Daily Sepsis Research Analysis
Three standout studies shape current sepsis research: a Nature Microbiology paper uncovers a host AAA-ATPase (VCP/p97) mechanism that mechanically lyses ubiquitinated intracellular bacteria and protects mice from fatal sepsis; a randomized trial analysis shows procalcitonin-guided early cessation of antibiotics preserves the gut microbiome and reduces gut inflammation; and a 17,099-patient ICU cohort identifies a U-shaped association between alactic base excess and mortality, outperforming lacta
Summary
Three standout studies shape current sepsis research: a Nature Microbiology paper uncovers a host AAA-ATPase (VCP/p97) mechanism that mechanically lyses ubiquitinated intracellular bacteria and protects mice from fatal sepsis; a randomized trial analysis shows procalcitonin-guided early cessation of antibiotics preserves the gut microbiome and reduces gut inflammation; and a 17,099-patient ICU cohort identifies a U-shaped association between alactic base excess and mortality, outperforming lactate or base excess alone for prognostication.
Research Themes
- Host-directed immunity and intracellular bacterial clearance
- Antibiotic stewardship and microbiome preservation in sepsis
- Biomarker-based risk stratification and prognostication
Selected Articles
1. Host AAA-ATPase VCP/p97 lyses ubiquitinated intracellular bacteria as an innate antimicrobial defence.
This mechanistic study identifies VCP/p97 as a host AAA-ATPase that mechanically extracts ubiquitinated bacterial surface proteins, leading to membrane lysis and pathogen killing, and demonstrates protection from fatal sepsis in mice. It reveals a distinct, proteostasis-linked innate antimicrobial pathway with translational potential for host-directed therapies.
Impact: It uncovers a previously unrecognized host mechanism for intracellular bacterial clearance that protects against lethal sepsis, opening avenues for host-directed antimicrobials.
Clinical Implications: While preclinical, augmenting p97 activity or mimicking its bacterial protein-extraction mechanism could inspire host-directed adjuvants to combat intracellular pathogens and reduce reliance on antibiotics.
Key Findings
- VCP/p97 binds cytosol-exposed ubiquitinated bacteria (S. pneumoniae, S. Typhimurium, S. pyogenes) and requires D2 ATPase activity to reduce intracellular bacterial loads.
- Optical trapping, MD simulations, and in vitro reconstitution show p97 extracts ubiquitinated surface proteins (BgaA, PspA) from S. pneumoniae, causing membrane lysis.
- In mice, p97 limits S. pneumoniae proliferation and protects from fatal sepsis, revealing a host proteostasis-linked antimicrobial defense.
Methodological Strengths
- Multi-system validation: optical trap biophysics, MD simulations, in vitro reconstitution, immunogold TEM, and in vivo murine sepsis protection
- Cross-pathogen generalizability across Gram-positive and Gram-negative intracellular bacteria
Limitations
- Preclinical study; human translational efficacy and safety remain untested
- Dependence on ubiquitination of bacterial surface proteins may vary by pathogen and host context
Future Directions: Define pharmacologic or genetic strategies to modulate p97 activity in vivo, map ubiquitinated bacterial substrates across pathogens, and evaluate host-directed adjuvants in infection models and early-phase human studies.
2. Procalcitonin-guided early cessation of antibiotics prevents gut inflammation and preserves gut microbiome: Data from the PROGRESS controlled trial.
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.
Impact: It links an evidence-based stewardship strategy to microbiome preservation and reduced gut inflammation, providing a biological rationale for improved outcomes and lower AMR.
Clinical Implications: Supports using PCT to individualize and shorten antibiotic courses in sepsis of common sources, balancing efficacy with microbiome protection and reduced MDR/C. difficile risk.
Key Findings
- PCT-guided early discontinuation reduced MDR/C. difficile infections and was associated with survival benefit in the parent trial.
- Microbiome profiling (16S rRNA Nanopore) showed better preservation of gut community structure with PCT-guided stopping versus standard durations.
- Fecal calprotectin levels indicated reduced intestinal inflammation with PCT-guided early cessation.
Methodological Strengths
- Randomized controlled design with predefined PCT algorithm and trial registration
- Multi-timepoint stool sampling with standardized 16S rRNA Nanopore sequencing and biomarker (calprotectin) assessment
Limitations
- Abstract-provided results are directional without granular effect sizes; full quantitative data not available here
- 16S sequencing limits strain-level resolution; trial not primarily blinded for antibiotic duration
Future Directions: Integrate metagenomics/metabolomics to refine microbial and functional shifts, and test PCT-guided stewardship across diverse settings with patient-centered outcomes and AMR endpoints.
3. Association between alactic base excess on mortality in sepsis patients: a retrospective observational study.
In 17,099 ICU sepsis patients, alactic base excess (ABE) showed a U-shaped association with 30- and 90-day mortality, outperforming lactate and base excess alone. Adding ABE to the SOFA score improved discrimination, and optimal ABE thresholds (≈2.5 and 2.2 mmol/L) were identified.
Impact: It proposes a practical, immediately computable biomarker that refines mortality risk stratification beyond lactate and BE, with direct implications for ICU triage and monitoring.
Clinical Implications: ABE can be calculated from routine lactate and BE to improve early risk stratification and may be integrated with SOFA for better prognostication; extreme ABE values could prompt closer monitoring and targeted resuscitation.
Key Findings
- ABE exhibited a U-shaped association with 30- and 90-day ICU all-cause mortality in 17,099 sepsis patients.
- ABE outperformed base excess and lactate for mortality prediction and improved SOFA-based prognostication (AUC, NRI, IDI).
- Optimal ABE thresholds (≈2.5 mmol/L for 30-day and ≈2.2 mmol/L for 90-day mortality) were identified.
Methodological Strengths
- Very large cohort (n=17,099) with multivariable Cox models and restricted cubic splines
- Rigorous comparative performance analyses versus lactate/BE and integration with SOFA using AUC, NRI, and IDI
Limitations
- Retrospective design with potential residual confounding; calculation depends on early lactate/BE availability and accuracy
- Single-country database may limit generalizability; optimal thresholds require external validation
Future Directions: Prospective multicenter validation of ABE thresholds, assessment of dynamic ABE trajectories, and interventional studies testing ABE-guided resuscitation strategies.