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

Area of Science:

• Neuroscience
• Immunology
• Aging Research

Background:

• Severe pneumonia is linked to cognitive decline and dementia, especially in the elderly.
• Disease-associated microglia (DAM) are implicated in cognitive decline and dementia.
• The impact of influenza A virus (IAV) pneumonia on brain microglia and its contribution to cognitive aging is not fully understood.

Purpose of the Study:

• To investigate how non-neuroinvasive influenza A virus (IAV) pneumonia affects brain microglia transcriptional responses.
• To determine if IAV pneumonia drives premature expansion of disease-associated microglia (DAM).
• To explore the age-dependent changes in neuroimmune populations and their response to IAV infection.

Main Methods:

• Bulk and single-cell RNA sequencing, metabolomics, and spatial transcriptomics were used in young, middle-aged, and old male mice.
• Neuroimmune populations were profiled during IAV infection and recovery.
• Human middle frontal gyrus (MFG) tissue from normal agers, SuperAgers, and dementia patients was analyzed using spatial transcriptomics.

Main Results:

• An increased abundance of DAM, interferon-responsive microglia (IRM), CD4+, and CD8+ T cells was observed in white matter, starting in middle age and persisting in old mice.
• DAM showed a metabolic shift towards aerobic glycolysis with disrupted TCA cycling and altered metabolite ratios.
• IAV pneumonia induced an acute immunosenescence-like response in microglia, accelerating DAM expansion in middle-aged mice, while old mice showed baseline elevations.
• Human MFG analysis revealed analogous DAM and CD8+ T cell accumulation in white matter of normal agers, SuperAgers, and dementia patients.
• The age-related DAM expansion was independent of microglia-intrinsic mechanisms, suggesting a role for the central nervous system (CNS) microenvironment.

Conclusions:

• IAV pneumonia induces an acute immunosenescence response in microglia.
• The study accelerates the age-dependent expansion of DAM in white matter, linking pneumonia to accelerated brain aging.
• Findings suggest that pneumonia-induced neuroinflammation contributes to cognitive decline risk, particularly in aging populations.