Weekly Sepsis Research Analysis
This week’s sepsis literature highlights three converging advances: a proteome atlas that maps plasma proteins to organ origin enabling organ-specific sepsis phenotyping; discovery of a host AAA-ATPase (VCP/p97) mechanism that mechanically lyses ubiquitinated intracellular bacteria and protects against fatal sepsis in mice; and randomized-trial–linked data showing procalcitonin-guided early antibiotic cessation preserves the gut microbiome and reduces intestinal inflammation. Together these stud
Summary
This week’s sepsis literature highlights three converging advances: a proteome atlas that maps plasma proteins to organ origin enabling organ-specific sepsis phenotyping; discovery of a host AAA-ATPase (VCP/p97) mechanism that mechanically lyses ubiquitinated intracellular bacteria and protects against fatal sepsis in mice; and randomized-trial–linked data showing procalcitonin-guided early antibiotic cessation preserves the gut microbiome and reduces intestinal inflammation. Together these studies accelerate precision diagnostics, nominate host-directed and genomic targets for therapeutics, and reinforce stewardship strategies that improve outcomes and reduce antimicrobial resistance.
Selected Articles
1. Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
The authors build a mass-spectrometry–based atlas linking plasma proteins to their tissue and cell origins across 18 vascularized organs and major blood cell types, and validate disease- and organ-enriched plasma protein panels in six clinical cohorts including sepsis. This resource enables inference of organ-specific plasma signatures and creates a scalable framework for precision diagnostics and monitoring of organ injury in sepsis.
Impact: Provides a foundational, validated resource to trace organ-origin signals in plasma, directly enabling organ-specific sepsis phenotyping and quicker identification of the primary injured compartment — a key step toward targeted interventions.
Clinical Implications: Allows development of organ-specific plasma panels (liver, kidney, endothelium, lung) to refine diagnosis, monitor response, and select organ-directed therapies in sepsis trials and clinical care.
Key Findings
- Constructed a mass-spectrometry human proteome atlas across 18 organs and 8 major blood cell types to infer tissue origin of plasma proteins.
- Demonstrated reproducible, disease-specific changes in organ-enriched plasma protein panels across six patient cohorts including sepsis.
2. Host AAA-ATPase VCP/p97 lyses ubiquitinated intracellular bacteria as an innate antimicrobial defence.
This mechanistic study shows that host AAA-ATPase VCP/p97 binds cytosol-exposed ubiquitinated bacteria and, via D2 ATPase activity, mechanically extracts ubiquitinated surface proteins leading to membrane lysis and killing. In vivo, p97 limits S. pneumoniae proliferation and protects mice from fatal sepsis, revealing a proteostasis-linked innate defense that could be harnessed for host-directed therapeutics.
Impact: Identifies a previously unrecognized, generalizable host antimicrobial mechanism with in vivo protection from lethal sepsis, opening a translational path to host-directed adjuvants that reduce reliance on antibiotics.
Clinical Implications: Suggests therapeutic strategies to augment or mimic p97-mediated extraction (small molecules, biologics) as adjuncts in infections with intracellular bacteria; requires safety and translational studies.
Key Findings
- VCP/p97 binds diverse cytosol-exposed ubiquitinated bacteria and requires D2 ATPase activity to reduce intracellular bacterial loads.
- Biophysical and imaging assays show p97 extracts ubiquitinated surface proteins (e.g., BgaA, PspA) from membranes, causing membrane lysis; p97 protects mice from fatal S. pneumoniae sepsis.
3. Procalcitonin-guided early cessation of antibiotics prevents gut inflammation and preserves gut microbiome: Data from the PROGRESS controlled trial.
Analysis of the PROGRESS randomized trial shows that PCT-guided early discontinuation of antibiotics in sepsis patients preserves gut microbiome composition and reduces intestinal inflammation (lower fecal calprotectin) compared with standard durations. These mechanistic microbiome data support previously observed reductions in MDR/C. difficile infections and survival benefits linked to PCT-guided stewardship.
Impact: Provides mechanistic microbiome and biomarker evidence linking an actionable stewardship intervention (PCT-guided stopping) to reduced intestinal inflammation and downstream benefits including lower MDR/C. difficile infections and survival gains.
Clinical Implications: Supports implementation of PCT-guided antibiotic duration algorithms in sepsis to shorten courses safely, protect the gut microbiome, and reduce AMR/C. difficile risk — informing stewardship policies and guideline updates.
Key Findings
- PCT-guided early discontinuation preserved gut microbiome composition compared with standard antibiotic durations.
- Fecal calprotectin was lower with PCT-guided stopping, indicating reduced intestinal inflammation; this mechanistically supports prior trial signals of reduced MDR/C. difficile infections and survival benefit.