Daily Sepsis Research Analysis
Today’s top sepsis papers span mechanistic immunometabolism, macrophage pyroptosis regulation, and large-scale AI prediction. A murine study identifies a GFAT–DRP1–calcium axis by which glutamine restores macrophage phagocytosis and survival, while another elucidates TGFBI as a suppressor of macrophage pyroptosis in septic shock. A multicenter JAMA Pediatrics study develops high-performing EHR-based models that predict pediatric sepsis within 48 hours.
Summary
Today’s top sepsis papers span mechanistic immunometabolism, macrophage pyroptosis regulation, and large-scale AI prediction. A murine study identifies a GFAT–DRP1–calcium axis by which glutamine restores macrophage phagocytosis and survival, while another elucidates TGFBI as a suppressor of macrophage pyroptosis in septic shock. A multicenter JAMA Pediatrics study develops high-performing EHR-based models that predict pediatric sepsis within 48 hours.
Research Themes
- Immunometabolism and macrophage function in sepsis
- Macrophage pyroptosis and epigenetic regulation in septic shock
- AI-driven early prediction of pediatric sepsis from EHR data
Selected Articles
1. Glutamine alleviates immunosuppression in polymicrobial sepsis by augmenting bacterial phagocytosis through sustaining the GFAT-DRP1 dependent mitochondrial calcium dynamics.
In murine polymicrobial sepsis, glutamine supplementation restored macrophage phagocytosis, reduced bacterial burden, modulated cytokines, and improved survival, effects lost with macrophage depletion. Mechanistically, glutamine activated a dual GFAT–DRP1 program—O-GlcNAcylation-driven DRP1 oligomerization and CDK1-dependent DRP1 Ser616 phosphorylation—to enhance mitochondrial fission, mitochondrial Ca2+ efflux, and sustain cytosolic Ca2+ essential for phagocytosis.
Impact: Identifies a previously unrecognized GFAT–DRP1–calcium axis linking immunometabolism to macrophage phagocytosis in sepsis, with in vivo survival benefit. It reframes glutamine as an immunorestorative adjunct with a defined mechanism.
Clinical Implications: Suggests testing glutamine or GFAT/DRP1-targeted strategies to reverse sepsis-associated immunosuppression, with careful attention to timing, dosing, and patient selection, given prior mixed clinical results for glutamine in critical illness.
Key Findings
- Glutamine deficiency impaired macrophage phagocytosis and worsened sepsis-induced immunosuppression; supplementation restored function and improved survival in septic mice.
- Dual mechanism: GFAT-dependent O-GlcNAcylation promoted DRP1 oligomerization, and GFAT–CDK1 signaling induced DRP1 Ser616 phosphorylation independent of O-GlcNAc.
- Enhanced DRP1-mediated mitochondrial fission increased mitochondrial Ca2+ efflux and sustained cytosolic Ca2+ required for phagocytosis; benefits abrogated by macrophage depletion.
Methodological Strengths
- Integrated in vivo polymicrobial sepsis model with survival, bacterial burden, and cytokine outcomes
- Mechanistic dissection using molecular/pharmacologic perturbations of GFAT, DRP1, O-GlcNAcylation, and CDK1 signaling
Limitations
- Preclinical murine and in vitro data limit direct clinical generalizability
- Prior clinical trials of glutamine in critical illness have yielded mixed or negative results, necessitating cautious translational steps
Future Directions: Prospective trials to evaluate glutamine timing/dose in immunosuppressed sepsis phenotypes; development of small-molecule modulators of the GFAT–DRP1–calcium axis with pharmacodynamic biomarkers (e.g., O-GlcNAcylation, DRP1 phosphorylation).
2. Derivation and Validation of Predictive Models for Early Pediatric Sepsis.
Across 2.3 million ED visits, gradient boosting and logistic regression models trained on the first 4 hours of EHR data predicted pediatric sepsis within 48 hours with AUROC up to 0.94. Positive likelihood ratios ranged 4–6 for sepsis and 4–6 for shock, with performance generally consistent across demographics.
Impact: Sets a new benchmark for multicenter, temporally validated EHR-based prediction of pediatric sepsis, offering deployable performance and fairness assessment to inform clinical decision support.
Clinical Implications: Supports prospective implementation trials of EHR-embedded sepsis early warning in pediatric EDs with human factors optimization, calibration to local incidence, and continuous post-deployment monitoring for safety and equity.
Key Findings
- Gradient boosting achieved AUROC 0.94 (95% CI, 0.93–0.94) to predict sepsis within 48 hours; logistic regression AUROC 0.92.
- Positive likelihood ratios were 4.67–6.18 for sepsis and 4.16–5.83 for septic shock; shock models had AUROC ≥0.92.
- Key predictors included emergency severity index, age-adjusted vital signs, and medical complexity; fairness similar across demographics except better AUROC for Medicaid vs commercial payers.
Methodological Strengths
- Very large, multicenter dataset with temporal external validation
- Adherence to TRIPOD-AI, comparison of algorithms, and fairness assessment
Limitations
- Retrospective EHR-based derivation; no prospective impact evaluation of clinical outcomes
- Definition relies on PSC and EHR accuracy; generalizability beyond participating systems remains to be tested
Future Directions: Prospective, stepped-wedge trials to test outcome impact; local calibration and drift monitoring; integration with clinician workflow, rapid feedback loops, and harm-mitigation triggers.
3. TGFBI Inhibits the Pyroptosis of Macrophages to Ameliorate Septic Shock.
TGFBI is downregulated in septic shock. Its overexpression suppresses non-canonical inflammasome-mediated macrophage pyroptosis, limits M1 polarization, and mitigates organ failure in CLP models. Epigenetic repression via SUV39H2 and co-activation by STAT1 reduce TGFBI; inhibiting this axis upregulates TGFBI and confers protection.
Impact: Reveals TGFBI as an immune checkpoint that restrains macrophage pyroptosis and polarization in septic shock, highlighting druggable epigenetic regulators (SUV39H2/STAT1) as targets.
Clinical Implications: Points to therapeutic strategies that boost TGFBI or inhibit SUV39H2/STAT1 to curb macrophage pyroptosis in septic shock; requires biomarker-driven stratification and careful safety evaluation.
Key Findings
- TGFBI expression is downregulated in septic shock patients/models; overexpression suppresses non-canonical inflammasome-mediated macrophage pyroptosis and reduces organ failure.
- TGFBI inhibits M1 macrophage polarization and enhances bacterial killing capacity.
- SUV39H2-mediated histone methylation and STAT1 co-activation repress TGFBI; inhibiting SUV39H2/STAT1 upregulates TGFBI and confers protection in vivo.
Methodological Strengths
- In vivo CLP septic shock model combined with comprehensive cellular assays for pyroptosis and polarization
- Mechanistic epigenetic mapping (ChIP, histone methylation) and pathway perturbation (SUV39H2/STAT1 inhibition, genetic deficiency)
Limitations
- Preclinical murine and cellular data without human interventional validation
- Potential off-target effects and safety concerns with epigenetic modulators require thorough evaluation
Future Directions: Develop TGFBI agonists or SUV39H2/STAT1 inhibitors with selective myeloid targeting; validate TGFBI as a biomarker for pyroptosis-active sepsis endotypes in clinical cohorts.