Microglia mediate cognitive dysfunction in elderly survivors of pneumonia

项目摘要 多线临床证据表明肺炎，认知障碍和痴呆症之间的联系 在老年人中。然而，这种易感性的机制仍不清楚。临床与实验 有证据表明，小胶质细胞-大脑中的巨噬细胞-在维持 正常的脑稳态和激活后可驱动神经变性和认知衰退。的作用 小胶质细胞在老年肺炎幸存者认知能力下降中的作用尚不清楚。在这个R21中，我们建议测试两个 高风险，高回报假设：首先，我们假设小胶质细胞的细胞自主变化， 衰老是老年动物肺炎后认知能力持续下降的必要条件。二是 假设在小鼠肺炎后观察到的小胶质细胞和脑中的转录组学变化将 这与肺炎患者中观察到的相似。我们建议用两个具体的假设来检验这些假设。 目标。目标1.为了确定小胶质细胞的细胞自主性，年龄相关的功能障碍是否排除了 老年小鼠在甲型流感病毒诱导的肺炎后的认知恢复。我们将使用 在从甲型流感恢复期间消耗年轻和老年小鼠中的小胶质细胞的药理学方法 感染和测量认知测试的表现，以及小胶质细胞和大脑中的转录组学变化 使用RNA-Seq并使用空间转录组学进行验证。目标2.为了比较小胶质细胞的激活， 死于SARS-CoV-2肺炎并伴有其他肺炎的患者和非肺炎对照组。 我们将在SARS-CoV-2肺炎后死亡的患者的快速尸检过程中收集海马组织， 使用单细胞RNA-seq和空间转录组学分析它。

PROJECT SUMMARY Multiple lines of clinical evidence demonstrate a link between pneumonia, cognitive impairment, and dementia in the elderly. The mechanisms underlying this susceptibility, however, remain unclear. Clinical and experimental evidence suggests that microglia – resident macrophages in the brain – play a key role in both maintaining normal brain homeostasis and upon activation can drive neurodegeneration and cognitive decline. The role of microglia in cognitive decline in elderly survivors of pneumonia is unknown. In this R21, we propose to test two high-risk, high-reward hypotheses: First, we hypothesize that cell-autonomous changes in microglia with aging necessary for the persistent cognitive decline after pneumonia in old animals. Second, we hypothesize that transcriptomic changes in the microglia and brain observed in mice after pneumonia will mirror those observed in patients with pneumonia. We propose to test these hypotheses with two Specific Aims. Aim 1. To determine whether cell-autonomous, age-related dysfunction in microglia precludes cognitive recovery in old mice following influenza A virus-induced pneumonia. We will use pharmacological approaches to deplete microglia in young and old mice during recovery from influenza A infection and measure performance on cognitive tests, and transcriptomic changes in microglia and the brain using RNA-Seq with validation using spatial transcriptomics. Aim 2. To compare microglial activation in patients who succumb to SARS-CoV-2 pneumonia with other pneumonia and non-pneumonia controls. We will collect hippocampal tissue during a rapid autopsy in patients who die after SARS-CoV-2 pneumonia and analyze it using single-cell RNA-seq and spatial transcriptomics.