Co-adjuvanting Nod2-stimulating bacteria with a TLR7 agonist elicits potent protective immunity against respiratory virus infection

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents Pub Date : 2024-10-29 DOI:10.1016/j.ijantimicag.2024.107369

Sujin An , Jeein Oh , Hoh-Jeong Shon , Jaehwan Song , Youn Soo Choi , Donghyun Kim

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引用次数: 0

Abstract

Objectives

This study investigates the synergistic effect of combining the TLR7 agonist Imiquimod with either the Nod2 agonist (muramyl dipeptide; MDP) or commensal bacteria as nasal vaccine adjuvants to enhance immunity against respiratory viruses.

Methods

Mice assessed immune responses, including antibody and cytokine profiles, after intranasal immunization with antigen and adjuvant combinations. BMDCs were cultured with these components to measure cytokine production. Germinal center formation and hapten-specific antibodies were evaluated using OT-II T-cell transfer and hapten-ovalbumin. Commensal bacteria from healthy nasal cavities were screened for Nod2-stimulating activity using a reporter assay. Protective efficacy against viral pathogens was evaluated using an influenza A infection model and a pseudovirus system for SARS-CoV-2 neutralizing antibodies.

Results

Screening identified Imiquimod as a potent enhancer of adaptive immune responses during nasal immunization, showing synergy with MDP. This combination elevated IL-12p40 and IL-6 levels, enhanced antibody production, and promoted T follicular helper cell differentiation. The Imiquimod-MDP combination provided robust protection against influenza and SARS-CoV-2. Screening of commensal bacteria revealed differential Nod2-stimulating capacities, with Staphylococcus aureus exhibiting superior synergy with Imiquimod compared to Staphylococcus epidermidis. Notably, this synergism was abolished in Nod2-deficient mice, and pretreatment with S. aureus significantly enhanced the protective efficacy of Imiquimod against influenza compared to S. epidermidis.

Conclusions

Combining Imiquimod with MDP or high Nod2-stimulating bacteria offers a promising strategy for nasal vaccine adjuvants. These combinations effectively boost humoral and cellular immune responses, providing strong protection against respiratory viruses.

Abstract Image

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将刺激 Nod2 的细菌与 TLR7 激动剂联合使用，可对呼吸道病毒感染产生有效的保护性免疫。

微生物群在诱导免疫反应方面发挥着至关重要的作用。我们之前的研究表明，含核苷酸结合寡聚化域蛋白 2（Nod2）受体的共生细菌感应参与了霍乱毒素的粘膜佐剂性。然而，霍乱毒素的潜在毒性限制了对人类的使用。在此，我们筛选了其他毒性较低的佐剂，结果显示类收费受体（TLR）4和7激动剂与微生物群协同诱导鼻腔免疫后的适应性免疫反应。特别是，TLR7 激动剂 Imiquimod 与细菌成分 MDP（一种 Nod2 配体）在诱导免疫反应方面表现出协同效应，如诱导免疫小鼠骨髓树突状细胞（BMDCs）产生 IL-12p40 和 IL-6，诱导免疫小鼠滤泡辅助 T 细胞（TFH）分化和产生高亲和力抗体。Imiquimod-MDP组合对流感和SARS-CoV-2感染具有显著的免疫保护作用。此外，我们还从健康捐献者的鼻腔中分离出了一些细菌，并利用报告细胞系测定了它们的 Nod2 刺激活性。金黄色葡萄球菌具有显著的 Nod2 刺激活性，与咪喹莫特的协同作用高于表皮葡萄球菌，而咪喹莫特与细菌的协同作用在 Nod2 基因敲除小鼠中消失。此外，与表皮葡萄球菌相比，金黄色葡萄球菌的预处理增强了咪喹莫特介导的疫苗对流感病毒的保护作用。这些结果表明，Imiquimod-MDP和Imiquimod-细菌组合可作为新型复合佐剂用于开发鼻内疫苗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Antimicrobial Agents 医学-传染病学

CiteScore

21.60

自引率

0.90%

发文量

176

审稿时长

36 days

期刊介绍： The International Journal of Antimicrobial Agents is a peer-reviewed publication offering comprehensive and current reference information on the physical, pharmacological, in vitro, and clinical properties of individual antimicrobial agents, covering antiviral, antiparasitic, antibacterial, and antifungal agents. The journal not only communicates new trends and developments through authoritative review articles but also addresses the critical issue of antimicrobial resistance, both in hospital and community settings. Published content includes solicited reviews by leading experts and high-quality original research papers in the specified fields.