Daily Sepsis Research Analysis
Three studies advance sepsis science and care from bench to bedside: (1) Berbamine promotes Notch1 degradation to blunt macrophage inflammation and improve survival in murine sepsis, revealing a druggable pathway. (2) In ED patients with suspected bacterial infection, endothelial glycocalyx injury mapped to distinct immune endotypes, decoupled from capillary density. (3) Hospital-wide cohorting of CRAB patients plus intensified cleaning halved CRAB bloodstream infections.
Summary
Three studies advance sepsis science and care from bench to bedside: (1) Berbamine promotes Notch1 degradation to blunt macrophage inflammation and improve survival in murine sepsis, revealing a druggable pathway. (2) In ED patients with suspected bacterial infection, endothelial glycocalyx injury mapped to distinct immune endotypes, decoupled from capillary density. (3) Hospital-wide cohorting of CRAB patients plus intensified cleaning halved CRAB bloodstream infections.
Research Themes
- Targeted immunomodulation via Notch1 degradation in sepsis
- Endothelial-immune crosstalk and patient endotyping in early infection
- System-wide infection prevention to reduce CRAB bloodstream infections
Selected Articles
1. Targeting notch1 with berbamine alleviates the inflammatory responses of macrophages in sepsis.
In murine LPS and CLP sepsis, berbamine improved survival and attenuated lung inflammation while suppressing TNF-α, IL-6, and IL-1β secretion by macrophages. Target deconvolution pinpointed Notch1, validated by CETSA; BBM accelerated Notch1 proteasomal degradation, and its anti-inflammatory effect was lost in Notch1-deficient macrophages, indicating Notch1-dependent action.
Impact: This work uncovers a druggable, mechanistically validated pathway—Notch1 proteasomal degradation—to quell macrophage-driven inflammation in sepsis, linking a small molecule to target engagement and survival benefit in vivo.
Clinical Implications: Notch1-directed immunomodulation emerges as a promising therapeutic strategy for sepsis. Berbamine could be a lead compound; however, clinical translation will require PK/PD, toxicity, and dose-finding studies followed by early-phase trials.
Key Findings
- Berbamine improved survival and reduced lung inflammation in LPS and CLP murine sepsis models.
- In BMDMs, BBM suppressed LPS-induced TNF-α, IL-6, and IL-1β without impairing differentiation or viability.
- Network pharmacology and CETSA identified and validated Notch1 as a direct BBM target.
- BBM accelerated Notch1 degradation via the ubiquitin–proteasome pathway, lowering Notch1 protein levels.
- BBM’s anti-inflammatory effect was abrogated in Notch1-deficient macrophages, indicating Notch1-dependent mechanism.
Methodological Strengths
- Use of two complementary in vivo sepsis models (LPS endotoxemia and CLP) with histopathology and cytokine profiling
- Target engagement validated by CETSA and functional genetics using myeloid-specific Notch1 knockout
Limitations
- Preclinical murine and cell-based models; no human data on efficacy or safety
- Pharmacokinetics, off-target profiling, and optimal dosing were not reported
Future Directions: Undertake PK/PD and toxicology; test BBM or analogs in large-animal sepsis; assess efficacy across sepsis etiologies; and initiate phase I/II trials with pharmacodynamic biomarkers of Notch1 modulation.
2. Changes in immune cell signatures during early infection reflect decoupling of capillary perfusion and glycocalyx dimensions.
Among ED patients with suspected bacterial infection, deep immunophenotyping identified two immune endotypes with opposing activation states and severity. Endothelial glycocalyx dimensions were reduced and strongly associated with specific monocyte and T-cell subsets, whereas capillary density changes were not correlated with immune signatures, revealing a decoupling of microvascular structure and perfusion.
Impact: The study links endothelial glycocalyx injury to distinct immune programs in early infection, advancing mechanistic understanding and enabling phenotype-driven stratification for future trials.
Clinical Implications: Bedside assessment of glycocalyx (e.g., sublingual microscopy) alongside immune profiling may help identify endotypes for targeted therapies and inform fluid/vascular strategies distinct from perfusion metrics.
Key Findings
- Two immune endotypes (E1 suppressed, E2 enhanced) were identified in ED infection patients and associated with disease severity.
- Glycocalyx dimensions and capillary density were both reduced, but their magnitudes were not correlated.
- Glycocalyx damage strongly associated with specific monocyte and T-cell subsets; such associations were not observed for capillary density.
Methodological Strengths
- Prospective design with concurrent microvascular imaging and deep flow cytometric immunophenotyping
- Use of healthy controls and unsupervised clustering to define immune endotypes
Limitations
- Single-center study with modest sample size limiting generalizability
- Observational design precludes causal inference between glycocalyx injury and immune changes
Future Directions: Validate endotypes and glycocalyx-immune links in larger, multicenter cohorts; test whether endotype-guided resuscitation or endothelial-targeted therapies improve outcomes.
3. Impact of cohorting carbapenem-resistant Acinetobacter baumannii (CRAB) patients combined with enhanced environmental cleaning on CRAB bloodstream infections: a prospective surveillance-based study.
A hospital-wide intervention combining CRAB patient cohorting with twice-daily routine and double terminal cleaning reduced CRAB bloodstream infections by 55%, with a sustained 9% monthly decline in incidence rate. Mortality remained unchanged, highlighting prevention rather than treatment effects.
Impact: This quasi-experimental, institution-wide program demonstrates that targeted cohorting plus enhanced cleaning can substantially curb CRAB BSI at scale, providing actionable infection prevention policy.
Clinical Implications: Hospitals with CRAB burden should consider cohorting and intensified environmental cleaning as core strategies; monitor incidence with robust surveillance and adjust resources accordingly.
Key Findings
- CRAB BSI incidence decreased by 55% (1.43 to 0.65 per 10,000 hospitalization-days) after intervention.
- Adjusted IRR showed a 9% monthly decline in BSI incidence (IRR 0.909; 95% CI 0.834–0.990; P=0.029).
- Among 610 CRAB patients, 57% were hospital-acquired and 39% developed BSI; 30-day mortality averaged 61% and did not change substantially.
Methodological Strengths
- Quasi-experimental design with hospital-wide implementation and prospective surveillance
- Poisson regression discontinuity with robust standard errors accounting for patient influx
Limitations
- Single-center design may limit generalizability; unmeasured confounding cannot be excluded
- Mortality did not improve, indicating intervention addresses transmission but not treatment
Future Directions: Multi-center stepped-wedge trials to validate effectiveness, cost-effectiveness analyses, and integration with antimicrobial stewardship to optimize CRAB control.