Daily Sepsis Research Analysis
Today’s top sepsis papers advance host-directed and vascular-targeted therapeutics and clarify mechanisms of viral reactivation in critical illness. Two rigorous preclinical studies identify RSK2–YAP–cGAS–IFN-β and endothelial STAT2 as actionable nodes to reverse immunosuppression and stabilize the vasculature, while a human nested case-control analysis links rising inhibitory immune checkpoints to impending CMV reactivation in ICU sepsis.
Summary
Today’s top sepsis papers advance host-directed and vascular-targeted therapeutics and clarify mechanisms of viral reactivation in critical illness. Two rigorous preclinical studies identify RSK2–YAP–cGAS–IFN-β and endothelial STAT2 as actionable nodes to reverse immunosuppression and stabilize the vasculature, while a human nested case-control analysis links rising inhibitory immune checkpoints to impending CMV reactivation in ICU sepsis.
Research Themes
- Host-directed sepsis therapeutics to reverse immunosuppression
- Endothelial signaling and vascular barrier stabilization in septic shock
- Immune checkpoint dynamics preceding CMV reactivation in sepsis
Selected Articles
1. Icariin rescues immune dysfunction in sepsis through RSK2-driven YAP-cGAS-IFN-β signaling activation.
In CLP mice challenged with secondary Pseudomonas aeruginosa, icariin improved survival, reduced organ injury and bacterial load, and increased M1/M2 ratio. Mechanistically, icariin binds RSK2 to promote YAP phosphorylation/degradation, relieving YAP’s inhibition of cGAS and thereby augmenting IFN-β via TBK1–IRF3 and activating STAT1/2, which enhanced macrophage phagocytosis and bactericidal function in endotoxin-tolerant BMDMs.
Impact: Identifies a druggable host pathway (RSK2–YAP–cGAS–IFN-β) to reverse sepsis-induced immunosuppression and prevent secondary infections, demonstrating survival benefit in vivo.
Clinical Implications: Suggests icariin or analogs as host-directed adjuvants to restore innate antiviral/antibacterial responses in the immunosuppressive phase of sepsis, warranting dose-finding and safety trials.
Key Findings
- Icariin improved survival and reduced organ injury and bacterial burden in CLP mice with secondary P. aeruginosa challenge.
- Icariin enhanced macrophage phagocytosis and killing in endotoxin-tolerant BMDMs and increased the M1/M2 ratio in vivo.
- Mechanistic mapping showed icariin binds RSK2, promotes YAP phosphorylation/degradation, disinhibits cGAS, and upregulates IFN-β via TBK1–IRF3, activating STAT1/2.
- Pharmacologic perturbation (EX527 SIRT1 inhibitor and erastin) reversed icariin’s protective and anti-ferroptotic effects in cells, supporting pathway specificity.
Methodological Strengths
- Clinically relevant secondary infection model combined with endotoxin-tolerant macrophage assays
- Multi-level mechanistic validation (binding/co-IP, pathway perturbation, dose–response) linking target engagement to functional immunity and survival
Limitations
- Preclinical study without human validation; sample size per arm not reported
- Pharmacokinetics, safety, and optimal timing/dosing in sepsis remain undefined
Future Directions: Translate to early-phase clinical trials assessing safety, pharmacokinetics, and immune restoration biomarkers in post-sepsis immunosuppression; evaluate synergy with antibiotics and antivirals.
2. Diacerein attenuates sepsis shock mortality through combined suppression of vascular inflammation, stiffness, and permeability.
In CLP septic mice, diacerein improved 72-hour survival, stabilized hemodynamics, reduced organ injury markers and systemic cytokines, and limited vascular leakage. Transcriptomics showed suppression of inflammatory/CXC chemokine pathways in mesenteric microvessels and inhibition of collagen synthesis genes in aorta with improved vascular tension. Mechanistically, diacerein selectively inhibited endothelial STAT2 (including Tyr690 phosphorylation), and endothelial STAT2 knockdown phenocopied its benefits.
Impact: Reveals endothelial STAT2 as a previously unrecognized, druggable node in septic shock and demonstrates multi-pronged vascular protection with a repurposable agent.
Clinical Implications: Supports clinical testing of diacerein as an adjunct to standard care to reduce vascular leakage and inflammation in septic shock, with biomarker-guided strategies focusing on STAT2 signaling.
Key Findings
- Diacerein improved 72-hour survival, attenuated hypotension, and reduced lactate, ALT/AST, creatinine, and BUN in CLP septic mice.
- Bulk RNA-seq revealed suppression of inflammatory/CXC chemokine pathways in mesenteric vessels and inhibition of collagen synthesis programs in aorta with improved vascular tension.
- Diacerein selectively inhibited endothelial STAT2 expression and Tyr690 phosphorylation in vasculature but not in spleen.
- Endothelial cell-specific STAT2 knockdown reduced vascular leakage and improved survival; combining it with diacerein conferred no additional survival benefit.
Methodological Strengths
- Integrated vascular transcriptomics across distinct beds with functional assays (permeability, tension) and survival readouts
- Causal interrogation of pathway via endothelial STAT2 knockdown and pharmacologic intervention
Limitations
- Preclinical mouse study; human validation and dosing/safety data in septic shock are lacking
- Observation window limited to 72 hours; long-term outcomes and organ-specific effects need assessment
Future Directions: Pilot clinical trials to assess diacerein’s safety, pharmacokinetics, and vascular leakage biomarkers in septic shock; explore patient stratification by endothelial STAT2 activity.
3. Cytomegalovirus reactivation and the host immune response in patients with sepsis.
Among 81 reactivators matched to 81 non-reactivators, six soluble inhibitory immune checkpoint regulators rose from three days before to the day of CMV viremia, while cytokine release, endothelial activation, coagulation, inflammation, and organ damage markers remained stable. Structural equation modeling identified inhibitory checkpoint regulation as the only independent factor associated with reactivation. Pre-viremia gene expression showed increased innate immunity/hemostasis and decreased adaptive immunity/cytokine signaling.
Impact: Provides temporal, multi-omic evidence that inhibitory checkpoint upregulation precedes CMV reactivation during sepsis, refining biological understanding and informing preventive strategies.
Clinical Implications: Supports risk stratification for CMV surveillance and potential preemptive therapy in CMV-seropositive sepsis, and suggests immune checkpoint pathways as targets for modulation.
Key Findings
- Six soluble inhibitory immune checkpoint regulators increased from −3 days to the day of CMV viremia onset in reactivators.
- Markers of cytokine release, endothelial activation, coagulation, inflammation, and organ damage remained stable over the same interval.
- Structural equation modeling identified inhibitory checkpoint regulation as the only variable independently associated with CMV reactivation.
- Gene expression three days before reactivation showed upregulated innate immunity, hemostasis, and CMV-related pathways with downregulated adaptive immunity and cytokine signaling.
Methodological Strengths
- Nested case-control design with careful matching and longitudinal sampling at defined time points
- Integrated plasma biomarker profiling with whole-blood transcriptomics and structural equation modeling
Limitations
- Observational design cannot establish causality; findings limited to CMV-seropositive ICU sepsis patients
- External validation and interventional testing (e.g., preemptive therapy guided by checkpoints) are needed
Future Directions: Validate checkpoint-based risk signatures in external cohorts and test preemptive antiviral or immune-modulatory strategies timed to early checkpoint elevation.