Daily Sepsis Research Analysis
Across diverse study designs, three papers stood out: a multi-site natural experiment showed digital sepsis screening tools were associated with lower 30-day mortality and age-specific effects; a mechanistic study identified a STAT1–ZBP1 axis in macrophages driving septic cardiomyopathy and demonstrated functional rescue by genetic and pharmacologic modulation; and a second mechanistic study uncovered SAMSN1-mediated immunosuppression via KEAP1–NRF2–dependent coinhibitory signaling that induces
Summary
Across diverse study designs, three papers stood out: a multi-site natural experiment showed digital sepsis screening tools were associated with lower 30-day mortality and age-specific effects; a mechanistic study identified a STAT1–ZBP1 axis in macrophages driving septic cardiomyopathy and demonstrated functional rescue by genetic and pharmacologic modulation; and a second mechanistic study uncovered SAMSN1-mediated immunosuppression via KEAP1–NRF2–dependent coinhibitory signaling that induces T-cell exhaustion. Together, they advance implementation and mechanistic pathways with therapeutic potential.
Research Themes
- Digital sepsis screening and implementation science
- Immune dysregulation and immunosuppression mechanisms in sepsis
- Pathogenesis and therapeutic targets in septic cardiomyopathy
Selected Articles
1. Myeloid deficiency of Z-DNA binding protein 1 restricts septic cardiomyopathy via promoting macrophage polarisation towards the M2-subtype.
Using multi-omic profiling and genetic models, the authors identify a STAT1–ZBP1 axis in macrophages that drives LPS-induced septic cardiomyopathy. Global and myeloid-specific ZBP1 deletion, as well as pharmacologic STAT1 inhibition, promote M2 polarization, reduce inflammatory infiltration, and improve cardiac function and survival.
Impact: Reveals a previously unrecognized macrophage pathway that is both mechanistically compelling and druggable, with functional rescue by an approved STAT1 inhibitor. Provides a clear translational path for targeting septic cardiomyopathy.
Clinical Implications: While preclinical, the data support testing STAT1–ZBP1 pathway modulation (e.g., STAT1 inhibitors or ZBP1-targeted strategies) to prevent or treat septic cardiomyopathy, potentially alongside macrophage-polarizing therapies.
Key Findings
- ZBP1 expression is upregulated in myocardial tissues of LPS-treated mice and predominantly in macrophages by sc/snRNA-seq.
- Global and myeloid-specific ZBP1 deletion promote M2 macrophage polarization, reduce inflammatory infiltration, and improve cardiac function and survival.
- LPS induces ZBP1 via STAT1; pharmacologic STAT1 inhibition (fludarabine) recapitulates M2 polarization and functional improvement.
Methodological Strengths
- Integrated single-cell and single-nucleus transcriptomics with genetic loss-of-function models
- Functional readouts including echocardiography, inflammatory infiltration, and survival, plus pharmacologic validation
Limitations
- Use of LPS model may not fully recapitulate polymicrobial sepsis (e.g., CLP) pathobiology
- Human validation is limited to expression-level associations; no clinical interventional data
Future Directions: Validate in polymicrobial sepsis models (CLP), develop specific ZBP1 modulators, and assess pathway biomarkers and responses in human septic cardiomyopathy cohorts.
2. Digital innovation in healthcare: quantifying the impact of digital sepsis screening tools on patient outcomes-a multi-site natural experiment.
In 718,000 admissions across four NHS Trusts, digital sepsis screening tools were associated with a 5–12% reduction in mortality odds, with significant reductions after trend adjustment in two of three Trusts. Age-specific effects suggest that algorithms and thresholds should be tailored, and leveraging richer EPR data may enhance personalized sepsis care.
Impact: Provides large-scale, quasi-experimental evidence that digital sepsis alerts can reduce mortality, informing system-level adoption and optimization strategies across hospitals.
Clinical Implications: Hospitals should consider deploying and refining digital sepsis alerts with attention to age-specific performance, local thresholds, and integration of additional EPR signals to maximize benefit.
Key Findings
- Across 718,000 patients, introduction of sepsis screening tools was associated with 5–12% lower odds of 30-day mortality before adjustment.
- After adjusting for pre-existing trends and casemix, two of three Trusts with digital tools showed significant mortality reductions.
- Age-specific effects indicate alerts may need tailoring by patient groups; additional EPR data could enhance personalization.
Methodological Strengths
- Multi-site, quasi-experimental interrupted time series with control cohorts
- Very large sample size with adjustment for trends and case mix
Limitations
- Heterogeneity of algorithms and implementation across Trusts limits direct comparability
- Residual confounding and secular changes cannot be fully excluded in non-randomized designs
Future Directions: Prospective evaluation (e.g., stepped-wedge trials) of tailored alert thresholds and actions, incorporating additional EPR features to improve precision and equity.
3. SAMSN1 causes sepsis immunosuppression by inducing macrophages to express coinhibitory molecules that cause T-cell exhaustion via KEAP1-NRF2 signaling.
SAMSN1 is upregulated in sepsis and correlates with mortality. Genetic deletion enhances T-cell survival and function and boosts macrophage proliferation and phagocytosis; mechanistically, SAMSN1 engages KEAP1–NRF2 to induce macrophage coinhibitory molecules (CD48/CD86/CEACAM1), which drive T-cell exhaustion via 2B4/CTLA-4/TIM3 interactions.
Impact: Defines a new immunosuppressive pathway linking SAMSN1–KEAP1–NRF2 to macrophage coinhibitory programming and T-cell exhaustion, directly addressing a central barrier to sepsis recovery.
Clinical Implications: Targeting SAMSN1 or downstream coinhibitory signaling on macrophages could reverse T-cell exhaustion and restore host defense in sepsis, informing immunotherapeutic strategies and biomarker development.
Key Findings
- SAMSN1 expression is increased in sepsis patients and positively correlates with mortality.
- Samsn1 knockout in mice improves T-cell survival/function and enhances macrophage proliferation and phagocytosis.
- Mechanism: SAMSN1 binds KEAP1, liberating NRF2 to induce macrophage coinhibitory molecules (CD48/CD86/CEACAM1) that engage 2B4/CTLA-4/TIM3 on T cells to induce exhaustion.
Methodological Strengths
- Human RNA-seq validation with mortality correlation plus in vivo knockout models
- CRISPR-based perturbations and mechanistic dissection of KEAP1–NRF2 signaling in macrophage–T cell crosstalk
Limitations
- Reliance on RAW264.7 cell line may limit generalizability; primary human macrophage validation needed
- No therapeutic intervention study targeting SAMSN1 in vivo beyond genetic deletion
Future Directions: Develop pharmacologic inhibitors or degraders of SAMSN1 or interrupt macrophage coinhibitory axes; validate in primary human immune cells and ex vivo sepsis models.