Breana Santos
Pronouns:
Research Mentor(s): Patricia De Assis
Research Mentor School/College/Department: Pathology / Medicine
Program:
Authors: Breana Santos, Tarana Varshney, Ron Allen, Jennifer Bermick, Matthew Schaller, Steve Kunkel, Patricia De Assis
Session: Session 6: 3:40 pm – 4:30 pm
Poster: 58
Abstract
Sepsis is a devastating disease with a high in-hospital mortality. Among the patients that survive, approximately 50% will experience long-term comorbidities, are more likely to be re-hospitalized, and ultimately have increased mortality rates. This suggests that the post-septic immune response is chronically suppressed. Our study investigates the effects of sepsis on the function and proliferative ability of T-cells and is meant to identify the mechanisms involved in the long-term immunosuppression in sepsis survivors. Flow cytometry analysis of CD4+ T-cells from post-septic mice shows significant reduction in proliferation and IFNg production. Additionally, analysis of different murine cell types revealed that MLL1 is downregulated specifically in CD4 T cells. MLL1 is a key regulator of activation, proliferation and effector function of Th1 cells. Conversely, type I IFNs present immunosuppressive effects on CD4 T cells. Notably, expression of IFNß is chronically elevated in post-septic patients and mice. Treatment with IFNß resulted in reduced MLL1 expression in CD4 T cells both in vivo and in vitro. MLL1 expression is induced by IL-12/ STAT4 signaling, whereas IFNß induces STAT1 signaling. To investigate the mechanism of MLL1 downregulation after sepsis, we performed Chromatin Immunoprecipitation (ChIP) assays in CD4 T cells. We observed that IFNß treatment inhibits STAT4 from binding to the MLL1 promoter region. Our future studies will focus in two possible mechanisms: (i) IFNß/IFNAR activation inhibits phosphorylation and consequent activation of STAT4; (ii) IFNß-induced STAT1 binds to STAT4, blocking its transcriptional activation of MLL1. In conclusion, our results show that IFNß inhibition of MLL1 is a valuable target for novel therapy applications to prevent post-sepsis immunosuppression.
