Elucidating the role of type I interferon signaling and macrophage-derived inflammation in the juvenile host with viral pneumonia

项目摘要： 病毒性呼吸道感染是儿童住院的主要原因。如果没有合并症， 儿童比成人更有可能因大多数呼吸道病毒而需要住院治疗，包括 甲型流感病毒（IAV）。在生命的最初几年，先天免疫信号的变化可能与疾病有关。 影响病毒性呼吸道感染的进程，但在某些情况下， 儿童不详。病毒载量与IAV肺炎儿童的疾病严重程度无关， 因此，未能控制病毒复制不太可能是儿童严重疾病的主要驱动因素。我们发现 幼年小鼠募集更多的单核细胞衍生的肺泡巨噬细胞， NLRP 3炎性小体与IAV感染后期的成年小鼠相比。这与增加 尽管病毒负荷相等，但在幼龄小鼠中产生I型干扰素（IFN）。重要的是，抑制 巨噬细胞募集降低I型IFN水平并提高幼年IAV感染的存活率。这些数据 提示IAV感染后I型IFN产生中年龄相关差异促进了IAV的募集， 并导致幼年小鼠死亡。在初步数据中，我们现在表明， 募集的巨噬细胞上I型IFN受体IFNAR 1的遗传缺失或药理学抑制 提高感染IAV的幼年小鼠的存活率。因此，我们假设儿童无法从 IAV感染是由于I型IFN信号传导增加和巨噬细胞向肺的募集。我们进一步 假设募集的巨噬细胞在青少年中维持损伤性炎症表型 由于年龄相关的肺部微环境差异，我们将测试这些假设在 目标1：确定是否年龄相关的差异，在微环境的 幼年肺促进募集巨噬细胞中炎性表型。目的2：确定抑制是否 招募的巨噬细胞中I型IFN信号转导减少肺损伤并改善幼年病毒感染的结局 肺炎目的3：确定上皮细胞中I型IFN信号传导的增加是否有助于严重的 青少年病毒性肺炎这些目标的完成将确定驱动病毒诱导的 呼吸衰竭的幼年宿主，并探讨靶向IFNAR1信号转导的潜在益处， 巨噬细胞，以尽量减少儿童病毒性呼吸道感染引起的肺损伤。使用适合年龄的 IAV肺炎小鼠模型和病毒诱导的呼吸道疾病患儿的多维表型 失败，我们定位于确定IAV肺炎儿童疾病严重程度的关键决定因素， 支持新治疗策略的基本原理设计，以最大限度地减少肺损伤并优化恢复。

Project Summary: Viral respiratory infections are a leading cause of hospitalization in children. In the absence of co-morbidities, children are much more likely than adults to require hospitalization for most respiratory viruses, including influenza A virus (IAV). Age-related changes in innate immune signaling over the first few years of life likely impact the course of viral respiratory infections, but the mechanisms driving viral-induced respiratory failure in children are unknown. Viral load has not been associated with severity of illness in children with IAV pneumonia, so failure to control viral replication is not likely the primary driver of severe illness in children. We have found that juvenile mice recruit more monocyte-derived alveolar macrophages and have increased activation of the NLRP3 inflammasome compared to adult mice late in IAV infection. This was associated with increased production of type I interferon (IFN) in juvenile mice, despite equal viral burden. Importantly, inhibition of macrophage recruitment decreased type I IFN levels and improved survival in juvenile IAV infection. These data suggest that age-related differences in type I IFN production in response to IAV infection promote the recruitment of inflammatory macrophages and contribute to mortality in juvenile mice. In preliminary data, we now show that genetic deletion or pharmacologic inhibition of the type I IFN receptor, IFNAR1, on recruited macrophages improves survival in IAV-infected juvenile mice. Therefore, we hypothesize that children fail to recover from IAV infection due to increased type I IFN signaling and macrophage recruitment to the lungs. We further hypothesize that recruited macrophages maintain an injurious inflammatory phenotype in the juvenile lung due to age-related differences in the lung microenvironment. We will test these hypotheses in the following specific aims: Aim 1: Determine whether age-related differences in the microenvironment of the juvenile lung promote an inflammatory phenotype in recruited macrophages. Aim 2: Determine whether inhibition of type I IFN signaling in recruited macrophages decreases lung injury and improves outcomes in juvenile viral pneumonia. Aim 3: Determine whether increased type I IFN signaling in epithelial cells contributes to severity of illness in juvenile viral pneumonia. Completion of these aims will identify mechanisms driving viral-induced respiratory failure in the juvenile host and explore the potential benefit of targeting IFNAR1 signaling in macrophages to minimize lung injury caused by viral respiratory infections in children. Using age-appropriate mouse models of IAV pneumonia and multidimensional phenotyping of children with viral-induced respiratory failure, we are positioned to define key determinants of disease severity in children with IAV pneumonia that will support the rationale design of new treatment strategies to minimize lung injury and optimize recovery.