Daily Sepsis Research Analysis

BACKGROUND: Hypervirulent Klebsiella pneumoniae (hvKp) induces severe pneumonia and sepsis. HIF-1α coordinates metabolic and immune responses in myeloid cells, but its role in hvKp-mediated pulmonary defense remains undefined. METHODS: Monocyte HIF-1α expression was assessed in patients with Klebsiella pneumoniae (K. pneumoniae) pneumonia. Myeloid-specific Hif-1α knockout mice and BMDMs were used to examine survival, bacterial burden, and macrophage function. RNA-seq, Seahorse flux analysis, and confocal microscopy were employed to investigate the regulatory effects of HIF-1α on phagocytosis and ROS production. The Hif-1α-NCF2-ROS signaling pathway was substantiated through the application of small interfering RNA (siRNA), JASPAR prediction tools, dual-luciferase reporter assays, chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), metabolic inhibitors, and dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. RESULTS: Clinical data showed a negative correlation between monocyte HIF-1α levels and serum CRP, procalcitonin, ICU stay duration, and SOFA scores. In vivo, myeloid Hif-1α knockout mice demonstrated heightened susceptibility to hvKp, with markedly reduced survival and widespread bacterial dissemination. Mechanistically, Hif-1α-deficient macrophages displayed impaired phagocytosis, phagolysosomal maturation, and glycolytic reprogramming in response to infection. RNA-seq identified NCF2, encoding p67-phox, as a critical HIF-1α-dependent component of the NADPH oxidase complex. JASPAR prediction, dual-luciferase reporter assays, and ChIP-qPCR further demonstrated that NCF2 is directly transcriptionally regulated by HIF-1α. HIF-1α deficiency impaired both glycolytic ATP production and NCF2-mediated ROS generation, thereby compromising macrophage antibacterial activity. Inhibition of glycolysis or silencing NCF2 abolished HIF-1α-dependent defense, whereas pharmacological stabilization of HIF-1α using DMOG significantly enhanced host resistance. CONCLUSION: HIF-1α serves as a pivotal regulator of host defense in experimental hvKp pneumonia and is clinically associated with disease severity in K. pneumoniae pneumonia, linking glycolytic metabolism to the NCF2-ROS bactericidal pathway. These findings highlight the potential of targeting immunometabolic pathways to improve host defense against severe K. pneumoniae infections.

OBJECTIVE: Sepsis is a syndrome of systemic inflammatory reaction caused by a severe infection, leading to multiorgan damage and a high mortality rate. In recent years, several studies have shown that decoy receptor 3 (DcR3) is positively correlated with the severity of infection, and its high specificity and sensitivity in the diagnosis of sepsis is expected to serve as a novel marker for sepsis. This meta-analysis aims to evaluate the diagnostic accuracy of decoy receptor 3 (DcR3) for sepsis in the intensive care unit (ICU) setting. METHODS: We conducted a comprehensive search in six databases, extracting data independently.Studies were included if they assessed the diagnostic accuracy of DcR3 for sepsis in the intensive care unit (ICU). A meta-analysis was performed using a random-effects model to calculate pooled sensitivity, specificity, and area under the curve (AUC). RESULTS: Four records assessing 681 patients were included in this meta-analysis. In distinguishing sepsis from normal controls, DcR3 demonstrated exceptional discriminatory power with an AUC of 0.99. The pooled sensitivity was 0.98 (95% CI 0.95-0.99), and the pooled specificity was 0.95 (95% CI 0.92-0.97). The pooled PLR was 21.21 (95% CI 12.71-35.40), the pooled NLR was 0.02 (95% CI 0.01-0.06), and the pooled DOR was 878.26 (95% CI 217.36-21062.55). In differentiating sepsis from systemic inflammatory response syndrome (SIRS), the AUC was 0.95. The pooled sensitivity was 0.93 (95% CI 0.87-0.96), and the pooled specificity was 0.87 (95% CI 0.68-0.95). The pooled PLR was 6.89 (95% CI 2.67-18.26), the pooled NLR was 0.08 (95% CI 0.04-0.15), and the pooled DOR was 86.17 (95% CI 27.35-271.55). CONCLUSION: On the basis of our meta-analysis, DcR3 is a helpful marker for early diagnosis of sepsis on ICU admission. However, the findings are limited by the small number of included studies and significant heterogeneity. Further large-scale, multicenter prospective studies are warranted to validate these results.

Neonatal septic encephalopathy is a severe complication of sepsis, yet its underlying neuropathological mechanisms remain poorly understood. This study investigated the role of the complement component C3a in mediating synaptic elimination and neurobehavioral deficits in later life of a lipopolysaccharide (LPS)-induced neonatal sepsis model. We found that activated hippocampal astrocytes upregulated C3a expression, while its receptor, C3aR, was elevated in both microglia and neurons. Blocking the C3a/C3aR axis with a C3a receptor antagonist (C3aRA) attenuated cognitive impairments, synaptic loss, and microglial engulfment of synapses. C3a led to downregulated expression of neurofilament medium (NF-M) and an increased accumulation of phosphorylated Tau (p-Tau) in primary neurons in vitro. Mechanistically, C3a activated the ERK signaling pathway in primary neurons. Inhibition of ERK with ASN007 mitigated C3a-induced synaptic elimination, neuronal damage, and behavioral deficits both in vivo and in vitro. Our results suggest that astrocyte-derived C3a may contributes to hippocampal synaptic elimination and cognitive deficits through C3a/C3aR/ERK pathway in later life of neonatal septic rats. These findings highlight the C3a/C3aR/ERK axis as a potential therapeutic target for preventing synaptic and cognitive deficits in neonatal septic encephalopathy.