Elucidating the roles of alveolar macrophage inflammation and self renewal duringinfluenza infection

摘要/摘要 甲型流感病毒(IAV)对全球健康构成持续威胁。IAV感染尤其成问题 在老年人中，估计近90%与IAV相关的死亡发生在老年人中。牙槽骨 巨噬细胞(AM)是主要的肺巨噬细胞群，在肺内稳态中起重要作用。 抗病毒免疫和组织恢复。AM显示出自我更新的茎状特征，但也可以迅速 在刺激下产生促炎介质，这可能有助于肺 IAV感染过程中的炎症和损伤。目前对AM的调节机制知之甚少 在体内决定增殖和炎症的命运，以及随后对组织炎症和 IAV感染后的康复。在这个应用中，我们假设b-连环蛋白，hif1-a的相互作用 而TCF-4调节AM的自我更新和炎症活动，从而调节肺组织 IAV感染过程中的炎症和组织修复。此外，我们假设夸张的b- 连环蛋白-HIF1-α的表达决定了AM自我更新和功能的衰老相关缺陷，从而 在老年宿主感染IAV后导致严重的肺部疾病和/或肺修复缺陷。 提出了三个具体目标。目的1：阐明b-半乳糖的相关机制。 连环蛋白/HIF1-a复合体调节AM炎症活动和自我更新，以及随后对AM的影响 宿主疾病和从IAV感染中恢复。目标2：确定技术合作框架-- 4在动态平衡和IAV后调节AM的发育、自我更新和/或炎症 感染。目的3：探讨AM b-catenin/HIF1-a轴在衰老中的作用。 AM功能和再生的相关缺陷，从而导致严重的IAV相关疾病 上了年纪的主人。

Summary/Abstract Influenza A virus (IAV) constitutes an ongoing threat to global health. IAV infection is especially problematic in aged individuals, with estimated close to 90% IAV-associated deaths occurring in the elderly. Alveolar macrophages (AMs) are the primary lung macrophage population that are important in lung homeostasis, anti-viral immunity and tissue recovery. AMs exhibit stem-like features of self-renewal, but also can rapidly produce pro-inflammatory mediators upon stimulation, which could potentially contribute to pulmonary inflammation and injury during IAV infection. Little is known currently about the mechanisms modulating AM proliferative and inflammatory fate decisions in vivo, and the subsequent effects on tissue inflammation and recovery following IAV infection. In this application, we hypothesize that the interplay of b-catenin, HIF1-a and TCF-4 modulates AM self-renewal and inflammatory activity, thereby regulating pulmonary inflammation and tissue repair during IAV infection. Furthermore, we hypothesize that exaggerated b- catenin-HIF1-a expression dictates the aging-associated defects in AM self-renewal and function, thereby leading to severe pulmonary diseases and/or defective lung repair following IAV infection in aged hosts. Three specific Aims are proposed. Aim 1: To elucidate the associated-mechanisms by which b- catenin/HIF1-a complex modulates AM inflammatory activity and self-renewal, and subsequent effects on host diseases and recovery from IAV infection. Aim 2: To define the underlying mechanisms by which TCF- 4 regulates AM development, self-renewal and/or inflammation during homeostasis and following IAV infection. Aim 3: To determine the roles of dysregulated AM b-catenin/HIF1-a axis in contributing to aging- associated defects in AM function and regeneration, thereby causing severe IAV-associated diseases in aged hosts.