Tissue niche influences immune and metabolic profiles to Staphylococcus aureus biofilm

Infection is a devastating post-surgical complication, often necessitating additional procedures and prolonged antibiotic therapy. This is especially relevant for craniotomy and prosthetic joint infections, both of which are characterized by biofilm formation on the bone or implant surface, respectively, with S. aureus representing a primary cause. The effectiveness of immune responses to these infections is predicated on both host- and pathogen-derived signals in the infection microenvironment. However, the extent to which these signals differ across distinct tissue niches and influence immune function remains relatively unknown. Using mouse models of S. aureus craniotomy and prosthetic joint infection complemented with patient samples from both infectious modalities, we show profound metabolomic, transcriptomic, and functional differences that are dependent on tissue niche. These signatures were both spatially and temporally distinct, differing not only between surgical site infections but evolving over time within a single model. These findings highlight the unique immune attributes of biofilms that are heavily influenced by the local tissue microenvironment, which will likely have important implications when designing therapeutic approaches to target specific infections. To investigate differential leukocyte responses to tissue niche, bulk RNA-seq was performed on FACS-isolated granulocytes from two surgical site infection mouse models, namely, the galea of craniotomy infection and the tissue of prosthetic joint infection. Craniotomy samples were also collected from a TNF KO genetic mouse background to assess the role of this cytokine in granulocyte responses during infection.