Targeting Immune Dysregulated Endotypes in Sepsis (TIDES)

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY / ABSTRACT Pediatric sepsis is the leading cause of death of hospitalized children worldwide. While sepsis is defined as life-threatening organ dysfunction that develops in the setting of immune dysregulation, optimal management of immune dysregulation in pediatric sepsis is a fundamental knowledge gap. A successful precision medicine approach to pediatric sepsis requires that we understand the molecular events that cause organ failure, which of these events are potentially reversible, and how to identify this reversible patient pathobiology in real-time. We recently identified features of cellular immune dysregulation in children with sepsis and used proteomics to define three molecular subphenotypes which predict the severity of organ failure and mortality. Reproducible, validated molecular sepsis subphenotypes are viable candidates for translation to clinical trials, as models based on clinical data and plasma proteins could be used to identify “treatable traits” in real-time for both prognostic and predictive enrichment. Our preliminary data also identifies a pathologic and potentially reversible role for STAT3 hyperactivation in our most severe sepsis subphenotype. The IL-6/JAK/STAT3 signaling pathway is a canonical inflammatory pathway associated with capillary leak, endothelial dysfunction, emergency granulopoiesis, and lymphocyte dysregulation. Selective and non-selective JAK inhibitors have been used clinically to treat COVID-19 ARDS and pediatric hemophagocytic lymphohistiocytosis (HLH). It is not known if JAK inhibition can reverse immune dysregulation in sepsis, despite its related pathobiology. We propose to address these current knowledge gaps by defining and validating molecular subphenotype that predicts sepsis severity and testing the reversibility of T cell STAT3 hyperactivation. The overall objectives of this application are to define and prospectively evaluate a model to identify prognostic molecular sepsis subphenotypes (Aim 1) and to determine the impact of ex vivo JAK/STAT inhibition to reduce immune dysregulation in pediatric patients with sepsis (Aim 2). My central hypothesis is that immune dysregulation in pediatric sepsis can be identified in the plasma proteome and reversed with targeted immunomodulation. By validating a model to prospectively identify prognostic molecular sepsis subphenotypes and determining the impact of JAK/STAT inhibition on immune dysregulation, this study will support a precision approach to immunomodulation in pediatric patients with sepsis. My long-term goal is to design precision approaches to immunomodulation in critically ill children as a translational critical care physician-scientist trained in computational human immunology. I am optimally situated to perform these studies given my background as a clinician, my experience in prospective cohort development and proteomic subphenotyping, and the strong mentorship and supportive environment at CHOP/UPenn. The K23 award will provide new skills in translational research and computational analysis, facilitating my development as an independent investigator with expertise in translational human immunology.