cpg介导的TLR9信号通路增强了具有cgas - sting激活特性的OprF/PcrV DNA疫苗的效力

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-08-29 DOI:10.1016/j.lfs.2025.123930

Linxia Tian, Hongxi He, Hanbai Liu, Yating Zhang, Xian Yu

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引用次数: 0

摘要

目的通过开发一种复杂的佐剂策略，克服双价DNA疫苗（DNA- oprf /PcrV）对铜绿假单胞菌（Pseudomonas aeruginosa， PA）感染保护作用有限的缺陷，增强免疫原性和保护作用，为临床提供一种新的候选疫苗。材料与方法制备PA抗原OprF和PcrV （DNA-OprF/PcrV）与TLR9激动剂CpG佐剂（DNA-OprF/PcrV + CpG）复合的二价DNA疫苗。体外机制研究评估了协同途径激活和树突状细胞成熟，而小鼠模型通过细菌负荷量化和炎症分析评估了体液免疫（抗体滴度）、细胞免疫（Th1/CTL反应）和肺部感染模型的保护功效。cpg佐剂疫苗协同激活cGAS-STING（疫苗介导）和TLR9 （cpg介导）途径，显著增强树突状细胞成熟和先天免疫。因此，它增强了适应性免疫，包括增强Th1极化和细胞毒性T淋巴细胞（CTL）活性，同时提高了pa特异性抗体滴度。在肺部感染模型中，与无佐剂疫苗相比，该配方具有显著减少细菌负担和减轻炎症的优越保护作用。本研究表明，cpg佐剂DNA疫苗复合物通过双途径协同作用克服了DNA疫苗的局限性，为临床提供了一种可翻译的抗多药PA感染策略，并开创了cGAS-STING/TLR9共激活的抗菌疫苗设计范式。

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CpG-mediated TLR9 signaling pathway enhances the efficacy of the OprF/PcrV DNA vaccine with cGAS-STING-activating properties

Aims

This study aimed to overcome the limited protective efficacy of the bivalent DNA vaccine (DNA-OprF/PcrV) against Pseudomonas aeruginosa (PA) infection by developing a complexed adjuvant strategy to enhance immunogenicity and protection, providing a novel clinical candidate vaccine.

Materials and methods

We formulated a bivalent DNA vaccine encoding PA antigens OprF and PcrV (DNA-OprF/PcrV) complexed with the TLR9 agonist CpG adjuvant (DNA-OprF/PcrV + CpG). In vitro mechanistic studies assessed synergistic pathway activation and dendritic cell maturation, while murine models evaluated humoral immunity (antibody titers), cellular immunity (Th1/CTL responses), and protective efficacy via pulmonary infection models with bacterial burden quantification and inflammation analysis.

Key findings

The CpG-adjuvanted vaccine synergistically activated both cGAS-STING (vaccine-mediated) and TLR9 (CpG-mediated) pathways, significantly enhancing dendritic cell maturation and innate immunity. Consequently, it amplified adaptive immunity, including potentiated Th1 polarization and cytotoxic T lymphocyte (CTL) activity alongside elevated PA-specific antibody titers. In pulmonary infection models, this formulation conferred superior protection marked by significantly reduced bacterial burden and attenuated inflammation compared to the non-adjuvanted vaccine.

Significance

This work demonstrates that the CpG-adjuvanted DNA vaccine complex overcomes DNA vaccine limitations through dual-pathway synergy, providing a clinically translatable strategy against multidrug-resistant PA infection and pioneering a cGAS-STING/TLR9 co-activation paradigm for antibacterial vaccine design.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.