Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung

项目摘要 虽然流感和肺炎球菌感染在历史上是导致重大发病率和死亡率的原因， 由一种新型冠状病毒(SARS-CoV-2)引起的呼吸道疾病大流行，导致 冠状病毒病2019年(新冠肺炎)，已被证明在严重疾病中发展，发病率最高 和发生在老年人(65岁)中的死亡率。我们相信，在这场竞争中的实验 修订将对我们目前在流感模型中的发现进行扩展，并将提供更深层次的理解 探讨老年肺中的分子和细胞通路如何促进冠状病毒的发病。基于 我们通过父母R01获得的初步发现，我们假设在 对线粒体功能障碍和ROS产生增加的反应，导致过度热情的促炎反应 对传染性病毒体，如流感或冠状病毒做出反应的信号。通过建立和剖析 老年肺组织细胞反应途径与炎症信号之间的关键机制联系 病毒感染，这项研究提案具有很高的潜力来阐明创新的调控途径，扩大我们的 目前对年龄相关线粒体稳态变化的理解，并设计出治疗方法 因应致病刺激而改善发病率和死亡率的策略。我们目前要求提供两个 多年的支持，以完成竞争修订中详细说明的所有实验：一年级将重点放在 完成具体目标1和第2年将侧重于完成具体目标2。 总结与影响：提高对利弊平衡的认识 发炎。众所周知，炎症反应是受到严格调控的，然而 对冠状病毒的有害反应和有益反应之间的平衡尚未完全阐明。需要进行的工作 在目前的提案中将检查炎症细胞渗透的位置和程度的影响以及 细胞因子的产生在老年肺炎和ARDS发病中的作用 强调流感和冠状病毒之间的异同，重点是 促炎免疫反应在老年肺疾病发病机制中的作用。目前，人们对此知之甚少 关于流感和冠状病毒在发病机制上的异同。增强了亲和力- 炎性宿主免疫反应，而不是病毒毒力，可能导致多器官组织病理 对CRS作出反应而发生的。这项工作将使我们能够研究免疫的启动和发展 老年人肺部对冠状病毒感染的反应及宿主的异同 对流感的反应性(关于流感的工作在家长R01中进行了描述)。

Project Summary While influenza and pneumococcal infections are historically responsible for significant morbidity and mortality, a pandemic of respiratory disease by a novel coronavirus (SARS-CoV-2), resulting in the development of coronavirus disease 2019 (COVID-19), has been shown to develop in severe illness, with the highest morbidity and mortality occurring in older persons (> 65 years of age). We believe that the experiments in this Competitive Revision will expand upon our current findings in the influenza model and will provide a deeper understanding into how molecular and cellular pathways in the aged lung contribute to coronavirus pathogenesis. Based upon our preliminary findings gained by our parent R01, we hypothesize that dysregulated immune activation, in response to increased mitochondrial dysfunction and ROS production, results in overzealous pro-inflammatory signaling in response to an infectious viral agent, such as influenza or coronavirus. By establishing and dissecting a pivotal mechanistic link between cellular response pathways and inflammatory signaling in aged lung during viral infection, this research proposal has high potential to elucidate innovative regulatory pathways, expand our current understanding of age associated changes in mitochondrial homeostasis, and devise therapeutic strategies to improve morbidity and mortality in response to pathogenic stimuli. We are currently requesting two years of support to complete all of the experiments detailed in the Competitive Revision: Year 1 will focus on completion of Specific Aim 1 and Year 2 will focus on completion of Specific Aim 2. Summary and impact: Improve our understanding the balance between beneficial and harmful inflammation. It has been well established that inflammatory responses are tightly regulated, however the balance between harmful and beneficial responses to coronavirus has not been fully elucidated. Work entailed in the current proposal will examine the impact of location and magnitude of inflammatory cell infiltration and cytokine production on the development of pneumonia and ARDS in aged lung in response to coronavirus. Highlight similarities and differences between influenza and coronavirus, with a focus on the role of a pro-inflammatory immune response on disease pathogenesis in aged lung. At present, very little is known regarding the similarities and differences in pathogenesis of influenza and coronavirus. Heightened pro- inflammatory host immune responses, rather than viral virulence, can contribute to multi-organ tissue pathologies occurring in response to CRS. This work will allow us to examine the initiation and progression of immune responses in the aged lung during coronavirus infection and identify similarities and differences in host responsiveness to influenza (work on influenza is described in the Parent R01).