Sepsis - Papers

Aggregating MARS and GAinS datasets, the authors define three robust consensus transcriptomic subtypes (CTS1–3) with distinct inflammatory, hemostatic, and interferon/lymphoid signatures. External validation (VANISH RCT cohort and Ugandan cohort) supports generalizability, and post hoc analyses suggest corticosteroids may be harmful in CTS2, highlighting actionable endotyping for trial design.

This study constructs a mass spectrometry-based atlas linking plasma proteins to their tissue of origin across 18 organs and major blood cell types, integrated with RNA/protein resources. The approach detects organ-enriched protein changes in six patient cohorts, including sepsis, providing a scalable framework for precision diagnostics and pathophysiology.

Across >7,074 samples from 37 cohorts, the authors derive cell-type-specific signatures that quantify myeloid and lymphoid dysregulation, linked to severity and mortality in sepsis and conserved across ARDS, trauma, and burns. Post hoc analyses of RCTs show differential mortality with anakinra and corticosteroids by dysregulation state, proposing a unifying, actionable framework.

A multicenter, cross-age cohort anchored mechanistic study identifies IGFBP6 as a regulator of sepsis outcomes and delineates an IGF-independent IGFBP6–PHB2–STAT1/Akt pathway that suppresses chemotaxis and macrophage bactericidal function. Genetic and pharmacologic interventions restored CCL2 expression, bacterial clearance, and survival in septic mice, nominating IGFBP6 as both biomarker and therapeutic target.

This large human cohort integrates single-cell transcriptomics, immune receptor sequencing, CITE-seq, bulk RNA-seq, and proteomics to show that the anatomical source of infection imprints distinct immune programs in sepsis across adults and children, including an NR4A2-linked signature. The dataset provides a reference map for site-specific immune states and candidate biomarkers.

Inflammation triggers cathepsin K–mediated cleavage of angiopoietin-2 into 25 and 50 kDa fragments that antagonize Tie2, destabilizing endothelium in sepsis. Pharmacologic inhibition of cathepsin K (odanacatib) improved survival in murine sepsis, and circulating ANGPT2 fragments in patients associated with worse outcomes.

In febrile term infants, 63% of extraintestinal infections had an intestinal strain essentially identical to the invasive pathogen (>99.999% ANI), supporting the gut as a reservoir. E. coli cases showed higher gut E. coli abundance, enrichment of phylogroup B2, and virulence loci in isogenic colonized infants.

Time-resolved transcriptomics in microbiologically confirmed neonatal sepsis identified a treatment-responsive host gene signature that reverses within 24 hours of vancomycin initiation and tracks clinical improvement. Adaptive immune pathways changed unexpectedly fast, and signatures were conserved across pediatric and adult cohorts, enabling a prognostic measure and implicating early transient antimicrobial defense activation in neonatal sepsis.

Across three cohorts, a three-biomarker model (procalcitonin, soluble TREM-1, IL-6) accurately quantified immune dysregulation (DIP stages and cDIP) independent of clinical severity. Validation in five external cohorts showed increasing cDIP associated with higher mortality and secondary infections, and CAPE COD reanalysis indicated hydrocortisone benefited only severely dysregulated patients.

A two-stage program derived and validated the BEYOND risk score and then tested precision bezlotoxumab in a double-blind RCT. In high-risk CDI patients, bezlotoxumab plus standard care significantly reduced the composite of organ dysfunction, relapse, or death versus placebo (31.8% vs 72.7%).

This mechanistic study identifies a host-nutrient cue—low blood leucine—that augments NMEC bacteremia and meningitis via an Lrp-dependent repression of sRNA NsrP, derepressing purD and de novo purine biosynthesis. Genetic perturbations validate causality, and intravenous leucine attenuates disease in vivo, suggesting a potential prophylactic/adjunctive strategy.

In a mouse model of acute endotoxemia, physiologic-range systemic LPS rapidly induced 100–10,000-fold blooms of gut-luminal facultative pathogens without overt enteropathy. The effect was TLR4-dependent, mediated by increased luminal reactive oxygen species that transiently halted microbial fermentation and enabled oxidative respiration-driven pathogen expansion.

