Weekly Sepsis Research Analysis
This week highlighted mechanistic and translational advances that reshape how we think about inflammatory propagation, immune–hematopoietic interactions, and stewardship in sepsis. A Cell paper uncovered extracellular-vesicle–mediated transplantation of gasdermin pores that propagates pyroptosis, a potentially paradigm-shifting mechanism. Preclinical work nominated macrophage BTK→Rap1→NF-κB signaling as a treatable driver of sepsis-induced thrombocytopenia, and a large systematic review supports
Summary
This week highlighted mechanistic and translational advances that reshape how we think about inflammatory propagation, immune–hematopoietic interactions, and stewardship in sepsis. A Cell paper uncovered extracellular-vesicle–mediated transplantation of gasdermin pores that propagates pyroptosis, a potentially paradigm-shifting mechanism. Preclinical work nominated macrophage BTK→Rap1→NF-κB signaling as a treatable driver of sepsis-induced thrombocytopenia, and a large systematic review supports omitting routine antibiotic prophylaxis for transperineal prostate biopsy without increasing sepsis risk, with direct stewardship implications.
Selected Articles
1. Transplantation of gasdermin pores by extracellular vesicles propagates pyroptosis to bystander cells.
Preclinical in vitro and in vivo work demonstrates that pyroptotic cells release extracellular vesicles bearing GSDMD pores that insert into bystander cell membranes, inducing lytic death and amplifying inflammation. Super-resolution DNA-PAINT and immuno-EM structurally visualize pores on EVs and functional experiments show intercellular propagation of pyroptosis.
Impact: Uncovers a previously unrecognized, structurally validated mechanism for propagation of inflammatory cell death via EVs carrying gasdermin pores — a conceptual shift with potential to change how tissue injury in sepsis is targeted.
Clinical Implications: Identifies intervention points (EV biogenesis/cargo loading, GSDMD pore assembly) that could be targeted to prevent bystander tissue damage in sepsis; motivates development of EV-based biomarkers for ongoing inflammatory propagation.
Key Findings
- Extracellular vesicles released by pyroptotic cells carry GSDMD pore structures visualized by DNA-PAINT and immuno-EM.
- Pyroptotic EVs can transplant GSDMD pores onto bystander cell plasma membranes, inducing lytic death.
- Intercellular propagation of pyroptosis via EVs demonstrated both in vitro and in vivo, revealing a domino-like spread mechanism.
2. Impaired megakaryopoiesis due to aberrant macrophage polarization via BTK/Rap1/NF-κB pathway in sepsis-induced thrombocytopenia.
Preclinical and translational work links macrophage pro-inflammatory polarization with elevated p-BTK to impaired megakaryopoiesis in sepsis-induced thrombocytopenia. BTK inhibition (BGB-3111) restored megakaryocyte and platelet production in mice; single-cell RNA-seq implicated Rap1 signaling mediating macrophage–megakaryocyte interactions.
Impact: Nominates a druggable immune–hematopoietic axis (macrophage BTK→Rap1→NF-κB) with coherent mechanistic evidence and pharmacologic rescue, enabling near-term translational testing using existing BTK inhibitors.
Clinical Implications: Supports early-phase trials of BTK inhibition in patients with severe sepsis-associated thrombocytopenia and suggests biomarker-guided selection (macrophage p-BTK signature); safety monitoring will be essential given immunomodulatory risks.
Key Findings
- SIT patients and septic mice showed increased pro-inflammatory macrophages and macrophage p-BTK correlating with lower platelet counts.
- BTK inhibitor BGB-3111 increased megakaryocyte and platelet production in SIT mice.
- Macrophage depletion and coculture studies confirmed macrophages mediate the platelet recovery after BTK inhibition; scRNA-seq implicated Rap1 signaling.
3. Infectious complications following transperineal prostate biopsy with or without periprocedural antibiotic prophylaxis-a systematic review including meta-analysis of all comparative studies.
Systematic review and meta-analysis of 23 comparative studies (~12,324 procedures) found no significant reduction in genitourinary infection, fever, sepsis (0.16% vs 0.13%), or readmission with periprocedural antibiotic prophylaxis for transperineal prostate biopsy. Results support de-implementation of routine prophylaxis in most patients.
Impact: Directly informs clinical practice and stewardship by showing negligible sepsis reduction from prophylaxis in TPB, enabling guideline and institutional practice changes to reduce unnecessary antibiotic use.
Clinical Implications: Supports omitting routine antibiotic prophylaxis for transperineal prostate biopsy in most settings, aligning with antimicrobial stewardship; high-risk patients should be identified separately and managed per local epidemiology.
Key Findings
- Pooled analysis of 23 comparative studies (6520 with PAP; 5804 without) showed no significant differences in GUI, fever, sepsis, or readmission (sepsis 0.16% vs 0.13%).
- Subgroup and sensitivity analyses were consistent; overall event rates were very low.
- Findings support safe de-implementation of routine prophylaxis for TPB in most patients.