The critical role of neutrophil-endothelial cell interactions in sepsis: new synergistic approaches employing organ-on-chip, omics, immune cell phenotyping and in silico modeling to identify new therapeutics

Abstract

Sepsis is a global health concern accounting for more than 1 in 5 deaths worldwide. Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis can develop from bacterial (gram negative or gram positive), fungal or viral (such as COVID) infections. However, therapeutics developed in animal models and traditional in vitro sepsis models have had little success in clinical trials, as these models have failed to fully replicate the underlying pathophysiology and heterogeneity of the disease. The current understanding is that the host response to sepsis is highly diverse among patients, and this heterogeneity impacts immune function and response to infection. Phenotyping immune function and classifying sepsis patients into specific endotypes is needed to develop a personalized treatment approach. Neutrophil-endothelium interactions play a critical role in sepsis progression, and increased neutrophil influx and endothelial barrier disruption have important roles in the early course of organ damage. Understanding the mechanism of neutrophil-endothelium interactions and how immune function impacts this interaction can help us better manage the disease and lead to the discovery of new diagnostic and prognosis tools for effective treatments. In this review, we will discuss the latest research exploring how in silico modeling of a synergistic combination of new organ-on-chip models incorporating human cells/tissue, omics analysis and clinical data from sepsis patients will allow us to identify relevant signaling pathways and characterize specific immune phenotypes in patients. Emerging technologies such as machine learning can then be leveraged to identify druggable therapeutic targets and relate them to immune phenotypes and underlying infectious agents. This synergistic approach can lead to the development of new therapeutics and the identification of FDA approved drugs that can be repurposed for the treatment of sepsis.

Distinct functional neutrophil phenotypes in sepsis patients correlate with disease severity

“…Neutrophils with the Hyperimmune and Hybrid phenotype, compared to the Hypoimmune phenotype, had significantly increased expression of proteins associated with adherence, cytoskeleton and defense proteins involved in proinflammatory cell functions (Figure 6) and these distinct proteomic signatures are associated with significant neutrophil functional differences. Detection of unique protein expression in the different neutrophil phenotypes may help identify novel therapeutic targets for a specific neutrophil phenotype (67,68).…”

Hospital Acquired Sepsis, Disease Prevalence, and Recent Advances in Sepsis Mitigation

“…A Targeted Real-time Early Warning System (TREWS) for sepsis has been designed and investigated to improve patient outcomes [ 106 ]. In silico models incorporating omics with additional information from clinical parameters and different sources may allow for improved drug treatment of sepsis as part of drug discovery and repurposing [ 107 ]. To achieve sensitivity and accuracy with machine learning, the selection of relevant variables and combinations such as lactic acid is essential to predict sepsis onset and patient outcomes.…”