Novel Burn Sepsis Prognostic Strategies: Deciphering Early Immune Progenitor Shifts in Burn Sepsis Development and Modulation of Host Burn Response through Angiopoietin-Tie Signaling - Recent advancements in the treatment of burn shock have improved acute survival (the first 48 hours) from severe burn injury; however, patients still experience more than 60% mortality due to infectious complications and sepsis. Burn injury triggers a unique and profound immune response from a combined hypovolemic, cardiogenic, and distributive shock that can lead to multisystem organ failure and death. Full-thickness burned skin can only be treated with surgical intervention and may require months of surgery to address. During that time, patients are highly susceptible to infectious complications, including sepsis. There is a pressing need for new strategies to reduce infection-related morbidity and improve overall survival after severe burn injury. Preliminary work has identified 2 unique features seen early after burn injury that correlate with the later development of sepsis: 1) a myeloid progenitor lineage selection; and 2) elevated angiopoietin-2 (Angpt-2). To improve the survival of all patients with sepsis, this proposed research program aims to address the following 2 critical challenges: Challenge 1 is the need to identify distinct phenotypes of immune responses to burn shock and their relation to the development of sepsis so that novel approaches to mitigate sepsis risk can be developed; and Challenge 2 is the need to identify the mechanism through which elevated Angpt-2 leads to an increased rate of sepsis development. This proposed research program will prospectively follow patients with severe burn and will combine the identification of immune system phenotypes with mechanistic drivers of endothelial dysfunction in order to identify sepsis earlier, better predict outcomes, and identify new mechanisms to help modulate the host response. The first project will address Challenge 1 by answering the translational question of whether early changes in immune progenitor lines can predict patients at risk for the development of sepsis. Not all patients response to severe burn is the same, which may be partly due to differences in their immune responses at the level of hematopoietic progenitor cells. The hypothesis is that an immune phenotype with increased myeloid progenitor cells will correlate with development of sepsis. A multiomics framework will be used to identify immune phenotypes in the peripheral blood and bone marrow for patients who do and do not develop sepsis. The second project will address Challenge 2 by determining whether the source of Angpt-2 is the burn injury itself or if the elevation in Angpt-2 is part of the systemic response to the burn. The hypothesis is that burned tissue is the primary driver of Angpt-2 release. This research program will integrate in vitro models, spatial transcriptomics, and a multiomics framework to define how Angpt-2 increases risk of sepsis development. Together, these proposed studies will test novel methods for diagnosing and predicting sepsis, which are critical to improving outcomes in burn survivors. The findings from these studies are anticipated to have broader scientific and clinical implications for the treatment of sepsis in critical illness by testing immune phenotype prognostication and by modulation of Angpt-2.
