Abstract
Traumatic brain injuries (TBIs) are a global source of hospitalization, long-term disability, and death. However, age, sex, and other demographics differ widely among patients and the variable characteristics of TBIs further obscure injury outcomes. Here, we used Drosophila melanogaster to assess the effects of mild, repeated TBI (multi-day, MD) compared to single, severe TBI (single-day, SD). In all genotypes tested, flies given an SD injury exhibited higher acute mortality, but in some genotypes, the surviving flies had a longer lifespan and better long-term locomotor ability than flies given an MD injury. We hypothesized that different immune responses to MD vs SD injury may mediate differences in short- and long-term outcomes. We measured antimicrobial peptide gene expression and found that it increased after each strike of the MD injury and was eventually equivalent or greater than in flies given SD injury. Additionally, increased expression of some immune genes persisted for up to four weeks, predominantly in flies given MD injuries. We measured TBI outcomes of mutant flies for each arm of the innate immune system (Imd and Toll) and found that Imd null mutants had worse short- and long-term survival across both injury conditions, indicating that Imd signaling is protective against both injury types. Interestingly, a partial loss of function mutant for Toll signaling led to higher acute mortality following SD injury, but lower acute mortality and longer lifespan after MD injury, suggesting that Toll signaling is detrimental following MD injury. However, weak and strong ubiquitous Gal4-driven RNAi knockdowns of Toll and Imd varied in their effects on acute mortality and lifespan, suggesting that the degree of immune signaling also contributes to TBI outcomes. Understanding differences in innate immune response to different types of TBI could enable development of targeted therapeutics.
