Babesiosis as a model of age-related immunosenescence

描述(申请人提供)：随着年龄的增长，更多的人变得容易感染。由于老年人在西方世界的人口中所占的比例越来越大，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。我们开发了一种由微小巴贝斯虫引起的人类巴贝斯虫病的小鼠模型，这是一种在老年人中特别严重的新感染。我们观察到幼龄DBA/2小鼠出现明显的寄生虫血症，而幼龄C57BL/6、B10.D2和BALB/c小鼠则没有。在DBA/2小鼠中，早期以强烈和短暂的寄生虫血症为特征，随后是低级别但持续的寄生虫血症的晚期。随着年龄的增长，DBA/2小鼠的急、慢性寄生虫血症均增加，而C57BL/6、B10.D2或BALB/c小鼠则无明显变化。利用B10.D2×DBA/2(BXD)和BALB/c×DBA/2(CXD)杂交小鼠和染色体替代小鼠，我们证实：1)抗性在幼龄和老年小鼠中是一个复杂的性状；2)幼龄小鼠的急性抗性与老年小鼠不同。我们得出结论，老年DBA/2小鼠对年龄受限的QTL有更大的易感性。我们现在建议识别抗性和易感等位基因，并揭示它们如何调节对微小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结合起来。在目标3中，我们将确定导致抗性的细胞，并受主要QTL的多态影响。将研究菌株在细胞功能上的差异，并用于指导遗传分析。我们希望，识别年龄敏感的多态，调节老年小鼠对巴贝斯虫病的免疫抵抗力，可能有助于寻找使老年个体易受感染的等位基因。与公共卫生相关：随着年龄的增长，许多人更容易受到感染。人们对其中的原因知之甚少。我们正在探索使衰老小鼠易受感染的基因。因为老鼠和人类的基因有很大的相似性，我们相信我们在老鼠身上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.