/c 小鼠则不会。在 DBA/2 小鼠中，早期阶段的特征是强烈和短暂的寄生虫血症，随后是低度但持续的寄生虫血症的晚期阶段。随着年龄的增长，DBA/2 小鼠中的急性和慢性寄生虫血症变得更加严重，但 C57BL/6、B10.D2 或 BALB/c 小鼠中则不然。使用 B10.D2 x DBA/2 (BXD) 和 BALB/c x DBA/2 (CXD) 杂交以及染色体替换小鼠，我们确定 i) 抵抗力是年轻和年老小鼠的复杂性状，ii) 急性年轻小鼠的抗性映射到与年老小鼠不同的QTL。我们得出的结论是，老年 DBA/2 小鼠对年龄限制的 QTL 具有更大的敏感性。我们现在建议鉴定抗性和易感性等位基因，并揭示它们如何调节对田鼠芽孢杆菌感染的反应。在目标#1 中，我们将确定 BXD 杂交老年小鼠急性耐药性的主要遗传决定因素。在目标#2 中，我们将确定 CXD 杂交老年小鼠急性耐药性的主要遗传决定因素。这两个目标都将定位克隆方法与生物信息学分析和基因表达研究相结合。在目标#3 中，我们将识别有助于抗性并受主要 QTL 多态性影响的细胞。将研究细胞功能的菌株差异并用于指导遗传分析。我们希望，调节老年小鼠对巴贝斯虫病免疫抵抗力的年龄敏感多态性的鉴定可以为寻找使老年人易于感染的等位基因提供信息。公共卫生相关性：随着年龄的增长，许多人变得更容易受到感染。其原因尚不清楚。我们正在探索使老年小鼠易受感染的基因。由于小鼠和人类的基因之间存在很大的相似性，我们相信我们在小鼠身上的发现将有助于了解人类与年龄相关的感染易感性的遗传基础。