Urinary Tract Infection Exaggerates Cognitive Deficits and Region-Specific Neuroinflammation Following Traumatic Brain Injury

(UPEC) and can cause delirium-like symptoms in vulnerable patients, but the specific neuroimmune and cognitive effects of post-injury UTI remain underexplored. To address this gap in knowledge, we present a unique combination of pre-clinical models of TBI and UTI to define the biological effects of bladder infection after brain injury. We hypothesize that UTI after TBI worsens the long-term outcome of brain injury. Female mice received either a sham injury or lateral fluid percussion TBI, and 3 days post-injury (DPI), mice were inoculated transurethrally with vehicle or UPEC to recapitulate a post-injury infection. Y-maze and open-field behavioral tests were administered 6 DPI and 8 DPI, respectively. Brains and blood were collected for flow cytometry and enzyme-linked immunosorbent assay from a subset of mice 6 DPI. Brains and urinary bladders were collected for immunohistochemistry from the remaining mice 10 DPI. TBI mice displayed spatial memory deficits, which were exacerbated following UTI; however, no differences in exploratory behavior were observed after TBI or UTI. TBI significantly elevated plasma interleukin-6, but strikingly, UTI following TBI dampened this response 6 DPI. Flow cytometry revealed no significant differences in circulating immune cells 6 DPI but confirmed that TBI elevated microglial reactivity and monocyte infiltration to the brain, independent of infection. TBI and UTI differentially modulated Glial Fibrillary Acidic Protein (GFAP) and Ionized Calcium-binding Adapter Molecule 1 (Iba1) expression in the hippocampus and cortex, reflecting additive and interaction-based effects. UTI after TBI elevated microglia CD68 expression in a brain region-specific manner further demonstrating that post-injury infection alters the neuroimmune landscape. Together, these data offer novel insight into the effects of UTI after TBI, showing that UTI after TBI is detrimental to overall outcome and warrant further investigation into the signaling mechanisms between bladder infection and neuroinflammation.