Daily Sepsis Research Analysis
A controlled human endotoxemia study in Nature Immunology delineates how systemic inflammation impairs myelopoiesis and type I interferon responses, providing mechanistic insight into vulnerability to secondary infections. Complementary mechanistic work identifies astrocytic FABP7 as a modulator of neuroinflammatory responses to endotoxemia, while a meta-analysis in preterm infants finds no increased late-onset sepsis risk with prolonged early antibiotics and hints that short courses may slightl
Summary
A controlled human endotoxemia study in Nature Immunology delineates how systemic inflammation impairs myelopoiesis and type I interferon responses, providing mechanistic insight into vulnerability to secondary infections. Complementary mechanistic work identifies astrocytic FABP7 as a modulator of neuroinflammatory responses to endotoxemia, while a meta-analysis in preterm infants finds no increased late-onset sepsis risk with prolonged early antibiotics and hints that short courses may slightly reduce risk.
Research Themes
- Mechanistic mapping of immune dysregulation across systemic inflammation phases
- CNS neuroinflammation modulation in endotoxemia/sepsis
- Antibiotic stewardship and late-onset sepsis risk in preterm infants
Selected Articles
1. Systemic inflammation impairs myelopoiesis and interferon type I responses in humans.
Using a controlled human LPS endotoxemia model, the authors mapped both hyperinflammatory and subsequent immunosuppressive phases. Single-cell RNA sequencing identified an inflammatory CD163+ population, and the study demonstrates that systemic inflammation impairs myelopoiesis and type I interferon responses in humans.
Impact: This work provides mechanistic human data linking systemic inflammation to impaired myelopoiesis and type I IFN signaling, offering biological explanations for vulnerability to secondary infections.
Clinical Implications: Identifying impaired myelopoiesis and type I IFN pathways may enable phase-specific biomarkers and targeted immunomodulation to mitigate post-inflammatory immunosuppression.
Key Findings
- A controlled human LPS-induced systemic inflammation model captured both hyperinflammatory and immunosuppressive phases.
- Single-cell RNA sequencing during the acute phase identified an inflammatory CD163+ population.
- Systemic inflammation impairs myelopoiesis and type I interferon responses in humans.
Methodological Strengths
- Controlled human in vivo endotoxemia model capturing distinct inflammatory phases
- High-resolution single-cell transcriptomics to define immune cell populations
Limitations
- Endotoxemia may not fully recapitulate pathogen-driven clinical sepsis
- Generalizability to diverse patient populations with comorbidities is uncertain
Future Directions: Validate findings in patients with sepsis of infectious etiology, develop biomarkers of phase transition, and test therapies restoring myelopoiesis and type I IFN pathways.
2. FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.
Across mouse, rat, and human iPSC-derived astrocyte systems, FABP7 knockdown attenuated NF-κB activation and reduced astrocyte-mediated neurotoxicity following inflammatory stimuli. In vivo, astrocytic FABP7 knockdown mitigated cortical glial activation and dampened NF-κB–dependent transcription after systemic LPS, positioning FABP7 as a target to modulate neuroinflammation in endotoxemia.
Impact: Identifies FABP7 as a tractable astrocytic target linking lipid handling to NF-κB–mediated neuroinflammation in endotoxemia, with consistent effects across in vitro human cells and in vivo models.
Clinical Implications: Targeting FABP7 could provide a strategy to mitigate sepsis-associated encephalopathy by dampening astrocyte-driven neuroinflammation.
Key Findings
- FABP7 silencing reduced NF-κB reporter activity and p65 nuclear translocation in astrocytes exposed to inflammatory stimuli.
- Astrocytic FABP7 knockdown decreased toxicity toward co-cultured motor neurons; similar effects were seen in human iPSC-derived astrocytes.
- In vivo astrocytic FABP7 knockdown reduced cortical glial activation after systemic LPS and attenuated NF-κB–dependent transcriptional responses.
Methodological Strengths
- Convergent evidence across in vitro rodent, human iPSC-derived cells, and in vivo mouse models
- Transcriptome-wide RNA-seq demonstrating attenuation of NF-κB–dependent programs
Limitations
- Endotoxemia models may not fully capture clinical sepsis complexity
- Translational relevance to human patients and druggability of FABP7 require further validation
Future Directions: Develop and test selective FABP7 inhibitors/modulators in sepsis-associated encephalopathy models and assess safety and efficacy in translational studies.
3. The association of early antibiotic exposure with subsequent development of late-onset sepsis in preterm infants: a systematic review and meta-analysis studies.
Across 10 adjusted studies (N=55,089), prolonged early antibiotic exposure in preterm infants with sterile cultures was not associated with increased late-onset sepsis compared with no exposure. Short courses were associated with a modestly lower LOS risk, supporting stewardship that avoids unnecessary prolonged antibiotics.
Impact: Provides a large, adjusted synthesis that challenges assumptions linking longer early antibiotics to LOS, informing neonatal antibiotic duration policies.
Clinical Implications: Supports limiting duration of empiric antibiotics in preterm infants with sterile cultures and monitoring for LOS, potentially reducing microbiome disruption and resistance.
Key Findings
- Ten studies (N=55,089) with confounder-adjusted analyses were synthesized under PRISMA.
- Prolonged versus short antibiotic exposure showed no significant association with LOS (pooled aOR 1.2; 95% CI 0.99–1.46; I²=67%).
- Prolonged exposure vs no exposure: aOR 0.91 (95% CI 0.82–1.02; I²=0); short exposure vs no exposure: aOR 0.87 (95% CI 0.77–0.98).
Methodological Strengths
- PRISMA-compliant systematic review with meta-analysis of adjusted estimates only
- Large cumulative sample size with prediction intervals and heterogeneity assessment
Limitations
- All included data are observational; residual confounding cannot be excluded
- Substantial heterogeneity in some comparisons and variable antibiotic definitions
Future Directions: Conduct randomized trials optimizing empiric antibiotic duration in preterm infants and integrate microbiome and pharmacodynamic endpoints.