Daily Sepsis Research Analysis
Analyzed 11 papers and selected 3 impactful papers.
Summary
Three studies advance sepsis science through complementary angles: a preclinical study identifies CDK9 as a target to mitigate sepsis-associated encephalopathy, an RCT-based translational analysis explains how clarithromycin prevents progression to respiratory failure and secondary sepsis via IL-1 axis modulation, and a mechanistic rat study reveals central A2a receptors counteract cholinergic cardiovascular protection in sepsis.
Research Themes
- Neuroimmune modulation and BBB protection in sepsis
- Host-directed immunomodulation to prevent secondary sepsis
- Autonomic-cardiovascular regulation via adenosine–cholinergic pathways
Selected Articles
1. Pharmacological inhibition of CDK9 counteracts neuroinflammatory impairments in sepsis-associated encephalopathy.
In a CLP mouse model, CDK9 activation contributed to neuroinflammation and BBB disruption characteristic of sepsis-associated encephalopathy. Pharmacologic CDK9 inhibition (LDC000067) reduced central and systemic inflammation, multiorgan dysfunction, and preserved endothelial barrier integrity, supported by in vitro human microglial and endothelial assays.
Impact: This study uncovers a previously unreported role for CDK9 in SAE and demonstrates therapeutic potential of CDK9 inhibition across multiple levels of the neurovascular unit.
Clinical Implications: CDK9 inhibitors could be developed as host-directed therapies for sepsis-associated encephalopathy, though human safety, dosing, and timing require evaluation.
Key Findings
- CLP-induced sepsis activated CDK9 in prefrontal cortex with microglial activation and BBB disruption (elevated plasma neurofilament light).
- LDC000067 reduced systemic cytokine storm, multiorgan dysfunction, and clinical severity at 24 hours post-CLP.
- CDK9 inhibition suppressed NF-κB-related transcription in human microglia and preserved claudin-5 and barrier integrity in brain endothelial cells.
Methodological Strengths
- Clinically relevant polymicrobial CLP model with multi-compartment readouts (central and peripheral).
- Convergent in vivo mouse and human in vitro mechanistic validation of CDK9 pathway effects.
Limitations
- Preclinical study in male mice only with short-term (24 h) endpoints.
- Single CDK9 inhibitor used; off-target effects and dose–response not fully explored.
Future Directions: Test multiple CDK9 inhibitors, extend to female animals and longer-term outcomes, and initiate early-phase clinical trials with pharmacodynamic biomarkers (e.g., NfL, microglial activation markers).
Sepsis-associated encephalopathy (SAE) is a diffuse dysfunction of the central nervous system and a major manifestation of sepsis, associated with acute clinical deterioration and poor prognosis. Despite advances in understanding its pathophysiology and sepsis-induced cerebral alterations, effective pharmacological treatments remain unavailable. Cyclin-dependent kinase 9 (CDK9) is a ubiquitous kinase implicated in several inflammatory processes, however, its role in sepsis remains poorly understood. This study investigated whether CDK9 activity contributes to SAE pathophysiology and whether its pharmacological inhibition confers protection in a clinically relevant sepsis model. Polymicrobial sepsis was induced in male C57BL/6OlaHsd mice using caecal ligation and puncture (CLP). One hour after the procedure, mice received the selective CDK9 inhibitor LDC000067 (50 mg/kg i.v.) or vehicle. At 24 h, sepsis induced marked CDK9 activation in the prefrontal cortex, accompanied by neuroinflammation, evidenced by microglial activation, and blood-brain barrier (BBB) disruption, reflected by increased plasma neurofilament light chain levels. Treatment with LDC000067 attenuated septic alterations both centrally and peripherally, reducing multiorgan dysfunction, the systemic cytokine storm, and clinical severity. In vitro, exposure of human microglial cells to a sepsis-like inflammatory stimulus increased NF-κB-related transcriptional responses, which were significantly reduced by CDK9 inhibition. Similarly, exposure of brain microvascular endothelial cells to the same stimulus resulted in endothelial barrier dysfunction, mitigated by CDK9 inhibition through preservation of claudin-5 expression and barrier integrity. Altogether, these findings identify a previously unreported role for CDK9 in SAE pathogenesis and show that its pharmacological inhibition attenuates key features of SAE, including microglial activation and BBB disruption.
