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

阐明 I 型干扰素信号传导和巨噬细胞衍生炎症在病毒性肺炎幼年宿主中的作用

• 批准号: 10651426
• 负责人: Bria M Coates
• 金额: $ 64.64万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-08 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651426
• 关键词: 5 year old; Address; Admission activity; Adolescent; Adoptive Transfer; Adult; Age; Alveolar Macrophages; Alveolus; Animal Model; Antiviral Agents; Antiviral Response; Automobile Driving; Bioinformatics; Bronchoalveolar Lavage Fluid; CCL2 gene; Cell model; Cells; Child; Childhood; Credentialing; Data; Dimensions; Disease; Epithelial Cells; Failure; Flow Cytometry; Gene Expression Profiling; Genetic; Goals; Hospitalization; IFNAR1 gene; Immune response; Immune signaling; Impairment; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; Injury; Interferon Type I; Life; Lung; Macrophage; Mediating; Modeling; Mus; Pathogenesis; Pathway interactions; Pediatric Intensive Care Units; Phenotype; Pneumonia; Positioning Attribute; Predisposition; Production; Recovery; Research; Respiratory Failure; Risk; Role; Sampling; Scientist; Severity of illness; Signal Transduction; Structure of mucous membrane of nose; Supportive care; Testing; Therapeutic; Up-Regulation; Viral; Viral Load result; Viral Pneumonia; Viral Respiratory Tract Infection; Virus; Virus Diseases; Virus Replication; age related; alveolar epithelium; chemokine; clinically relevant; comorbidity; design; epithelial repair; improved; improved outcome; influenza infection; influenza pneumonia; lung injury; mature animal; monocyte; mortality; mouse model; novel therapeutic intervention; novel therapeutics; pharmacologic; recruit; respiratory virus; response; therapeutic target; type I interferon receptor

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.

项目概要： 病毒性呼吸道感染是儿童住院的主要原因。在没有合并症的情况下， 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）。在生命的最初几年中，先天免疫信号可能会发生与年龄相关的变化 影响病毒性呼吸道感染的病程，但驱动病毒引起的呼吸衰竭的机制 孩子们未知。病毒载量与 IAV 肺炎儿童的病情严重程度无关， 因此，未能控制病毒复制不太可能是儿童患严重疾病的主要原因。我们发现 幼年小鼠招募了更多单核细胞来源的肺泡巨噬细胞，并且增强了 NLRP3 炎性体与 IAV 感染后期成年小鼠的比较。这与增加 尽管病毒负荷相同，但幼年小鼠仍会产生 I 型干扰素 (IFN)。重要的是，抑制 巨噬细胞的募集降低了 I 型 IFN 水平并提高了幼年 IAV 感染的存活率。这些数据 表明针对 IAV 感染的 I 型 IFN 产生与年龄相关的差异促进了募集 炎症巨噬细胞的影响并导致幼年小鼠的死亡。在初步数据中，我们现在表明 I 型干扰素受体 IFNAR1 的基因缺失或药物抑制对募集的巨噬细胞 提高感染 IAV 的幼年小鼠的存活率。因此，我们推测儿童无法从 IAV 感染是由于 I 型 IFN 信号传导增加和巨噬细胞向肺部募集所致。我们进一步 假设招募的巨噬细胞在幼体中维持有害的炎症表型 由于肺部微环境与年龄相关的差异。我们将在 以下具体目标： 目标 1：确定个体微环境是否存在与年龄相关的差异 幼年肺促进募集的巨噬细胞的炎症表型。目标 2：确定是否存在抑制 募集的巨噬细胞中 I 型 IFN 信号传导减少了肺损伤并改善了幼年病毒的结果 肺炎。目标 3：确定上皮细胞中 I 型 IFN 信号传导的增加是否会导致疾病的严重程度 幼年病毒性肺炎的疾病。完成这些目标将确定驱动病毒诱导的机制 幼年宿主呼吸衰竭并探索靶向 IFNAR1 信号传导的潜在益处 巨噬细胞可以最大限度地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性呼吸道感染儿童的多维表型分析 如果失败，我们将确定 IAV 肺炎儿童疾病严重程度的关键决定因素，这将 支持新治疗策略的合理设计，以尽量减少肺损伤并优化康复。