173 Transcriptomic Insights into Post-Traumatic Immune Susceptibility: A Translational Bench-to-Bedside Model of TBI and Infectious Encephalitis

INTRODUCTION: It is known that traumatic brain injury (TBI) predisposes patients to chronic immune-susceptibility. However, chronic neurologic deficits and key pathways associated with post-traumatic infections, such as encephalitis, are poorly characterized. METHODS: The TriNetX database was queried for all patients 18 years or older with a confirmed diagnosis of encephalitis between 2016 and 2024. Patient cohorts included those with a diagnosis of TBI at least one month before encephalitis (N = 1,038), TBI anytime before encephalitis (N = 1,886), and encephalitis but no TBI, which constituted the control group (N = 45,210; N = 45,215). After 1:1 propensity score matching, neurologic outcomes at one year were compared across cohorts. A murine model of controlled cortical impact (CCI) injury and Venezuelan equine encephalitis virus (VEEV) infection was developed to reflect the clinical model, followed by extracting hippocampal tissue for bulk RNA sequencing and analysis. RESULTS: Compared to patients with no TBI history, patients with a TBI history at least one month before infectious encephalitis have an increased risk of mortality, epilepsy, and dementia or delirium. Bulk RNA sequencing of the murine hippocampus demonstrated that key pathways, specifically those involved in granzyme-mediated cell death, are enriched in CCI and VEEV compared to VEEV infection alone. CONCLUSIONS: Our findings reveal that post-traumatic infectious encephalitis portends worse neurologic outcomes, and altered granzyme mediated-cell death signaling in the hippocampus may play a key role in post-traumatic immune susceptibility.