Genetic Epidemiology of Life-Threatening Influenza Infection in Children

摘要 甲型流感和B型流感病毒感染每年在全世界造成数十万人死亡，给社会造成巨大损失 数十亿美元的发病率和破坏。这项危及生命的流感的多中心研究降低了 急性呼吸衰竭儿童呼吸道感染（LRTI），由一个既定的 儿科重症监护临床试验研究人员，是为了评估如何主机先天免疫 反应与疾病易感性和临床结果相关。我们假设先天免疫 介导流感识别的组分，包括Toll样受体（TLR 2、3、7、8和9）， 视黄酸诱导蛋白（RIG-I）、胶原凝集素表面活性蛋白A和D（SP-A、SP-D）和甘露糖 结合凝集素（MBL）、维生素D相关基因（VDR）和影响下游细胞因子的基因， 干扰素-α（IFN-γ）在宿主对严重流感感染易感性中起重要作用。另外我们 假设这些儿童先天性免疫反应在进入ICU时具有特定特征 将预测疾病的严重程度和恢复时间。我们将通过招募一名 240名患有危及生命的流感LRTI的重症儿童的代表性样本，重要的系列检测 炎症和免疫介质从外周血和肺，进行敏感的测试，以确定 共感染，并获得DNA，以实现3个特定目的：1.）为了比较炎症和先天性 危及生命下呼吸道感染儿童流感病毒感染与7种对照组免疫应答 包括肺部健康的儿童、呼吸道合胞病毒引起的严重LRTI和流感引起的LRTI 与重要的病毒和细菌亚群如S. aureus，2.）为了评估先天的 免疫应答与疾病的严重程度和疾病恢复的持续时间有关， 免疫反应性（免疫麻痹）、白细胞介素8（脓毒症和急性肺损伤预后预测因子） 损伤）、维生素D以及SP-A和SP-D（对肺功能和病毒免疫很重要），以及3.）以识别 危及生命的流感LRI易感性与11个重要先天性 与流感免疫应答相关的免疫基因（TLR 2、3、7、8和9，VDR，SFTPA 1，SFTPA 2， SFTPD、RIG-1、MBL），并对超过69个与I型糖尿病相关的额外基因进行探索性分析。 干扰素应答我们的方法将涉及儿科急性肺损伤的31个研究中心 和脓毒症研究者网络（PALISI），一个由临床研究者组成的成熟联盟， 在美国和加拿大的儿科重症监护病房，具有良好的生产力记录。最终，该项目将 提供了先天免疫基因和免疫麻痹在免疫系统中的作用的更复杂的理解， 流感感染，为未来的预防（免疫佐剂和/或疫苗）提供新的靶点， 降低流感相关发病率和死亡率的治疗方法。

ABSTRACT Influenza A and B viral infections kill hundreds of thousands of people worldwide each year, costing society many billions of dollars in morbidity and disruption. This multicenter study of life-threatening influenza lower respiratory tract infection (LRTI) in children with acute respiratory failure, designed by an established group of pediatric critical care clinical trial investigators, was developed to evaluate how the host innate immune response is associated with disease susceptibility and clinical outcome. We hypothesize that innate immune components that mediate recognition of influenza, including Toll-like receptors (TLRs 2, 3, 7, 8, and 9), retinoic-acid inducible protein (RIG-I), the collectins surfactant proteins A and D (SP-A, SP-D) and mannose binding lectin (MBL), Vitamin D related genes (VDR), and genes influencing down-stream cytokines such as interferon-alpha (IFN-¿), play important roles in host susceptibility to severe influenza infection. In addition, we hypothesize that specific features of the innate immune response of these children on presentation to the ICU will predict disease severity and duration of recovery. We will test these hypotheses by recruiting a representative sample of 240 critically ill children with life-threatening influenza LRTI, serially testing important inflammatory and immune mediators from peripheral blood and lung, performing sensitive tests to identify coinfection, and obtaining DNA, to achieve 3 Specific Aims: 1.) To compare the inflammatory and innate immune response of children with life-threatening LRTI from influenza infection alone to 7 control groups including children with healthy lungs, severe LRTI from respiratory syncytial virus, and LRTI from influenza coinfected with important viral and bacterial subgroups such as S. aureus, 2.) To assess how the innate immune response is associated with disease severity and duration of disease recovery focusing on innate immune responsiveness (immunoparalysis), Interleukin 8 (a predictor of outcome for sepsis and acute lung injury), Vitamin D, and SP-A and SP-D (important for lung function and viral immunity), and 3.) To identify associations between life-threatening influenza LRI susceptibility and polymorphisms in 11 important innate immunity genes related to the immune response to influenza (TLRs 2, 3, 7, 8, and 9, VDR, SFTPA1, SFTPA2, SFTPD, RIG-1, MBL) and to perform an exploratory analysis of over 69 additional genes related to the type I interferon response. Our approach will entail engagement of 31 sites across the Pediatric Acute Lung Injury and Sepsis Investigator's (PALISI) Network, a well-established consortium of clinical investigators across pediatric ICUs in the US and Canada with a proven track record of productivity. Ultimately, this project will provide a more sophisticated understanding of the role of innate immune genes and immunoparalysis in influenza infection, providing new targets for future preventive (immune adjuvant and/or vaccine) and therapeutic approaches to decrease influenza-related morbidity and mortality.