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bioRxiv · 10.1101/2025.06.06.658266

Infection-Specific Reprogramming of Microglia Reveals Distinct Virulence Pathways Linking Periodontal Pathogens to Alzheimer's Disease

Kaminska, M.·Dudzinska, N.·Klapper, A.·Geissler, S.·Taudte, N.·Greiser, S.·Potempa, J.·Cynis, H.·Mydel, P.
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Abstract

Microglial dysregulation is increasingly recognized as a driver of Alzheimers disease (AD), yet how pathogen-specific cues sculpt microglial diversity remains unclear. Here we integrate high-dimensional single-cell cytometry in vitro with spatial proteomics in vivo to dissect the impact of two major periodontal pathogens on microglia. Using a 36-marker CyTOF panel, we exposed SIM-A9 microglia to wild-type Porphyromonas gingivalis (Pg) or Tannerella forsythia (Tf) and to gingipain-deficient or S-layer-deficient mutants, resolving 38 clusters. Virulence-factor "switches" redirected cells from homeostatic states toward i) oxidative, antigen-presenting programmes driven by Pg gingipains and ii) an immunosuppressive, exhausted-like state driven by the Tf S-layer. Complementary 37-marker imaging mass cytometry of 5xFAD x hTau knock-in mice chronically infected with Pg identified 21 microglial subclusters. The cortex--but not hippocampus--lost two Arg1/IL-10 immunoregulatory subsets (>2-fold decrease) while NADPH-oxidase-high microglia accumulated around amyloid-{beta} and tau aggregates. These data demonstrate pathogen-specific reprogramming of microglia across model systems and brain regions, linking virulence-factor activity to AD-relevant neuroinflammation. By pinpointing gingipains and the bacterial S-layer as molecular "switches," our study highlights tractable therapeutic targets for limiting infection-driven microglial dysfunction in Alzheimers disease.

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Kaminska, M., Dudzinska, N., Klapper, A., Geissler, S., Taudte, N., Greiser, S., Potempa, J., Cynis, H., Mydel, P.. 2025-06-08. Infection-Specific Reprogramming of Microglia Reveals Distinct Virulence Pathways Linking Periodontal Pathogens to Alzheimer's Disease. https://doi.org/10.1101/2025.06.06.658266

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