Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in infants and young children. The vaccine-enhanced disease (VED) has greatly hindered the development of an RSV vaccine. Currently, there are no licensed vaccines for RSV. In this study, immunization of mice with hepatitis B virus core particles containing a conserved region of the G protein (HBc-tG) combined with interleukin-35 (IL-35) elicited a Th1-biased response and a high frequency of regulatory T (Treg) cells and increased the levels of IL-10, transforming growth factor β, and IL-35 production. Importantly, immunization with HBc-tG together with IL-35 protected mice against RSV infection without vaccine-enhanced immunopathology. To explore the mechanism of how IL-35 reduces lung inflammation at the gene expression level, transcription profiles were obtained from lung tissues of immunized mice after RSV infection by the Illumina sequencing technique and further analyzed by a systems biology method. In total, 2,644 differentially expressed genes (DEGs) were identified. Twelve high-influence modules (HIMs) were selected from these DEGs on the basis of the protein-protein interaction network. A detailed analysis of HIM10, involved in the immune response network, revealed that Il10 plays a key role in regulating the host response. The selected DEGs were consistently confirmed by quantitative real-time PCR (qRT-PCR). Our results demonstrate that IL-35 inhibits vaccine-enhanced immunopathology after RSV infection and has potential for development in novel therapeutic and prophylactic strategies.

中文翻译：

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含有G蛋白保守区的B型肝炎病毒核心颗粒结合白介素35保护的小鼠，可在没有疫苗增强免疫病理学的情况下抵抗呼吸道合胞病毒感染。

呼吸道合胞病毒（RSV）是婴幼儿下呼吸道感染的最重要原因。疫苗增强疾病（VED）极大地阻碍了RSV疫苗的开发。当前，没有针对RSV的许可疫苗。在这项研究中，使用含有G蛋白保守区（HBc-tG）和白介素35（IL-35）的乙型肝炎病毒核心颗粒对小鼠进行免疫接种，可引起Th1偏向反应和高频率的调节性T（ Treg细胞）并增加IL-10，转化生长因子β和IL-35的产生。重要的是，用HBc-tG和IL-35免疫可保护小鼠抵抗RSV感染，而无需增强疫苗的免疫病理学。为了探索IL-35如何在基因表达水平上减轻肺部炎症的机制，通过Illumina测序技术从RSV感染后的免疫小鼠的肺组织获得转录谱，并通过系统生物学方法进一步分析。总共鉴定出了2,644个差异表达基因（DEG）。在蛋白质-蛋白质相互作用网络的基础上，从这些DEG中选择了十二个高影响力模块（HIM）。对参与免疫反应网络的HIM10的详细分析显示，Il10在调节宿主反应中起关键作用。通过定量实时PCR（qRT-PCR）始终确认所选的DEG。我们的研究结果表明，IL-35抑制RSV感染后可增强疫苗的免疫病理性，并且在新的治疗和预防策略中具有发展潜力。