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bioRxiv · 10.64898/2026.05.19.726323

Age Dependent Immunopathology Drives Pneumonia-Associated Cardiac Dysfunction During Streptococcus pneumoniae Infection

Rajaram, M.·Matoo, S. S.·Kumar, N.·Salem, M.·Thomas, A.·Shah, A.·Kumar, P.·Dhariwala, M.·Zhiwei, L.·Wen, H.·Seveau, S.·Ganesan, L. P.·Lafuse, W.·Philips, R.·Collins, P.
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Abstract

Aging is a major risk factor for severe Streptococcus pneumoniae (Spn) infection and pneumonia-associated - major adverse cardiac events (PA-MACE), yet underlying mechanisms remain unclear. Using young and aged murine models, we show that aging exacerbates bacterial burden, mortality, and cardiac dysfunction following Spn infection, associated with impaired macrophage bacterial killing. Single-cell RNA sequencing infected hearts revealed extensive age-dependent remodeling across immune and stromal compartments. Aged mice exhibited heightened pro-inflammatory myeloid responses, with increased neutrophil infiltration characterized by elevated S100A8/9 and LCN2 and reduced antimicrobial programs. Macrophages displayed defective efferocytosis, including disruption of the GAS6-AXL axis. Aging also drove expansion of an infection-responsive fibroblast population with inflammatory signatures and reduced extracellular matrix gene expression. These changes were linked to oxidative stress and impaired glucose oxidation. Notably, anti-inflammatory treatment rescued cardiac dysfunction, implicating excessive inflammation as a central driver of PA-MACE. Together, these findings define mechanisms linking aging to pneumococcal cardiac complications and identify potential therapeutic targets.

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Rajaram, M., Matoo, S. S., Kumar, N., Salem, M., Thomas, A., Shah, A., Kumar, P., Dhariwala, M., Zhiwei, L., Wen, H., Seveau, S., Ganesan, L. P., Lafuse, W., Philips, R., Collins, P.. 2026-05-21. Age Dependent Immunopathology Drives Pneumonia-Associated Cardiac Dysfunction During Streptococcus pneumoniae Infection. https://doi.org/10.64898/2026.05.19.726323

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