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.
Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163
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.
Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.
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.
BACKGROUND: Early antibiotic exposure in preterm infants may disrupt gut microbiome development, affecting health. However, its link to late-onset sepsis (LOS) remains unclear. This meta-analysis aims to clarify the association while addressing confounding bias. METHODS: This systematic review and meta-analysis, conducted per PRISMA guidelines, utilized PubMed, Scopus, Google Scholar, and Web of Science for comprehensive literature retrieval. Studies comparing preterm infants with sterile blood cultures who received early antibiotics (short or prolonged) to those without, using LOS as the primary outcome, were included. Comparisons between short- and prolonged-course antibiotics were also considered. Only studies with adjusted analyses for confounders were considered. Adjusted odds ratios (aOR) were meta-analyzed, and the prediction interval (PI) was calculated using R software. RESULTS: Ten studies met the eligibility criteria, comprising a total sample size of 55,089 preterm infants. Among these, nine studies included 33,549 preterm infants and compared prolonged antibiotic exposure to short exposure. Prolonged exposure was not significantly associated with LOS (pooled aOR = 1.2, 95% CI 0.99-1.46, P = 0.066, PI = 0.66 to 2.19, I² = 67%). Limiting the analysis to five studies with sample sizes over 1,000 reduced heterogeneity (I² = 30%) and provided a more precise confidence interval (pooled aOR = 1.03, 95% CI 0.91-1.15). Four studies, involving 41,938 preterm infants, examined preterm infants exposed to prolonged antibiotics versus those not exposed and found no significant association (aOR = 0.91, 95% CI 0.82-1.02, P = 0.1, PI = 0.72 to 1.16, I² = 0). All four studies had sample sizes exceeding 1,000. Additionally, these studies compared preterm infants with short antibiotic exposure to non-exposure, revealing a slightly lower risk of LOS (aOR = 0.87, 95% CI 0.77-0.98, P = 0.024, I² = 0) and a PI of 0.76 to 1.14. CONCLUSIONS: Our findings indicate that prolonged early antibiotic exposure in preterm infants with sterile cultures does not significantly increase the risk of LOS compared to no antibiotic exposure. Interestingly, a shorter duration of antibiotic exposure might be associated with a slightly lower risk of LOS.