Astrocyte-derived complement C3 facilitated microglial phagocytosis of synapses in Staphylococcus aureus-associated neurocognitive deficits

The presence of pathogens is a significant challenge in causing brain infections and tissue damage. There is growing evidence that pathogen infections are commonly associated with cognitive dysfunction and mental health problems, but the underlying mechanisms are not yet fully understood. Here, we found microglia and astrocyte activation, neuronal damage, synapse loss, and cognitive impairment in a Staphylococcus aureus (S. aureus) induced mouse model. An unbiased transcription profile of isolated microglia derived from S. aureus-infected mice identified the involvement of microglial phagosome and regulation of neurogenesis. Our findings indicate that the complement C1q and C3 are upregulated, and astroglial release of C3 activates microglia to phagocytose synapses. Blocking the C3-C3aR axis can improve microglial phagocytosis, thus rescuing synapse loss and cognitive impairment in infected mice. These results indicate that S. aureus induces synapse elimination and cognitive impairment by activating microglia and astrocytes through C3-C3aR signaling. This suggests a mechanism of complement signaling bridged crosstalk between astrocyte and microglia in the S. aureus-associated post-infectious synapse loss and cognitive dysfunction, and provide potential therapeutic targets for managing pathogen-associated brain infections.