The impact of infection on post-stroke cognitive dysfunction

In this project, we will test our hypothesis that instead of augmenting systemic inflammation, infection enhances stroke injury and PSCI through persistent bacteremia and bacterial infection in the brain which exacerbate blood brain barrier (BBB) damage, neuroinflammation and neuronal injury. We will demonstrate that (1) compared with mice with stroke alone, mice with stroke complicated by S. aureus pneumonia will have persistent bacteremia and higher load of bacteria in the brain, more severe BBB breakdown, neuroinflammation and neuronal damage at acute stage of stroke and pneumonia, and these changes will be potentiated by aging; (2) under ischemic conditions, human brain microvascular endothelial cells (HBMVECs) infected with S. aureus potentiates inflammatory activation of HBMVECs and exacerbates BBB breakdown versus non-infected ischemic cells; and (3) S. aureus infection enhances long-term PSCI in young and aged mice through chronic BBB breakdown, neuroinflammation and neuronal damage. Bulk and single cell RNA sequence will be used to analyze transcriptome changes in infected and uninfected mice with or without stroke and cultured HBMVECs with or without infection to explore targets that can be used to develop therapies to prevent or treat post-stroke cognitive impairment in future.