Using ALI and sepsis models, the study shows epithelial BDNF is reduced, inversely tracks inflammation, and directly antagonizes macrophage TLR4. A BDNF-derived dodecapeptide (BDP-12) preserves TLR4 antagonism and anti-inflammatory activity without pro-proliferative effects, nominating it as a therapeutic lead.

In a cluster-randomized trial across 59 facilities (431,394 births) in Malawi and Uganda, the APT-Sepsis program reduced a composite of infection-related maternal death, near-miss, or severe infection from 1.9% to 1.4% (risk ratio 0.68, P<0.001). Effects were consistent across contexts and sustained, supporting implementation of WHO-aligned practices and the FAST-M bundle.

Two independent sepsis cohorts showed elevated IL-40 at admission correlating with PCT, CRP, lactate/LDH, and SOFA, enabling early-death stratification. Genetic IL-40 inhibition/knockout reduced NETosis and mitigated multi-organ damage in experimental sepsis, indicating IL-40 as both a prognostic biomarker and therapeutic target.

Gut-microbiota-derived indoles activate macrophage AhR to enhance bacterial clearance and survival in murine sepsis, while the pathogen siderophore enterobactin suppresses AhR signaling and worsens outcomes. Tryptophan supplementation restored survival, highlighting a microbiota–host–pathogen tug-of-war over AhR.

Using specific pathogen-free and germ-free mice, targeted metabolomics, and human-derived colonoid monolayers, the study identified branched-chain fatty acids, particularly isovalerate, as microbiota-derived regulators of intestinal barrier integrity. Isovalerate enemas and leucine gavage restored claudin-8 localization and reduced permeability in malnourished male mice, providing a mechanistic link between malnutrition, dysbiosis, gut leak, and sepsis risk.

The study identifies an activin A–driven, TGF-β–independent activation of Smad3 in macrophages as a natural brake on innate inflammation. By promoting mitochondrial ATP production and adenosine generation via CD73, this axis limits inflammatory outputs; macrophage-specific loss of activin A signaling worsened survival in murine sepsis.

This study identifies PITTs as proinflammatory platelet membrane structures that anchor to leukocytes/endothelium, promoting leukocyte activation and vascular inflammation. In mouse infection/endotoxemia models, αIIbβ3 blockade reduced immune-mediated tissue damage; in human sepsis/COVID-19, PITT formation and platelet αIIbβ3 loss correlated with disease severity.

This study reveals that NETs directly program Treg differentiation by anchoring ENO1 (via MPO) on CD4+ T cells and recruiting IFITM2 as a DNA receptor to trigger RAP1B–ERK signaling. ENO1 inhibition reduced NET-driven Treg induction and ameliorated sepsis in mice, defining a targetable pathway for sepsis-induced immunosuppression.

This mechanistic study identifies suburothelial perivascular macrophages as a bladder–blood immune barrier that captures UPEC, maintains vascular integrity, and deploys METosis with MMP-13 to trap bacteria and recruit neutrophils. Monocyte-derived replenishment confers protection against recurrent UTIs, suggesting new strategies to prevent urosepsis.

Single-nucleus RNA-seq and cross-species models reveal that sepsis drives contractile cardiomyocytes into an injury-responsive subtype via ERRγ reduction, trading contractility for cytoprotection. ERRγ agonism after the acute phase reconverts cells to the contractile state, improving cardiac function; findings are validated in human hearts.

Using live-cell imaging, ATAC-seq, and an in vivo sepsis model, the authors show that sequential inflammatory stimuli imprint memory in individual macrophages by reprogramming NF-κB signaling and chromatin accessibility. Deep learning and transcriptomics reveal coordinated transcription factor–chromatin dynamics that fine-tune responses to subsequent signals.

This mechanistic study identifies a cardiomyocyte-enriched lncRNA (Cpat) that preserves mitochondrial TCA cycle flux by inhibiting GCN5-mediated citrate synthase acetylation and stabilizing the MDH2-CS-ACO2 complex. Cpat protects against myocardial injury in sepsis-induced cardiomyopathy, highlighting a metabolic RNA-based therapeutic target.