Genetic susceptibility to mucosal infections with aging (Resubmission)

随着年龄的增长，对粘膜感染的遗传易感性（重新提交）

• 批准号: 10001809
• 负责人: Chelsie Elizabeth Armbruster
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001809
• 关键词: Address; Age; Aging; Anti-Inflammatory Agents; Bacteremia; Bacterial Infections; Bacterial Pneumonia; Cause of Death; Cell physiology; Cells; Cessation of life; Chronic; Communities; Data; Deterioration; Disease; Economic Burden; Elderly; Exhibits; Female; Future; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Predisposition to Disease; Geriatric Nursing; Homeostasis; Human; Immune; Immune response; Immune system; Incidence; Infection; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Integration Host Factors; Knowledge; Life; Link; Longevity; Lung; Lung infections; Measures; Mediating; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Nursing Homes; Organ; Pathology; Pathway interactions; Phenotype; Pneumococcal Pneumonia; Pneumonia; Population; Predictive Value; Predisposition; Prevalence; Prevention strategy; Proteus mirabilis; Quantitative Trait Loci; Research; Resistance; Role; Serum; Severities; Severity of illness; Single Nucleotide Polymorphism; Site; Source; Streptococcus pneumoniae; Surface; Systems Development; Testing; Urinary tract infection; Urine; Vulnerable Populations; Woman; Youth; adaptive immune response; age related; aged; aging population; catheter associated UTI; chemokine; cytokine; design; genetic resistance; genomic locus; health economics; human disease; immunosenescence; male; men; mortality; mouse model; mucosal site; neutrophil; phenomics; potential biomarker; recruit; resistance factors; response; sex; trait; treatment strategy

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.

项目摘要/摘要 衰老与细菌感染后的死亡率和发病率的增加密切相关，这是 负责老年人所有死亡的三分之一。老年人中最常见的两种感染是 肺炎和尿路感染（UTI），两者都发生在粘膜表面，并且遍布各地 寿命但疾病严重程度的年龄依赖性增加。这些年龄的严重程度 感染被认为是由免疫反应的干扰驱动的，包括免疫细胞功能的下降 （免疫衰老）和慢性低度炎症（炎症）。而年龄驱动的改变 自适应免疫反应的特征很好，对驱动先天的驱动的知之甚少 免疫衰老。多形核白细胞（PMN）是具有关键且 在控制粘膜感染以及随后恢复体内平衡以及PMN功能和PMN功能以及 在衰老期间，招聘都失调，进一步导致感染敏感性和严重程度。 因此，影响PMN募集和激活对感染的遗传多态性是 与感染的敏感性和严重程度增加有关。但是，存在根本的差距 有关可能与年龄驱动的易感性有关的遗传特征的知识 感染。该提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，其中一些保护性表型可能具有抗性 年龄驱动的恶化。该假设将通过两个具体目标解决。在AIM 1，25 cc菌株中 将评估表现出易感表型的C57BL/6J创始人菌株 肺炎（雄性）和UTI（女性）。宿主生存，器官特异性细菌负担，感染指标 严重程度（例如器官病理）和炎症反应将测量以确定哪个 表型与给定感染模型相关。链接的表型将用于识别相关的QTL 每种感染模型的疾病表现形式，两种感染之间的表型 模型将作为感染严重程度的预测指标探索。在AIM 2，C57BL/6和3 cc菌株的子集中 在青年中表现出耐药表型将被老化并评估是否易感肺炎（男性）和 UTI（女性）。将评估上述疾病表现的指标，以确定宿主遗传学是否是否 可以减轻年龄驱动的对粘膜感染的敏感性。拟议的研究预计将产生 大量现象数据，与免疫系统开发和功能有关的信息 体内平衡，并在生活的各个阶段应对抗原挑战，以及尿液和血清的效用 细胞因子和趋化因子作为预测感染敏感性和严重程度的潜在生物标志物。