Immune biomarker discovery in children susceptible to recurrent otitis media

项目摘要/摘要 病毒和细菌的混合感染通常是幼儿最严重的感染事件，导致 非计划的办公室和医院访问，以及严重的发病率。急性中耳炎(AOM)是典型的 病毒和细菌的混合感染，机会主义的鼻咽定殖者爬上咽鼓管到达 在并发病毒上呼吸道感染期间感染中耳。在一项针对1000名儿童的队列研究中 在过去的14年里，我们从6个月到5个月研究了AOM的发病机制、流行病学和免疫学。 几年前。易患多个AOM的儿童，在我们的研究中被称为严格定义的易感中耳炎(SOP)儿童 队列，约占儿童总人口的10%，但占卫生保健的大部分 由于AOM造成的负担，他们更有可能接受鼓室造口置管手术。很明显，SOP 与非易感中耳炎(NOP)相比，儿童在生命早期就被定居，带有一种或多种潜在的耳部病原体 儿童，但这种易感性的预测性特征需要在整个早期生活中持续监测，以便 来确定。初步数据显示，除了鼻咽(NP)耳部病原体的变化 定居和人口学危险因素，SOP儿童在NP后有促炎表型 年龄。肺炎支气管炎免疫反应的免疫网络模型比较 提示IL-6、IL-10、IL-17A和CCL5免疫网络可能是造成免疫差异的原因 在SOP儿童中观察到。根据这些数据，我们的假设是，早期生活中耳部病原体的移居改变了 NP免疫，因此使一些儿童易患复发性AOM。此外，可溶的NP因子可以 确定，当在生命早期测量时，将是复发的AOM的预测因子，并为个性化护理提供信息。 AIM 1将在匹配的SOP和NOP样本中使用基于LC-MS的蛋白质组学来确定NP蛋白质组 在AOM之前、期间和之后的规定年龄进行生物标记物鉴定。目标2将测量 来自Aim 1的候选生物标记物在400个儿童队列中的鼻洗样本中确定稳健性 儿童年龄和协变量的生物标记物。因此，这项赠款提案侧重于确定 预示严重复发AOM的生物标志，因此需要鼓室造口置管 与两岁以下儿童在AOM感染之前或期间进行的警觉等待相比 几年前。

Project Summary/Abstract Viral-bacterial co-infections are often the most serious infectious events in young children, leading to unplanned office and hospital visits as well as significant morbidity. Acute otitis media (AOM) is a canonical viral-bacterial co-infection, where an opportunistic nasopharyngeal colonizer ascends the Eustachian tube to infect the middle ear during a concurrent viral upper respiratory infection. In a cohort study of >1000 children over the last 14 years, we have studied AOM pathogenesis, epidemiology, and immunity from six months to five years of age. Children prone to multiple AOMs, termed stringently-defined otitis prone (sOP) children in our cohort, comprise approximately 10% of the total child population but account for the majority of the health care burden due to AOM and are more likely to undergo surgery for tympanostomy tube insertion. It is clear that sOP children are colonized early in life with one or more potential otopathogens compared to non-otitis prone (NOP) children, but this predictive feature of susceptibility requires continuous monitoring throughout early life in order to determine. Preliminary data suggests that, in addition to changes in nasopharyngeal (NP) otopathogen colonization and demographic risk factors, sOP children have a pro-inflammatory phenotype in the NP after one year of age. Immune network modeling of the NP immune response to AOM comparing sOP and NOP children suggests an IL-6, IL-10, IL-17A, and CCL5 immune network may be responsible for the immune differences observed in sOP children. From these data, our hypothesis is that early life colonization with otopathogens alters NP immunity, thus leaving some children susceptible to recurrent AOM. Further, soluble NP factors can be identified that, when measured in early life, will be a predictor of recurrent AOM and inform individualized care. Aim 1 will employ LC-MS based proteomics in matched sOP and NOP samples to determine the NP proteome at defined ages before, during, and after AOM susceptibility for biomarker identification. Aim 2 will measure the candidate biomarkers from Aim 1 in 400 nasal wash samples across the child cohort to determine robustness of the biomarkers across child age and covariates. Therefore, this grant proposal focuses on the determination of a bio-signature predictive of severe recurrent AOM and therefore the need for tympanostomy tube insertion versus watchful waiting that will be measured before or during the onset of AOM infections in children under two years of age.