Daily Sepsis Research Analysis
Analyzed 23 papers and selected 3 impactful papers.
Summary
Analyzed 23 papers and selected 3 impactful articles.
Selected Articles
1. Intracellular LRG1 recruits MARCH2 to ubiquitinate and degrade endothelial VE-cadherin in septic lung injury.
This mechanistic study shows that endothelial intracellular LRG1 recruits MARCH2 to catalyze K48-linked polyubiquitination of VE-cadherin (Lys633), triggering proteasomal degradation and barrier failure in septic ALI. Genetic Lrg1 deletion or PROTAC-based pharmacology preserved VE-cadherin, reduced hyperpermeability, and mitigated lung injury in septic mice.
Impact: It uncovers a previously unrecognized intracellular LRG1–MARCH2–VE-cadherin axis driving vascular leakage in sepsis, and demonstrates pharmacologic rescue, defining a tractable target for endothelial repair.
Clinical Implications: Therapeutic strategies that block LRG1–MARCH2 interaction or prevent VE-cadherin ubiquitination may stabilize the endothelial barrier in sepsis-associated ALI/ARDS. This supports biomarker-driven patient stratification and informs development of PROTAC-guided approaches.
Key Findings
- Endothelial intracellular LRG1 is upregulated in septic ALI and promotes VE-cadherin degradation via MARCH2-mediated K48-linked polyubiquitination at Lys633.
- Loss of VE-cadherin disrupts adherens junctions, driving endothelial hyperpermeability and lung injury in septic mice.
- Genetic Lrg1 deletion or PROTAC-based intervention preserved VE-cadherin and mitigated endothelial leak and ALI.
Methodological Strengths
- Multi-level validation across endothelial cells and septic mouse models with genetic and pharmacologic interventions
- Precise mechanistic mapping including ubiquitination linkage (K48) and target lysine (Lys633)
Limitations
- Preclinical models; absence of human tissue validation and clinical outcomes
- Potential off-target effects and translational safety of PROTAC strategy not characterized
Future Directions: Validate LRG1–MARCH2 signaling in human sepsis tissues; develop selective inhibitors or biologics targeting the axis; assess pharmacodynamics and safety in large animals before early-phase trials.
Endothelial barrier dysfunction and consequent vascular injury are central contributors to acute lung injury (ALI) during sepsis. However, the underlying mechanisms remain incompletely understood, and effective therapeutic strategies targeting endothelial repair are still lacking. Here, we identify that intracellular leucine-rich α2-glycoprotein 1 (LRG1) in endothelial cells (EC) is significantly upregulated and directly promotes the degradation of vascular endothelial cadherin (VE-cadherin), a core adherens junction protein essential for maintaining vascular barrier integrity in septic ALI. Mechanistically, LRG1 recruits the E3 ubiquitin ligase membrane-associated ring-CH-type finger 2 (MARCH2) to catalyze K48-linked polyubiquitination of VE-cadherin at lysine 633, leading to its proteasomal degradation and subsequent endothelial barrier disruption. Genetic deletion of Lrg1 or pharmacological intervention with a proteolysis targeting chimera (PROTAC)-based degradation strategy significantly reduced VE-cadherin loss, alleviated endothelial hyperpermeability, and mitigated ALI in septic mice. Collectively, our study elucidates a previously unrecognized role of endothelial LRG1 in disrupting EC adherens junctions, providing novel insights into the pathogenesis of sepsis-associated injury and proposing a potential therapeutic strategy for sepsis-induced ALI and acute respiratory distress syndrome (ARDS).
2. Targeting STIM1 attenuates LPS-induced cardiac dysfunction by reshaping calcium homeostasis and mitochondrial function.
In LPS-sepsis models, STIM1 upregulation drives store-operated calcium entry, causing cytosolic and mitochondrial Ca2+ overload, Drp1-mediated mitochondrial fragmentation, ROS elevation, and NLRP3 inflammasome-dependent pyroptosis, culminating in cardiac dysfunction. Myocardial STIM1 knockdown and the SOCE inhibitor BTP2 ameliorated dysfunction, nominating STIM1/SOCE as a therapeutic target for SICM.
Impact: It mechanistically connects calcium entry to mitochondrial injury and pyroptosis in sepsis-induced cardiomyopathy and demonstrates target engagement by genetic and pharmacologic approaches.
Clinical Implications: Supports testing of STIM1/SOCE modulators and downstream Drp1/NLRP3 pathways to prevent or treat sepsis-induced cardiomyopathy; biomarker strategies could track Ca2+ dysregulation and inflammasome activation.
Key Findings
- STIM1 is upregulated in LPS-induced sepsis and its myocardial knockdown improves cardiac function.
- STIM1 amplifies SOCE leading to cytosolic/mitochondrial Ca2+ overload, Drp1-mediated mitochondrial fragmentation, ROS increase, and NLRP3-dependent pyroptosis.
- SOCE inhibitor BTP2 alleviates LPS-induced cardiomyopathy by improving calcium handling and mitochondrial function.
