Microglia mediate cognitive dysfunction in elderly survivors of pneumonia

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.