Th17 effector cytokines induce shared and distinct microglial and endothelial cell responses in a mouse model for post-streptococcal encephalitis

Abstract

Group A Streptococcus (GAS) infections cause neuropsychiatric complications in children, but the mechanisms linking peripheral infection to brain dysfunction remain unclear. Using mouse genetics, single-cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory transcriptional programs in microglia and brain endothelial cells (BECs), accompanied by loss of blood-brain barrier (BBB) gene expression in female mice. Spatial transcriptomic analyses reveal that GAS-responsive microglia localize near infiltrating CD4+ T cells. Several microglial chemokines induced in mice are elevated in sera from affected patients. Deletion of GM-CSF in CD4⁺ T cells partially reduces microglial chemokine gene expression, without restoring BBB integrity. In contrast, IL-17A neutralization partially rescues BBB transcriptional changes, but not BBB dysfunction, and reduces microglial chemokine expression. Microglia-specific deletion of IL-17 receptor A partially restores BBB integrity after GAS infections. Our findings identify microglial IL-17A–IL17RA signaling as a potential mediator of BBB dysfunction and neuroinflammation after GAS infections. Group A Streptococcus (GAS) infections can cause neuropsychiatric symptoms in children, but the underlying mechanisms remain unclear. Here, the authors show that IL-17A–IL17RA signaling in microglia mediates blood brain barrier dysfunction and neuroinflammation after GAS infection in a mouse model.