Daily Sepsis Research Analysis

Elevated heme levels, a consequence of hemolysis, are strongly associated with increased susceptibility to bacterial infections and adverse sepsis outcomes, particularly in older populations. However, the underlying mechanisms remain poorly understood. Using a cecal ligation and puncture (CLP) model of sepsis, we demonstrate that elevated heme levels correlate with Kupffer cell loss, increased bacterial burden, and heightened mortality. Mechanistically, we identify mitochondrial damage as a key driver of heme- and bacterial-induced Kupffer cell PANoptosis, a form of cell death integrating pyroptosis, apoptosis, and necroptosis, as well as cellular senescence. Specifically, heme activates phospholipase C gamma (PLC-γ), facilitating the translocation of cleaved gasdermin D (c-GSDMD) to mitochondria, resulting in GSDMD pore formation, mitochondrial dysfunction, and the release of mitochondrial DNA (mtDNA) during bacterial infection. This mitochondrial damage amplifies PANoptosis and triggers the cGAS-STING signaling pathway, further driving immune senescence. Notably, PLC-γ inhibition significantly reduces mitochondrial damage, cell death, and senescence caused by heme and bacterial infection. Furthermore, we show that hemopexin, a heme scavenger, effectively mitigates sepsis-induced Kupffer cell death and senescence, enhances bacterial clearance, and improves survival outcomes in both young and aged mice.

Sepsis is a major contributor to global health loss, yet effective therapeutic options remain scarce. This study aims to identify potential therapeutic targets for sepsis. We integrated data from the druggable genome, expression quantitative trait loci (eQTLs) from human blood, and genome-wide association studies on sepsis. Mendelian randomization (MR) was employed to investigate causal relationships between drug target genes and sepsis. The eQTLGen Consortium data served as the discovery set and was validated using genotype-tissue expression (GTEx) eQTLs. Sensitivity and colocalization analyses were conducted to support causal inferences. Additionally, phenome-wide MR (Phe-MR) was used to assess potential side effects of druggable genes. The expression levels of the target genes were validated using the GSE154918 dataset. In the discovery MR analysis phase, we identified 26 potential targets with significant expression in blood (PFDR < 0.05). PDGFB and BPI were further validated in the replication MR analysis. Colocalization analysis provided strong evidence (PPH4 > 0.75) supporting PDGFB as a therapeutic candidate for sepsis. Phe-MR analysis suggested that targeting PDGFB is unlikely to cause adverse effects. PDGFB downregulation was confirmed in sepsis groups via the GEO dataset. PDGFB is identified as a promising druggable target for sepsis treatment, supported by strong evidence of its therapeutic potential.

BACKGROUND: Antimicrobial resistance (AMR) is a growing global health threat. Acinetobacter baumannii (A. baumannii) emerged as one of the most concerning critical priority pathogens due to its ability to develop resistance to multiple antimicrobial agents. In Ethiopia, the public health impact of AMR is increasingly significant, with A. baumannii responsible for a variety of infections. Although A. baumannii causes a range of infections in Ethiopian patients, the drug resistance status of the clinical isolates has not been thoroughly assessed. Therefore, this systematic review and meta-analysis aimed to determine the country-wide AMR of A. baumannii. METHODS: This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We conducted a search of articles on PubMed, Web of Science, Science Direct, Scopes electronic databases, Google Scholar search engine, and institutional repositories/libraries for studies published between 2015 and 2024. Eligible studies on A. baumannii-related infections and AMR in Ethiopia were assessed for quality using the Joanna Briggs Institute (JBI) criteria. Data on study characteristics were extracted, and statistical analyses, including heterogeneity (Invers of variance), publication bias (Eggers test), and subgroup analyses, were performed using STATA 17.0. A random effect model was used to compute the pooled prevalence of AMR. RESULTS: This systematic review and meta-analysis of 26 Ethiopian studies (26,539 participants) found an A. baumannii prevalence of 3.99% (95% CI: 3.01-4.98%) and 9.13% of all bacterial infections (95% CI: 6.73-11.54%). The most common infections were surgical site infections, urinary tract infections, pneumonia, and sepsis. Pooled resistance to antibiotics varied, with amikacin showing the lowest resistance (20.27%) (95% CI: 11.51-29.03) and cefotaxime the highest (83.18) (95% CI: 71.87-94.48). A pooled multi-drug resistant (MDR) A. baumannii was found in 88.22% (95% CI: 82.28-94.15) of isolates, with regional and infection-type variations, particularly in higher prevalence in Oromia and Amhara regions and sepsis cases. CONCLUSION: This systematic review underscores the alarming rise of antimicrobial resistance in A. baumannii, particularly against carbapenems. The findings highlight a high prevalence of MDR A. baumannii and widespread extended-spectrum beta-lactamase production, with notable regional variations in resistance patterns. These high resistance rates reinforce A. baumannii as a critical global health threat, necessitating urgent interventions such as enhanced antimicrobial stewardship programs, improved infection control measures, and the development of alternative treatment strategies. Healthcare professionals, policymakers, and researchers must collaborate to mitigate the clinical and public health impact of this pathogen. PROTOCOL REGISTRATION: This systematic review and meta-analysis was registered on PROSPERO (Registration ID: CRD42024623927).