Methodological Strengths
- Combined genetic (myocardial STIM1 knockdown) and pharmacologic (BTP2) interventions
- Integrated in vivo rat and in vitro cardiomyocyte mechanistic dissection
Limitations
- LPS model may not recapitulate polymicrobial sepsis; lack of human validation
- BTP2 is not fully selective; off-target effects and safety require evaluation
Future Directions: Validate STIM1/SOCE activation and downstream signatures in human SICM; test selective SOCE inhibitors or STIM1 modulators and Drp1/NLRP3-targeted therapies in polymicrobial models and early-phase trials.
Dysregulated calcium homeostasis and mitochondrial impairment are critical factors in the pathogenesis of sepsis-induced cardiomyopathy (SICM). STIM1 is crucial for maintaining calcium homeostasis. However, whether improving STIM1-mediated calcium handling can alleviate SICM remains unknown. This study aims to clarify the mechanism and the role of STIM1 in SICM. In this study, we first established a rat model of sepsis induced by LPS and clarified that the upregulation of STIM1 protein is associated with sepsis-induced cardiomyopathy (SICM). Myocardial-specific knockdown of STIM1 significantly improved cardiac function in septic rats. Moreover, using the calcium influx inhibitor BTP2, we elucidated that BTP2 could alleviate LPS-induced cardiomyopathy by improving calcium handling and mitochondrial function. Subsequently, we treated cardiomyocytes with LPS to explore the mechanism by which STIM1 promotes SICM. The results demonstrated that STIM1 amplifies store-operated calcium entry, triggering concomitant cytosolic and mitochondrial calcium overload. This induces Drp1-dependent mitochondrial fragmentation and dysfunction, resulting in elevated ROS production and subsequent activation of the NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes, ultimately leading to LPS-induced cardiomyopathy. In conclusion, this study indicate that STIM1 promotes calcium overload, thereby facilitating mitochondrial dysfunction and ultimately resulting in pyroptosis. Targeting STIM1 may thus represent a promising therapeutic strategy for SICM.
3. Vancomycin-resistant Enterococcus often spreads from hospitalized patients into the local environment and less often spreads from the environment into patients.
In a prospective medical ICU cohort with synchronized patient and room sampling (n=90 patients; 680 samples), VRE colonization was common and genomic analyses showed clusters emerging first in patients and then in rooms, with no room-first events. Findings support patient-to-environment dominance and suggest gut-targeted and source control interventions for infection prevention.
Impact: By pairing longitudinal patient and room sampling with WGS, this study clarifies transmission directionality, directly informing ICU infection-prevention policies.
Clinical Implications: Prioritize measures that reduce patient intestinal VRE burden (e.g., stewardship, selective decolonization), optimize barrier precautions and cleaning around colonized patients, and focus surveillance on high-risk rooms after VRE-positive occupancy.
Key Findings
- Among 90 ICU patients with sepsis, 52% of patients and 40% of rooms showed VRE colonization at ≥1 timepoint.
- Room Enterococcus abundance increased when housing a VRE-positive patient (0.63% vs <0.01% by 16S; p<0.01) and patient–room nodes connected only for VRE-positive cases.
- WGS identified 23 VRE clusters; three patient-first then room events, three simultaneous events, and zero room-first events, indicating dominant patient-to-environment transmission.
Methodological Strengths
- Prospective, synchronized patient–environment sampling across multiple ICU timepoints
- Integration of 16S profiling with WGS to infer transmission directionality
Limitations
- Single-network medical ICU cohort; generalizability may be limited
- Directionality inference cannot exclude unmeasured shared sources; sample size modest
Future Directions: Test targeted decolonization and enhanced environmental protocols in interventional trials; extend WGS-based surveillance to multicenter ICUs and include patient-to-patient transmission mapping.
BACKGROUND: Uncertainty remains about how gut-based organisms such as vancomycin-resistant Enterococcus (VRE) are spread within the local hospital environment. We hypothesized that, in the medical intensive care unit (ICU), VRE is spread predominantly patient-to-environment rather than environment-to-patient. METHODS: Medical ICU patients with sepsis and receiving broad-spectrum antibiotics were sampled via deep rectal swabs at ICU admission and on ICU days 3, 7, 14, and 30. Corresponding ICU room environmental samples were taken at the same timepoints. All samples were analyzed with 16S sequencing and selective culture, and VRE isolates were genetically characterized via whole genome sequencing (WGS). RESULTS: There were 680 samples gathered from 90 unique patients and their ICU rooms. 47/90 (52%) patients and 36/90 (40%) rooms showed VRE colonization at one or more timepoint. On 16S sequencing, Enterococcus relative abundance was enriched in room samples when the room housed a VRE positive patient (0.63% VRE(+) vs. <0.01% VRE(-), p<0.01). In a network analysis, patient and room Enterococcus were connected for VRE positive but not VRE negative patients. WGS identified 23 genetically distinct clusters of VRE. There were 3 events when distinct clusters appeared first in the patient gut and then in the room and 3 events when clusters appeared simultaneously in the gut and room; in no cases was a cluster first detected in the room. CONCLUSIONS: We detected three events when spread of genetically distinct VRE clusters from hospitalized patients into their local ICU environment but no reverse events. Effectiveness of infection prevention might be increased by gut-targeting interventions.