Microglia in aged mice infected with influenza have increased polarization towards M1-like phenotypes that display gene expression profiles associated with neurodegeneration 2849

Abstract Description Rationale Influenza infection in older humans can lead to long-term central nervous system damage with subsequent development of dementia. How influenza A virus (IAV) infection causes these adverse effects in the elderly is unclear. Methods Young (12-week) and old (70-week) C57BL/6J mice were infected with non-neurotropic IAV PR8. Single-cell RNA sequencing (scRNA-seq) of brain tissue was performed to identify the effects of peripheral IAV infection on age-related central nervous system neuroinflammation and cognitive function related gene expression. Results Brain microglia of IAV-infected old mice exhibited a more pronounced proinflammatory M1-like gene expression phenotype associated with neuroinflammation compared to IAV-infected young mice. Differential expression analysis confirmed that proinflammatory gene expression (e.g., IL-6, TNF, Nos2, and IRF7) was higher in microglia from IAV-infected old mice than in those from IAV-infected young mice. KEGG pathway analysis revealed that changes in pathways in macroglia and oligodendrocytes in PR8-infected old mice were associated with neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. Conclusions Our mouse models indicate that aging affects the innate response of microglia to influenza infection, resulting in an M1-like phenotype 7 days post-infection. These altered immune responses in microglia from the aged are also similar to those seen in neurodegenerative diseases. Funding Sources The research described in this work was partially supported by the Merit Review Program of the Department of Veterans Affairs, grant number I01 BX005023 to JPM, and the National Institute of General Medical Sciences, grant number 5P20GM103648 to JPM. Topic Categories Immune Mechanisms of Human Disease (HUM)