Genetic susceptibility to mucosal infections with aging (Resubmission)

项目总结/摘要 衰老与细菌感染后死亡率和发病率的增加密切相关， 占老年人死亡总数的三分之一。老年人最常见的两种感染是 肺炎和尿路感染（UTI），这两种疾病都发生在粘膜表面， 但疾病严重程度表现出年龄依赖性增加。年龄相关的严重程度 感染被认为是由免疫反应的破坏，包括免疫细胞功能的下降驱动的 （免疫衰老）和慢性低度炎症（炎症）。虽然年龄驱动的变化， 适应性免疫反应的特征很好，但对先天免疫反应的驱动因素知之甚少。 免疫衰老多形核白细胞（PMN）是先天性免疫细胞，具有关键的和 在控制粘膜感染和随后恢复稳态中的多方面作用，以及PMN功能和 在衰老过程中，细胞募集都失调，进一步导致感染易感性和严重性。 因此，影响感染后PMN募集和激活的遗传多态性是 与感染易感性和严重性增加相关。然而，在这方面存在着根本性的差距。 关于可能与防止年龄驱动的易感性相关的遗传特征的知识 感染这一建议的假设是，某些遗传基因座将与保护有关， 粘膜感染后的严重疾病，并且这些保护性表型中的一些可能对 老化导致的恶化这一假设将通过两个具体目标来解决。在目标1中，25个CC菌株 并且将评估表现出易感表型的C57 BL/6 J创始者菌株对以下的易感性： 肺炎（雄性）和UTI（雌性）。宿主存活率、器官特异性细菌负荷、感染指标 将测量严重性（如器官病理学）和炎症反应，以确定 表型与给定的感染模型相关联。连锁表型将被用于鉴定相关的QTL 每种感染模型的疾病表现，以及两种感染之间共同的表型 将探讨模型作为感染严重程度的预测因子。在目标2中，C57 BL/6和3种CC菌株的子集， 在青年中表现出耐药表型的将被老化，并评估对肺炎的易感性（男性）， UTI（女性）。将评估疾病表现的上述指标，以确定宿主遗传学是否 可以减轻年龄对粘膜感染的易感性。这项研究预计将产生一个 丰富的表型数据，有关免疫系统发育和功能的信息， 在生命的所有阶段，体内平衡和对抗原攻击的反应，以及尿和血清的效用 细胞因子和趋化因子作为预测感染易感性和严重性的潜在生物标志物。

Project Summary/Abstract Aging is strongly associated with increased mortality and morbidity following bacterial infections, which are responsible for one third of all deaths in older adults. The two most common infections in older adults are pneumonia and urinary tract infection (UTI), both of which occur at mucosal surfaces and are prevalent across the lifespan but exhibit an age-dependent increase in disease severity. The age-dependent severity of these infections is thought to be driven by disruptions in immune responses, including decline in immune cell function (immunosenescence) and chronic low-grade inflammation (inflammaging). While age-driven alterations in adaptive immune responses are well characterized, less is known about what drives innate immunosenescence. Polymorphonuclear leukocytes (PMNs) are innate immune cells that have a critical and multi-faceted role in control of mucosal infection and subsequent return to homeostasis, and PMN function and recruitment are both dysregulated during aging, further contributing to infection susceptibility and severity. Accordingly, genetic polymorphisms that impact PMN recruitment and activation in response to infection are associated with increased infection susceptibility and severity. However, there is fundamental gap in knowledge regarding genetic traits that may be associated with protection against age-driven susceptibility to infection. The hypothesis of this proposal is that certain genetic loci will be associated with protection against severe disease following mucosal infection, and that some of these protective phenotypes may be resistant to age-driven deterioration. This hypothesis will be addressed through two specific aims. In Aim 1, 25 CC strains and a C57BL/6J founder strain that exhibits a susceptible phenotype will be assessed for susceptibility to pneumonia (males) and UTI (females). Host survival, organ-specific bacterial burden, indicators of infection severity (such as organ pathology) and inflammatory responses will be measured to determine which phenotypes are linked for a given infection model. Linked phenotypes will be used to identify QTLs associated with disease manifestation for each infection model, and phenotypes in common between both infection models will be explored as predictors of infection severity. In Aim 2, C57BL/6 and a subset of 3 CC strains that exhibit resistant phenotypes in youth will be aged and assessed for susceptibility to pneumonia (males) and UTI (females). The above indicators of disease manifestation will be assessed to determine if host genetics can alleviate age-driven susceptibility to mucosal infections. The proposed research is expected to yield a wealth of phenomic data, information pertaining to immune system development and function during homeostasis and in response to antigenic challenge at all stages of life, and the utility of urine and serum cytokines and chemokines as potential biomarkers to predict infection susceptibility and severity.