Viral Immunology and Respiratory Disease group, University of Newcastle, Newcastle, Australia.
Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
Eur Respir J. 2021 Jul 1;58(1). doi: 10.1183/13993003.01584-2020. Print 2021 Jul.
We assessed whether Toll-like receptor (TLR)2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases.
We employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III interferon (IFN) production, as well as the lung tissue and epithelial cell immune transcriptome.
We show, , that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7 days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1 day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7 days before infection, suggesting an alternate mechanism, potentially establishment of immune cell-mediated mucosal innate immunity. , INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for nuclear factor (NF)-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response.
Airway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.
我们评估了 Toll 样受体 (TLR)2 的激活是否能增强鼻病毒感染的先天免疫反应，作为病毒诱导的呼吸道疾病的治疗策略。
我们在小鼠感染鼻病毒之前使用新型 TLR2 激动剂 (INNA-X) 进行治疗，并在源自哮喘供体的分化人支气管上皮细胞中进行 INNA-X 治疗。我们评估了病毒载量、免疫细胞募集、细胞因子、I 型和 III 型干扰素 (IFN) 的产生，以及肺组织和上皮细胞免疫转录组。
我们表明，单次 INNA-X 处理可诱导先天免疫启动，其特征为低水平 IFN-λ、Fas 配体、趋化因子表达和气道淋巴细胞募集。感染前 7 天治疗可显著降低肺病毒载量，增加 IFN-β/λ 的表达并抑制中性粒细胞炎症。皮质类固醇治疗增强了 INNA-X 的抗炎作用。感染前 1 天治疗可增加 190 个肺组织免疫基因的表达。与感染前 7 天 INNA-X 处理不同，这种组织基因表达谱表明存在另一种机制，可能是建立免疫细胞介导的粘膜先天免疫。此外，INNA-X 处理诱导了一种由 IFN-λ、趋化因子和抗菌基因表达上调定义的启动反应，随后是对感染的加速反应，富含核因子 (NF)-κB 调节基因，并降低病毒载量，即使在源自具有内在延迟抗病毒免疫反应的哮喘供体的上皮细胞中也是如此。
气道上皮细胞 TLR2 的激活诱导了持久的先天免疫启动，其特征为早期 NF-κB 激活、IFN-λ 的表达和淋巴细胞募集。这种反应增强了抗病毒的先天免疫并减轻了病毒引起的气道炎症。
