Host-Derived Delta-Like Canonical Notch Ligand 1 as a Novel Diagnostic Biomarker for Bacterial Sepsis—Results From a Combinational Secondary Analysis

Abstract

Background: Sepsis is a life-threatening syndrome, resulting from a dysbalanced host response to infection. However, especially the early, pro-inflammatory immune response in sepsis is similar to other inflammatory conditions without infectious cause, e.g., trauma or surgery. This aspect challenges the value of current biomarkers for diagnosis, as these are often broadly induced. We earlier identified Delta-like Protein 1 (DLL1), a canonical Notch ligand, to be released from monocytes upon bacterial stimulation. Considering the importance of monocytes in the pathophysiology of sepsis, we hypothesized that this mechanism might occur also in the clinical setting and DLL1 might serve as a biomarker of life-threatening bacterial infection. Methods: We combined samples from three different studies, including subgroups of patients with sepsis ( n = 80), surgical patients ( n = 50), trauma patients ( n = 36), as well as healthy controls ( n = 50). We assessed plasma concentrations of DLL1 using ELISA. We performed Area-under-receiver-operator-curve (AUROC) analysis to evaluate the diagnostic performance of DLL1 compared to leucocytes, C-reactive protein (CRP), and procalcitonin (PCT). Results: Plasma concentrations of DLL1 were strongly elevated already at sepsis onset and maintained elevated until day 7. In contrast, neither surgical patients nor patients after severe trauma presented with elevated levels, while conventional biomarkers of inflammation (e.g., leucocytes and CRP), responded. AUROC analysis revealed a cut-off of 30 ng/ml associated with the best diagnostic performance, yielding a superior accuracy of 91% for DLL1, compared to 75, 79, and 81% for CRP, leucocytes, and PCT. Conclusion: DLL1 is a novel host-derived biomarker for the diagnosis of sepsis with a better performance compared to established ones, most likely due to its high robustness in non-infectious inflammatory responses. Clinical Trial Registration: POCSEP-Trial DRKS00008090 ; MIRSI DRKS00005463 ; SPRINT DRKS00010991 .

Notch Signaling Pathway Is Activated by Sulfate Reducing Bacteria

“…The soluble factor responsible for activating Notch signaling in recipient cells remains to be determined. Notch ligand DLL1 has been found in the plasma of sepsis patients and the soluble form of DLL1 was observed in cell supernatants of human monocytes (Hildebrand et al, 2019). It is therefore conceivable that soluble DLL1 may be one of the factors responsible for the effect observed in our study.…”

Machine learning identification of specific changes in myeloid cell phenotype during bloodstream infections

“…Recently, Hildebrand et al identified soluble Delta-like canonical Notch ligand 1 (DLL1) released from monocytes as a predictive marker for sepsis, with a performance superior to that of CRP and PCT 70 . It has also been suggested that Notch signaling is involved in regulating monocyte cell fate 71 .…”

A Review of Natural Therapies Potentially Relevant in Triple Negative Breast Cancer Aimed at Targeting Cancer Cell Vulnerabilities

“…Delta-like canonical Notch ligand 1 (DLL1) has been used as a novel biomarker for sepsis during upregulation of the Notch pathway in human monocytes. 98 Quantification of soluble DLL1 in plasma has been performed using a commercially available ELISA kit. As the Notch Ligand 1 is implicated in TNBC, 99 this may also work in measuring downregulation of the Notch pathway during consumption of Notch pathway suppressers identified in Step 2.…”

“…For instance, high plasma levels of genistein may indicate p53 is regulated by MDM2. Verheus et al 98 found that high plasma levels of genistein were associated with reduced breast cancer risk in Dutch women.…”