Interferon-gamma receptor signaling regulates innate immunity during Staphylococcus aureus craniotomy infection

A craniotomy is a neurosurgical procedure performed to access the intracranial space. In 3-5% of cases, infections can develop, most caused by Staphylococcus aureus biofilm formation on the skull surface. Medical management of this infection is difficult, as biofilm properties confer immune and antimicrobial recalcitrance to the infection and necessitate additional surgical procedures. Furthermore, treatment failure rates can be appreciably high. These factors, compounded with rapidly expanding rates of antimicrobial resistance, highlight the need to develop alternative treatment strategies to target and reverse the immune dysfunction that occurs during biofilm infection. Our recent work has identified CD4⁺ Th1 and Th17 cells as potent regulators of innate immune cell activation during craniotomy infection. Here, we report the role of IFN-γ, versus other Th1- and Th17-derived cytokines, in programing the immune response to biofilm infection using both global and cell type-specific IFN-γR1-deficient (Ifngr1^-/-) mice. Bacterial burdens were significantly higher in Ifngr1^-/- relative to WT animals despite few changes in immune cell abundance. Single-cell transcriptomics identified candidate explanations for this phenotype as alterations in cell death pathways, innate immune cell activation, MHC-II expression, and T cell responses were significantly reduced in Ifngr1^-/- mice. While caspase-1 activation in PMNs and macrophage/microglial MHC-II expression were regulated by IFN-γ signaling, no phenotypes were observed with either granulocyte- or macrophage/microglia Ifngr1^-/- conditional knockout mice, suggestive of redundancy. Instead, a decreased Th1/Th17 ratio was identified in Ifngr1^-/- animals that was corroborated by elevated IL-17 levels and correlated with dysfunctional T cell-innate immune communication. Further, Th17 cells were less effective than Th1 cells in promoting S. aureus bactericidal activity in microglia and macrophages. Collectively, this work identifies a key protective role for IFN-γ during craniotomy infection by enhancing macrophage and microglial antibacterial activity. Therefore, controlled programming of IFN-γ responses may represent a novel therapeutic strategy for chronic craniotomy infections.