Babesiosis as a model of age-related immunosenescence

描述（由申请人提供）：随着年龄的增长，越来越多的人容易受到感染。由于老年人在西方世界人口中所占比例不断增加，因此感染引起的发病率很高。我们感兴趣的是确定这种年龄获得性易感性的等位基因。我们开发了一个小鼠模型的人类巴贝虫病由于巴贝虫microti，一个新兴的感染，特别是严重的老年人。我们观察到年轻的DBA/2小鼠经历了显著的寄生虫血症，而年轻的C57 BL/6、B10.D2和BALB/c小鼠没有。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，随后是低级别但持续的寄生虫血症的晚期阶段。随着年龄的增长，DBA/2小鼠的急性和慢性寄生虫血症都变得更严重，但C57 BL/6、B10.D2或BALB/c小鼠则没有。使用B10.D2 x DBA/2（BXD）和BALB/c x DBA/2（CXD）杂交以及染色体置换小鼠，我们已经确定i）抗性在年轻和老年小鼠中是一个复杂的性状，ii）年轻小鼠的急性抗性映射到与老年小鼠不同的QTL。我们的结论是，老年DBA/2小鼠的易感性更大的年龄限制的QTL地图。我们现在提出鉴定抗性和易感性等位基因，并揭示它们如何调节对B的反应。真菌感染在目标#1中，我们将确定BXD杂交的老年小鼠中急性抗性的主要遗传决定因素。在目标#2中，我们将确定CXD杂交的老年小鼠中急性抗性的主要遗传决定因素。这两个目标联合收割机结合定位克隆方法与生物信息学分析和基因表达研究。在目标#3中，我们将鉴定有助于抗性并受主要QTL的多态性影响的细胞。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，年龄敏感的多态性，调节老年小鼠巴贝斯虫病的免疫抵抗力的鉴定，可能会通知搜索的等位基因，使老年人感染。公共卫生相关性：随着年龄的增长，许多人变得更容易感染。原因不明。我们正在探索使老年小鼠易受感染的基因。因为小鼠和人类的基因之间有很大的相似性，我们相信我们在小鼠中的发现将有助于理解人类与年龄相关的感染易感性的遗传基础。

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.