The weight of multiple hits: how TBI and infectious encephalitis co-modulate adverse outcomes

Chronic neurologic deficits from traumatic brain injury (TBI) and subsequent infectious encephalitis are poorly characterized. Using TriNetX database we queried 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 (<i>N</i> = 1,038), those with a diagnosis of a TBI anytime before encephalitis (<i>N</i> = 1,886), and those with encephalitis but no TBI, (<i>N</i> = 45,210; <i>N</i> = 45,215). A murine model of controlled cortical impact (CCI) injury and Venezuelan equine encephalitis virus (VEEV) infection was used to reflect the clinical model, followed by extracting hippocampal tissue for bulk RNA sequencing and analysis. 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 hippocampus from mice subjected to CCI injury and VEEV infection demonstrated that key pathways, specifically those involved in granzyme mediated cell death, were enriched compared to VEEV infection alone. Our findings reveal that infectious encephalitis in patients with TBI history portends worse neurologic outcomes, and the hippocampus may be vulnerable to granzyme mediated cell death under these conditions.