Influenza A infection accelerates disease-associated microglia formation during physiological aging

Grant, R. A.; Runyan, C. E.; Minogue, G. A.; Stoolman, J. S.; Watanabe, S.; Chen, F.; Senkow, K. J.; Cusick, L.; Schleck, M. J.; Nafikova, R.; Lu, Z.; Bunyan, E. G.; Abdala-Valencia, H.; Sznajder, J. I.; Vassar, R.; Castellani, R.; Geula, C.; Gefen, T.; Chandel, N. S.; Misharin, A. V.; Budinger, G. S.

doi:10.64898/2025.12.11.693336

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bioRxiv · 10.64898/2025.12.11.693336

Influenza A infection accelerates disease-associated microglia formation during physiological aging

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Abstract

Severe pneumonia is associated with an increased risk of cognitive decline and dementia, particularly in the elderly. Changes in microglia, the most abundant immune cell population in the brain, are also associated with cognitive decline and dementia, including the emergence of a transcriptional cell state referred to as disease-associated microglia (DAM). We sought to test the hypothesis that non-neuroinvasive influenza A virus (IAV) pneumonia results in transcriptional responses in brain microglia that drive premature expansion of DAM. Using bulk and single-cell RNA-sequencing, metabolomics, and spatial transcriptomics, we profiled neuroimmune populations in young, middle-aged, and old male mice during IAV infection and recovery. We observed an increased abundance of DAM, interferon-responsive microglia (IRM), CD4+ T cells, and CD8+ T cells in white matter regions beginning in middle age and persisting in old animals, irrespective of IAV infection. DAM exhibited a metabolic shift toward aerobic glycolysis with disrupted TCA cycling, citrulline depletion, and an elevated itaconate/-ketoglutarate ratio. Spatial transcriptomic profiling of the human middle frontal gyrus (MFG) in normal agers, SuperAgers, and patients with dementia revealed an analogous accumulation of DAM and CD8+ T cells in white matter. IAV pneumonia induced a transient immunosenescent-like response in microglia, marked by glucocorticoid-responsive gene expression and Ccnd3 upregulation. In response to IAV pneumonia, DAM expanded in middle-aged mice, whereas old mice were elevated at baseline and were largely unaffected by IAV infection. The age-related expansion of DAM was unaffected by pharmacological depletion and repopulation of microglia with a CSF1R antagonist or genetic gain or loss of function of the phagocytic receptor MERTK, suggesting the DAM phenotype is driven by the CNS microenvironment, rather than cell-intrinsic mechanisms. Our findings suggest that IAV pneumonia induces an acute immunosenescence response in microglia and accelerates the age-dependent expansion of DAM in white matter.

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Grant, R. A., Runyan, C. E., Minogue, G. A., Stoolman, J. S., Watanabe, S., Chen, F., Senkow, K. J., Cusick, L., Schleck, M. J., Nafikova, R., Lu, Z., Bunyan, E. G., Abdala-Valencia, H., Sznajder, J. I., Vassar, R., Castellani, R., Geula, C., Gefen, T., Chandel, N. S., Misharin, A. V., Budinger, G. S.. 2025-12-14. Influenza A infection accelerates disease-associated microglia formation during physiological aging. https://doi.org/10.64898/2025.12.11.693336

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