2. Molecular pathways driving clarithromycin benefit in community-acquired pneumonia: analysis of the ACCESS randomised trial.
Within a double-blind RCT, clarithromycin modulated host responses: downregulating IL-1 signaling and neutrophil degranulation while enhancing antigen presentation and select monocyte-derived cytokines, correlating with reduced progression to respiratory failure and secondary sepsis.
Impact: Provides mechanistic underpinnings for macrolide benefit in CAP, linking IL-1 axis attenuation and improved antigen presentation to prevention of deterioration, including secondary sepsis.
Clinical Implications: Supports adjunctive macrolide therapy in hospitalized CAP and suggests IL-1 pathway biomarkers to stratify patients at risk of progression to respiratory failure or secondary sepsis.
Key Findings
- Clarithromycin uniquely upregulated T-cell activation and MHC-II genes, while downregulating IL-1 receptor and neutrophil degranulation genes.
- Fewer patients on clarithromycin showed increases in IL-1 cluster cytokines (OR 0.47; 95% CI 0.23–0.96; p=0.038).
- Increases in monocyte-derived pro-inflammatory cytokines/chemokines (excluding IL-1) associated with achieving the primary endpoint (OR 1.87; 95% CI 1.05–3.35; p=0.035).
Methodological Strengths
- Embedded in a double-blind randomized controlled trial with paired gene expression and functional PBMC assays.
- Robust bioinformatics (DESeq2, Reactome, GO) and trajectory analyses linking molecular shifts to clinical endpoints.
Limitations
- Ancillary mechanistic analysis with unspecified sample size; not primarily powered for molecular endpoints.
- Findings pertain to CAP; generalizability to other infections or established sepsis needs validation.
Future Directions: Prospective validation of IL-1 axis and antigen presentation biomarkers to guide macrolide use; explore synergy with IL-1–targeted agents to prevent deterioration and secondary sepsis.
BACKGROUND: The double-blind randomised controlled ACCESS trial (ClinicalTrials.gov NCT04724044), conducted in hospitalised patients with community-acquired pneumonia (CAP), showed that the addition of clarithromycin to the standard-of-care (SoC) provided earlier resolution of symptoms during the first 72 h and prevented progression to respiratory failure and secondary sepsis. The molecular pathways underpinning these favourable effects of action of clarithromycin were investigated in this research. METHODS: Gene expression was compared between treatment arms and within each arm between baseline and 72 h using DESeq2. Reactome pathway and Gene Ontology analyses were followed. Cytokine stimulation data of peripheral blood mononuclear cells (PBMCs) from the same time points were also analysed. FINDINGS: Trajectory analysis showed that the unique upregulated genes in the clarithromycin group were mainly involved in pathways of T-cell activation and positive regulation of cytokine production. The expression of genes encoding for the major histocompatibility complex II was upregulated; genes encoding for the receptors of interleukin (IL)-1 and for neutrophil degranulation were downregulated. The production of cytokines of the IL-1 cluster was positively associated with progression to respiratory failure; fewer patients treated with clarithromycin experienced increases in production of IL-1 cytokines (odds ratio 0.47; 95% confidence intervals 0.23-0.96; p = 0.038). The production of monocyte-derived pro-inflammatory cytokines and chemokines (other than the IL-cytokines) was positively associated with attainment of the primary endpoint; more patients treated with clarithromycin exhibited increases in production of monocyte-derived cytokines and chemokines (odds ratio 1.87; 95% confidence intervals 1.05-3.35; p = 0.035). Production of anti-inflammatory cytokines by PBMCs was also attenuated in clarithromycin-treated patients. INTERPRETATION: Treatment with clarithromycin attenuates the IL-1 pathway, increases production of other monocyte-derived pro-inflammatory cytokines and chemokines, improves antigen presentation and decreases neutrophil degranulation. These effects may explain the clinical benefit of clarithromycin in hospitalised patients with CAP. FUNDING: Hellenic Institute for the Study of Sepsis; Abbott Products Operations.
