Myeloid-Derived Suppressor Cells in Immunological Endotyping and Intervention of Chronic Critical Illness after Sepsis

University Of Florida, Gainesville FL

Investigators

Abstract

ABSTRACT Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection leading to organ dysfunction. It frequently occurs in hospitalized patients undergoing surgical procedures and is associated with prolonged hospital stays and increased mortality. Despite improved in-hospital survival, 30-50% of surgical sepsis patients will never fully recover, but develop a syndrome recently described as “chronic critical illness (CCI)” which is characterized by persistent inflammation, immune suppression, and protein catabolism (PICS) and poor long-term outcomes. Currently, two important critical questions continue to vex clinical intensivists: i) why do otherwise similar surgical sepsis patients have very different clinical trajectories where some rapidly recover while others develop CCI despite our best supportive efforts? and ii) can we “endotype” patients with sepsis and identify subsets with different immunological responses who would benefit from individualized interventions. We believe that current efforts to endotype sepsis have not been fully successful because they fail to directly assess key host-pathogen responses (e.g., cells, molecules, pathways) driving immune suppression and inflammation, instead selecting either genomic or proteomic markers of immune status which have been shown to exhibit limited predictive power due to sepsis heterogeneity and usually small sample sizes. Our recent efforts have highlighted the role of unresolving “pathologic myelopoiesis” and ensuing expansion of myeloid- derived suppressor cells (MDSCs) in driving both the persistent inflammation and immune suppression in CCI patients. The overarching goal of the PI laboratory’s research program over the next five years is to: 1) assess whether multi-omic data of MDSCs can improve the sepsis endotyping and predict clinical trajectories than the commonly-used static measurements based on protein levels and nucleic acid concentrations; 2) delineate the longitudinal change in the cross-talk between MDSCs and T cells in patients with different clinical trajectories; 3) identify potential drugs for intervention of persistent inflammation and/or immune suppression in sepsis from FDA-approved drugs. These goals will be achieved by integratively leveraging the existing and ongoing efforts (RM1 GM-139690 and R01 GM-139046) examining the MDSC-specific multi-omic landscape (transcriptomics, chromatin accessibility, DNA methylation, metabolomics, clinical variables) and large-scale of bulk blood leukocyte transcriptomes, an existent comprehensive assessment of clinical immunosuppression and functions of MDSCs and T cells, with powerful statistical modeling and artificial intelligence (AI). We believe that only through a complete understanding of the immunological endotypes surrounding sepsis can effective therapeutic interventions evolve. This MIRA would support and enable the PI and his laboratory to identify and understand immunological endotypes of sepsis, explore how MDSC driving persistent immune suppression, and how to work towards resolving this to improve patient outcomes. The outcomes of this project will provide key data, knowledge and drug candidates to apply precision medicine to sepsis therapy.