Understanding Immune Dysregulation During Sepsis

National Heart, Lung, And Blood Institute

Investigators

Abstract

This is a natural history study intended to allow the characterization of neutrophil biology and other contributors on the pathogenesis along with short-term outcomes of patients hospitalized with sepsis. Patients admitted to INOVA Fairfax Hospital with sepsis are enrolled, undergo clinical evaluation, clinical data capture, and have blood drawn that is processed and analyzed at in our lab at the NIH. In the last year we have enrolled approximately 100 patients. Using this blood we have performed detailed characterization of neutrophils across a variety of assays including, high dimensional flow cytometry, single-cell RNA-sequencing with cite-sequencing, metabolomics, and measurement of soluble biomarkers. Furthermore, we have been characterizing a subset of neutrophils suspected to be pathogenic in sepsis called low density neutrophils using different functional assays including evaluating differences in their ability to perform release neutrophil extracellular traps, reactive oxygen species, migration, release of soluble cytokines, and phagocytosis. Specific accomplishments of this work include the identification that spleen tyrosine kinase is upregulated across whole blood and low dentistry neutrophils in patients with sepsis. Furthermore, we have observed that SYK expression associates with disease severity including the need for mechanical ventilation, SOFA score, and length of stay. In total this works suggests that spleen tyrosine kinase may be a therapeutic target in bacterial sepsis (this work is currently in the process of having the manuscript written). In a separate but concurrent project we have been working on detailed characterization of the metabolome of sepsis neutrophils. This work identified that sepsis neutrophils have increased lipid metabolites compared to healthy controls and in patients with septic shock, there is an elevation in acyl carnitines which are required for mitochondrial respiration in neutrophils. Additionally, this study low density neutrophils, in patients with sepsis have increased mitochondrial respiration which may be attributable to increased fatty acid oxidation (this work was accepted for an oral presentation at the 2025 Society of Leukocyte Biology Meeting).