Daily Sepsis Research Analysis
Three studies advanced sepsis science across translational, microbial, and immunometabolic fronts. A Science Translational Medicine paper defines a rapid host gene expression signature predicting antibiotic response in neonatal sepsis, conserved across ages. Nature Communications reveals frequent within-patient translocation of nosocomial Pseudomonas aeruginosa from lung to gut, while a mechanistic study links impaired AMPK-mediated NET clearance by aged macrophages to worse liver injury in seps
Summary
Three studies advanced sepsis science across translational, microbial, and immunometabolic fronts. A Science Translational Medicine paper defines a rapid host gene expression signature predicting antibiotic response in neonatal sepsis, conserved across ages. Nature Communications reveals frequent within-patient translocation of nosocomial Pseudomonas aeruginosa from lung to gut, while a mechanistic study links impaired AMPK-mediated NET clearance by aged macrophages to worse liver injury in sepsis.
Research Themes
- Treatment-responsive host transcriptomic signatures for antibiotic stewardship
- Within-host ecology and translocation of nosocomial pathogens
- Aging, AMPK signaling, and NET clearance in sepsis organ injury
Selected Articles
1. A rapid time-resolved host gene expression signature predicts responses to antibiotic treatment in neonatal bacterial sepsis.
Time-resolved transcriptomics in microbiologically confirmed neonatal sepsis identified a treatment-responsive host gene signature that reverses within 24 hours of vancomycin initiation and tracks clinical improvement. Adaptive immune pathways changed unexpectedly fast, and signatures were conserved across pediatric and adult cohorts, enabling a prognostic measure and implicating early transient antimicrobial defense activation in neonatal sepsis.
Impact: Provides a biologically grounded, rapid biomarker for antibiotic response with cross-age conservation, directly addressing antibiotic stewardship in neonatal sepsis. Offers mechanistic insights and a practical prognostic metric aligned with clinical assessments.
Clinical Implications: Enables early (within 24 hours) assessment of antibiotic efficacy to support de-escalation and duration decisions, potentially reducing unnecessary exposure. Can be integrated into rapid transcriptomic diagnostics to guide personalized therapy and monitoring in neonatal sepsis.
Key Findings
- Identified a treatment-responsive host gene signature in neonatal sepsis with rapid reversal within 24 hours of antibiotic initiation.
- Adaptive immune system responses were among the fastest changing pathways.
- Signatures were conserved and reversible across pediatric and adult sepsis cohorts.
- A prognostic measure derived from treatment-responsive genes agreed with clinical assessments.
- Network modeling revealed an early transient rise in antimicrobial defense genes, suggesting impaired bactericidal responses in neonates.
Methodological Strengths
- Longitudinal, time-resolved transcriptomics nested within an RCT with microbiologically confirmed cases
- Cross-cohort validation across pediatric and adult sepsis with network modeling and clinical concordance
Limitations
- Exact sample size and cohort diversity not specified in the abstract
- Antibiotic exposure centered on vancomycin may limit generalizability to other regimens; prospective clinical validation needed
Future Directions: Prospective multicenter validation of the signature’s predictive performance, expansion to diverse pathogens/antibiotics, integration into rapid point-of-care transcriptomic platforms, and interventional trials using signature-guided de-escalation.
2. High frequency body site translocation of nosocomial Pseudomonas aeruginosa.
Metagenomic analysis across 256 hospitalized patients shows frequent within-host translocation of P. aeruginosa clones, predominantly from lung to gut, with resistance mutations enriched irrespective of site. Simulations and ancestral reconstruction support within-patient movement over environmental reacquisition, implicating lower respiratory tract infections as a source of persistent gut colonization and sepsis risk.
Impact: Reveals previously underappreciated lung-to-gut seeding of a major nosocomial pathogen, reframing surveillance and decolonization strategies to prevent bloodstream infection in high-risk patients.
Clinical Implications: Supports targeted screening of gut colonization following lower respiratory tract infection, informs cohorting and infection control, and motivates trials of selective digestive decontamination or microbiome-based interventions to reduce sepsis risk.
Key Findings
- Among 256 patients, 27/84 with recoverable genomes harbored identical P. aeruginosa clones across multiple body sites.
- Simulations indicate within-patient translocation rather than independent environmental acquisition accounts for most site sharing.
- Ancestral reconstruction suggests a predominant lung-to-gut direction of clone movement.
- Within-patient variation showed enrichment for antimicrobial resistance gene mutations independent of sample type.
Methodological Strengths
- Combined deconvoluted metagenomics, simulation, and ancestral reconstruction for directionality inference
- Multi-site sampling within patients enabled robust within-host comparisons
Limitations
- Observational design with limited temporal resolution; causality and timing of translocation cannot be definitively established
- Sampling restricted to respiratory and gut sites; other reservoirs and environmental sources not comprehensively assessed
Future Directions: Prospective longitudinal sampling to resolve timing and triggers of translocation, interventional studies testing decolonization strategies, and integration with clinical outcomes to quantify bloodstream infection risk.
3. Impaired AMP-Dependent Protein Kinase-Mediated Neutrophil Extracellular Trap Clearance by Aged Macrophages in Sepsis-Induced Liver Injury.
In sepsis-induced liver injury, aged mice exhibited increased NET accumulation, worsened pathology, and higher 7-day mortality. Suppressed AMPK/CaMKK2 signaling impaired macrophage NET clearance; activating AMPK with AICAR reduced NETs, improved liver injury, and decreased mortality. Elderly patients mirrored elevated NET markers, reduced AMPK phosphorylation, and impaired NET phagocytosis.
Impact: Defines an age-specific mechanistic axis (AMPK–NET clearance) driving organ injury in sepsis with interventional rescue in vivo, nominating AMPK activation and NET-targeting as therapeutic strategies for elderly patients.
Clinical Implications: Supports testing NET-directed therapies (e.g., DNase) and AMPK activators to mitigate liver injury in elderly sepsis, and motivates incorporating NET/AMPK biomarkers for risk stratification and therapeutic monitoring.
Key Findings
- Aged septic mice had higher hepatic NET accumulation, worse liver injury, and increased 7-day mortality (HR 2.50).
- DNase I reduced NETs and liver inflammation; young bone marrow transplantation decreased hepatic NETs in aged recipients.
- AMPK and CaMKK2 phosphorylation were suppressed with age; AMPK activation (AICAR) lowered NETs, improved histopathology, and reduced mortality (HR 0.37).
- Elderly sepsis patients showed elevated NET markers, reduced AMPK phosphorylation, and impaired NET phagocytosis.
Methodological Strengths
- Integrated murine CLP model with pathway-targeted interventions and bone marrow chimera experiments
- Human corroboration with patient biomarker profiling and functional phagocytosis assays
Limitations
- Human cohort size was modest and limited to peripheral markers; clinical interventional data are lacking
- Potential off-target effects of AICAR and species differences limit direct translation; focus on liver may not generalize to other organs
Future Directions: Evaluate clinically suitable AMPK activators or NET-targeting agents in aged sepsis models, expand organ-level analyses, and conduct early-phase trials incorporating NET/AMPK biomarkers in elderly sepsis.