Sepsis - Papers

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.

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.

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.

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.

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 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.

In preclinical models, fluoxetine protects against sepsis lethality by elevating circulating IL-10, independent of peripheral serotonin, thereby preventing sepsis-induced hypertriglyceridemia and cardiac metabolic dysfunction. The study defines an immunometabolic defense mechanism with repurposing potential for a widely used SSRI.

This mechanistic study shows that NINJ1-mediated plasma membrane rupture is a key step linking inflammasome activation to the release of procoagulant TF-positive microvesicles, driving coagulopathy and inflammation. Genetic haploinsufficiency or glycine inhibition of NINJ1 reduced microvesicle and cytokine release and partially protected against flagellin-induced coagulopathy and death.

Building on the PROGRESS RCT, PCT-guided early cessation of antibiotics preserved gut microbiome composition and reduced intestinal inflammation (lower fecal calprotectin) compared with standard durations. These findings mechanistically support the survival and AMR benefits previously observed with PCT-guided stewardship.

In CLP-induced sepsis, ILC2s expand and their IL-4 restores impaired autophagic flux via STAT3-driven LAMP2 upregulation. IL-4 promotes a LAMP2–FLOT2 interaction that enhances autophagosome-lysosome fusion in cardiac endothelial cells, reducing inflammation and improving cardiac function. Loss of FLOT2 abrogates these protective effects.

In sepsis patients, soluble CD72 levels rise while cell-surface CD72 declines. Exogenous sCD72 worsens sepsis survival in mice in a dose-dependent manner by binding CD100 on T cells, entering cells, and impairing T-cell functions (including reduced CD4+ T cells), while enhancing inflammatory responses. The study positions sCD72 as a mechanistic mediator of sepsis-induced adaptive immunosuppression.

This translational study links site-specific fucosylation of haptoglobin to augmented inflammation in sepsis via the C-type lectin receptor Mincle. The authors integrate human plasma glycoproteomics, single-cell RNA-seq, receptor interaction assays, and in vivo mouse validation, positioning fucosylated haptoglobin as a clinically relevant biomarker and potential therapeutic target.

A conserved SDR family (CprA/HlyF orthologs) drives outer membrane vesicle production that blocks autophagy and enhances non-canonical inflammasome activation, increasing Gram-negative virulence. Deletion of cprA reduces virulence in a murine sepsis model, highlighting anti-virulence targets.

Using TLR4 knockout mice plus single-cell RNA-seq, the authors show that TLR4-deficient macrophages upregulate Abca1, increase cholesterol efflux, dampen glycolysis, and adopt M2 polarization, thereby attenuating inflammation and altering interactions with pulmonary endothelial and lymphatic endothelial cells. Endothelial TLR4 both sensitizes cells to LPS and determines susceptibility to macrophage-derived inflammatory signals. These data position TLR4 across macrophages and endothelium as a coordinated driver of sepsis-induced ALI.

Using scRNA-seq and transcriptomics across blood, spleen, lymph nodes, and bone marrow, the authors show pervasive suppression of adaptive immunity in sepsis. They uncover a CD47-driven amyloid-β signal that engages CD74 on B cells to suppress adaptive responses; pharmacologic blockade restores immune function, reduces organ injury, and improves survival in septic mice. Sepsis-related gene signatures also discriminated sepsis from common infections in clinical datasets.

Macrophage mitochondrial complex III-derived superoxide is required for IL-10 secretion after TLR3/4 stimulation. Complex III-deficient mice are more susceptible to endotoxic shock, and PKA activation rescues IL-10 release, implicating an immunometabolic axis central to sepsis tolerance.

Macrophage EVs carrying GBP2 trigger endothelial ferroptosis via direct binding to OTUD5 and promotion of GPX4 ubiquitination, disrupting the vascular barrier in sepsis-induced lung injury. Plantainoside D binds GBP2, disrupts the GBP2–OTUD5 interaction, reduces GPX4 ubiquitination, and mitigates lung injury in preclinical models.

This preclinical study connects macrophage BTK activation to impaired megakaryopoiesis in sepsis-induced thrombocytopenia. Pharmacologic BTK inhibition (BGB-3111) restored megakaryocyte and platelet production in mice via a Rap1/NF-κB–dependent effect on macrophage polarization.