Mechanisms of Immune Dysfunction after Trauma and Surgical Sepsis

Project Summary/Abstract Trauma and Surgical Sepsis are among the leading causes of morbidity and death worldwide. Both of these acute insults can lead to immune dysfunction that then contributes to a state of persistent critical illness. This immune dysfunction is manifested by an excessive systemic inflammatory response that can lead to organ dysfunction; and a simultaneous suppression of immune defenses that renders patients susceptible to secondary infections. However, we lack a comprehensive and integrated view of how humans respond to severe injury, and more importantly, how these responses differ between patients that recover quickly vs. those that die and/or development persistent critical illness. Advances in single cell multiomics and blood analysis using multi- platform, multiomics now makes it possible to characterize changes across a broad range of cell states and patterns within the circulating biomolecule landscape to great depth. In the previous funding cycle, we were the first to perform single cell genomics and large-scale multi-platform, multiomics on blood samples from severely injured patients. This published work identified many novel findings, including the early massive release of cellular constituents into the circulation of trauma patients that follow a complicated course or die. In addition, open chromatin analysis of PBMC found that patients who remain critically ill also have global epigenetic changes evident early across immune cell types, representing de-repression of polycomb targets. In one line of research, we will reverse translate the these and other novel findings from our initial human multiomic analyses into our mouse model of hemorrhagic shock and trauma to pursue potential therapeutic targets. In another line of research, we will extend our analysis of multiomic data to create a Blood Atlas of the human trauma response. This online resource will incorporate data on the range of circulating immune cell states commonly seen after severe injury and integrate these with the longitudinal changes in high dimensional datasets of circulating proteins, lipids and other metabolites. We will apply state-of-the-art computational strategies to identify biomarkers and therapeutic targets with patients stratified by outcomes, treatments, age and sex. We will compare our results with similar published studies in sepsis. In addition to the discoveries and mechanistic insights our analysis will yield, we hope that the resources we provide will stimulate comparative studies and further analyses of our datasets.