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.
BACKGROUND: Septic cardiomyopathy is a frequent complication in patients with sepsis and is associated with a high mortality rate. Given its clinical significance, understanding the precise underlying mechanism is of great value. METHODS AND RESULTS: Our results unveiled that Z-DNA binding protein 1 (ZBP1) is upregulated in myocardial tissues of lipopolysaccharide (LPS)-treated mice. Single-cell mRNA sequencing (scRNA-seq) and single-nucleus mRNA sequencing (snRNA-seq) indicated that Zbp1 mRNA in endothelial cells, fibroblasts and macrophages appeared to be elevated by LPS, which is partially consistent with the results of immunofluorescence. Through echocardiography, we identified that global deletion of ZBP1 improves cardiac dysfunction and the survival rate of LPS-treated mice. Mechanistically, snRNA-seq showed that ZBP1 is mainly expressed in macrophages and deletion of ZBP1 promotes the macrophage polarisation towards M2-subtype, which reduces inflammatory cell infiltration. Notably, myeloid-specific deficiency of ZBP1 also promotes M2 macrophage polarisation and improves cardiac dysfunction, validating the role of macrophage-derived ZBP1 in septic myocardial dysfunction. Finally, we revealed that LPS increases the transcription and expression of ZBP1 through signal transducer and activator of transcription 1 (STAT1). Fludarabine, the inhibitor of STAT1, could also promote M2 macrophage polarisation and improve cardiac dysfunction of LPS-treated mice. CONCLUSIONS: Our study provides evidence of a novel STAT1-ZBP1 axis in macrophage promoting septic cardiomyopathy, and underscores the potential of macrophage-derived ZBP1 as a therapeutic target for septic cardiomyopathy. KEY POINTS: Macrophage-derivedZBP1 exacerbates LPS-induced myocardial dysfunction and inflammatory cellinfiltration. Deletionof ZBP1 promotes macrophage polarisation from M1 to M2. STAT1-ZBP1axis promotes septic cardiomyopathy. ZBP1has emerged as a potential therapeutic target for inflammationand septic cardiomyopathy.
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.
INTRODUCTION: The National Health Service (NHS) 'move to digital' incorporating electronic patient record systems (EPR) facilitates the translation of paper-based screening tools into digital systems, including digital sepsis alerts. We evaluated the impact of sepsis screening tools on in-patient 30-day mortality across four multi-hospital NHS Trusts, each using a different algorithm for early detection of sepsis. METHODS: Using quasi-experimental methods, we investigated the impact of the screening tools. Individual-level EPR data for 718 000 patients between 2010 and 2020 were extracted to assess the impact on a target cohort and control cohort using interrupted time series analysis, based on a binomial regression model. We included one Trust which uses a paper-based screening tool to compare the impact of digital and paper-based interventions, and one Trust which did not introduce a sepsis screening tool, but did introduce an EPR. RESULTS: All Trusts had lower odds of mortality, between 5% and 12%, after the introduction of the sepsis screening tool, before adjustment for pre-existing trends or patient casemix. After adjustment for existing trends, there was a significant reduction in mortality in two of the three Trusts which introduced sepsis screening tools. We also observed age-specific effects across Trusts. CONCLUSION: Our findings confirm that patients with similar profiles have a lower mortality risk, consistent with our previous work. This study, conducted across multiple NHS Trusts, suggests that alerts could be tailored to specific patient groups based on age-related effects. Different Trusts may require unique indicators, thresholds, actions and treatments. Including additional EPR information could further enhance personalised care.
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.
BACKGROUND: Immunosuppression is closely related to the pathogenesis of sepsis, but the underlying mechanisms have not yet been fully elucidated. In this study, we aimed to examine the role of the Sterile Alpha Motif, Src Homology 3 domain and nuclear localization signal 1 (SAMSN1) in sepsis and elucidate its potential molecular mechanism in sepsis induced immunosuppression. METHODS: RNA sequencing databases were used to validate SAMSN1 expression in sepsis. The impact of SAMSN1 on sepsis was verified using gene knockout mice. Flow cytometry was employed to delineate how SAMSN1 affects immunity in sepsis, focusing on immune cell types and T cell functions. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated gene editing in RAW264.7 macrophages enabled interrogation of SAMSN1 's regulatory effects on essential macrophage functions, including cell proliferation and phagocytic capacity. The mechanism of SAMSN1 in the interaction between macrophages and T cells was investigated using the RAW264.7 cell line and primary cell lines. RESULTS: SAMSN1 expression was significantly increased in patients with sepsis and was positively correlated with sepsis mortality. Genetic deletion of Samsn1 in murine sepsis model improved T cell survival, elevated T cell cytolytic activity, and activated T cell signaling transduction. Concurrently, Samsn1 knockout augmented macrophage proliferation capacity and phagocytic efficiency. In macrophage, SAMSN1 binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), causing nuclear factor erythroid 2-related factor 2 (NRF2) to dissociate from the KEAP1-NRF2 complex and translocate into the nucleus. This promotes the transcription of the coinhibitory molecules CD48/CD86/carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), which bind to their corresponding receptors natural killer cell receptor 2B4/CD152/T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on the surface of T cells, inducing T-cell exhaustion. CONCLUSIONS: SAMSN1 deletion augmented adaptive T cell immunity and macrophage phagocytic-proliferative dual function. Furthermore, it mediates the KEAP1-NRF2 axis, which affects the expression of coinhibitory molecules on macrophages, leading to T-cell exhaustion. This novel immunosuppression mechanism potentially provides a candidate molecular target for sepsis immunotherapy.