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.
Sepsis is a leading cause of mortality and morbidity in neonates yet remains difficult to diagnose. This leads to widespread empiric antibiotic therapy, which can facilitate the development of antimicrobial resistance. How the dysregulated host response to infection and sepsis evolves after antibiotic treatment is poorly understood. Temporal gene expression in neonates with microbiologically confirmed sepsis, treated with the antibiotic vancomycin as part of a randomized controlled trial, was profiled to reveal a treatment-responsive gene signature. The signature exhibited a rapid reversal of the septic state, observable within 24 hours of the initiation of therapy. Unexpectedly, response rates associated with the adaptive immune system were among the fastest, and these changes were reproduced in both pediatric and adult patients with sepsis, indicating conservation and reversibility of sepsis signatures across the life course. We demonstrated how these treatment-responsive genes could be translated into a prognostic clinical measure, exhibiting strong agreement with clinical assessments. Network modeling of sepsis-responsive genes identified a signature associated with treatment comprising an early transient elevation of antimicrobial defensive genes, suggesting an impaired bactericidal response in neonatal sepsis. These findings suggest that the host response is regulated in sepsis and offer insights into early prognostic approaches for reducing antibiotic overuse.
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.
Pseudomonas aeruginosa is an important nosocomial pathogen which can cause serious infections across diverse anatomic locations. Infections can spread within an individual to different body sites, but the rate and directionality of this process is unknown. Here, we explore within-host diversity as well as the body site translocation dynamics using de-convoluted metagenomic P. aeruginosa reads from 256 hospital patients sampled at both respiratory and gut sites. Of the 84 patients where P. aeruginosa genomes could be recovered, there were 27 cases where the same P. aeruginosa clone was detected across multiple body sites. Using a simulation approach, we find that the majority of body site sharing is likely due to within-patient translocation of clones rather than independent acquisition from the hospital environment. Using ancestral reconstruction, we predict that most clones likely occupied a respiratory niche, and that the probable direction of clone transmission is lung-to-gut. Analysis of within-patient variation highlights strong enrichment of mutations in genes associated with antimicrobial resistance, irrespective of sample type. We report significantly more translocation than has been previously reported and highlight that lower respiratory tract infections can result in persistent gut colonisation of P. aeruginosa, a major risk factor for sepsis in vulnerable patients.
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.
BACKGROUND: This study investigates the role and mechanism of neutrophil extracellular trap (NET) clearance by aged macrophages during sepsis-induced liver injury, as elderly patients show higher rates of organ damage and mortality in sepsis. METHODS: A sepsis model was established using cecal ligation and puncture (CLP) in aged (100-week-old) and young mice (8-week-old) to study NET clearance by macrophages, assessing liver injury and inflammatory responses with interventions targeting AMP-dependent protein kinase (AMPK) and phagocytosis pathways. Additionally, the study included 40 sepsis patients, with 25 elderly (65-89 years) and 15 young (31-62 years) individuals, and collected peripheral blood samples from all for in vitro experiments. RESULTS: In aged mice, a significant increase in 7-day mortality was observed (hazard ratio [HR] = 2.50, 95% confidence interval [CI], 1.10-5.65, P = .009), alongside heightened inflammatory response and liver injury (histopathology score: 3.2 ± 0.4 vs 2.4 ± 0.6; P = .021), compared to young mice post-CLP. Hepatic NET accumulation markedly increased (mean difference [MD] = 0.43%, 95% CI, 0.25%-0.61%; P < .001), which was attenuated by DNase I-mediated NET inhibition, reducing hepatic enzymes and inflammatory responses. Consistently, transplantation of young bone marrow into aged recipients significantly reduced NET accumulation (MD = -0.33%, 95% CI, -0.43% to -0.22%; P < .001). Mechanistically, the phosphorylation of AMPK (0.68-fold vs young; P < .001) and Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) was suppressed in aged septic mice. Activation of AMPK via 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) led to a decrease in hepatic NET accumulation (MD = -0.30%, 95% CI, -0.41% to -0.19%; P < .001), improved liver injury (histopathology score: 2.49 ± 0.24 vs 3.07 ± 0.28; P = .006), and reduced 7-day mortality (HR = 0.37, 95% CI, 0.15-0.94, P = .038). Critically, elderly patients exhibited elevated NET-related markers, compounded by suppressed AMPK phosphorylation and impaired NET phagocytosis (MD = -16.34%, 95% CI, -24.31% to -8.37%; P = .002). CONCLUSIONS: Aging impairs AMPK-mediated macrophage clearance of NETs in the liver, exacerbating liver inflammatory injury. Focusing on NETs could offer a therapeutic strategy to mitigate liver damage and reduce mortality in elderly sepsis patients.