3. Adenosine A2a receptors offset cholinergic control of blood pressure, autonomic neuropathy, and brainstem neuroinflammation in sepsis.
In septic rats, nicotine restored blood pressure and HRV indices, whereas intracisternal A2a receptor activation worsened hypotension and negated nicotine’s cardiovascular and autonomic benefits while abolishing its suppression of TNFα/A2aAR upregulation in NTS and RVLM. A2aAR blockade preserved nicotine effects, implicating medullary A2aARs as brakes on the cholinergic anti-inflammatory pathway.
Impact: Reveals a central mechanism by which adenosine A2a receptors antagonize vagal cholinergic protection in sepsis, highlighting a potentially druggable node in autonomic-immune crosstalk.
Clinical Implications: Therapies aiming to augment the cholinergic anti-inflammatory pathway in sepsis may benefit from concomitant A2a receptor modulation; however, translation requires peripheral-targeting strategies and safety data.
Key Findings
- Nicotine (100 μg/kg i.v.) at 24 h post-CLP reversed sepsis-induced hypotension and improved HRV indices and sympathovagal balance.
- Intracisternal CGS21680 (A2aAR agonist) worsened hypotension and blunted nicotine-induced BP rises and vagal HRV indices.
- CGS21680 abolished nicotine’s suppression of TNFα and A2aAR protein upregulation in NTS and RVLM; A2aAR blockade with CSC preserved nicotine’s effects.
Methodological Strengths
- Integrated hemodynamic, HRV, and molecular assessments with targeted intracisternal pharmacology.
- Use of both agonist and antagonist to triangulate A2aAR causality in sepsis physiology.
Limitations
- Rat model with central (intracisternal) drug delivery limits clinical translatability.
- Short observation window and lack of survival or organ injury outcomes.
Future Directions: Assess peripheral A2aAR modulators, extend to survival and organ injury outcomes, and explore interactions with vagus nerve stimulation or nicotinic agonists.
The cholinergic antiinflammatory pathway functions to counterbalance the innate immune response to inflammatory disorders including sepsis. Considering the reported contradictory role of adenosine in inflammation, the present study investigated whether central adenosine A2a receptors (A2aARs) arbitrate the cholinergic modulation of cardiovascular and autonomic dysfunction induced by sepsis. Rats were instrumented with femoral and intracisternal (i.c.) catheters for hemodynamic monitoring and central drug administration, respectively, and sepsis was induced by cecal ligation and puncture (CLP). The intravenous treatment with nicotine (100 μg/kg) 24-h post-CLP reversed the hypotension, depression of time- and frequency-domain indices of heart rate variability (HRV) and sympathovagal imbalance induced by sepsis. Intracisternal (i.c.) administration of CGS21680 (A2aAR agonist, 2 μg/rat) accentuated the hypotensive response to sepsis on its own and blunted the rises in blood pressure caused by subsequently administered nicotine. Additionally, CGS21680 suppressed the nicotine-evoked increments in HRV index of cardiac vagal control. The ameliorating action of CGS21680 on cardiovascular protection conferred by nicotine was paralleled with the abolition of nicotine counteraction of the sepsis-evoked augmentation of the protein expression of tumor necrosis factor α (TNFα) and A2aARs in brainstem nuclei of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM). On the other hand, the interrelated cardiovascular and molecular effects of nicotine were maintained following central blockade of A2aARs by 8-(3-chlorosteryl) caffeine (CSC, 40 μg/rat i.c.). The data suggest that medullary A2aARs restrain the machinery by which the cholinergic antiinflammatory pathway acts defensively to rectify cardiovascular and autonomic consequences of sepsis.