Hepatitis B virus core particles containing a conserved region of the G protein combined with interleukin-35 protected mice against respiratory syncytial virus infection without vaccine-enhanced immunopathology.

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 RSV vaccine. Currently, there is no licensed vaccines for RSV. In this study, mice immunized with hepatitis B virus core particles containing a conserved region of the G protein (HBc-tG) combined with interleukin-35 (IL-35) elicited Th1-biased response, high frequency of regulatory T (Treg) cells and increased IL-10, TGF-beta and IL-35 production. Importantly, immunization of 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 gene expression level, transcription profiles were obtained from lung tissues of immunized mice after RSV infection by Illumina sequencing technique and further analyzed by a system biology method. In total, 2644 differentially expressed genes (DEGs) were identified. Twelve high influence modules (HIMs) were selected from these DEGs based on the protein-protein interaction network. A detailed analysis of HIM10 involved in immune response network revealed that Il10 play a key role in regulating the host response. The selected DEGs were consistently confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Our results demonstrated that IL-35 inhibits vaccine-enhanced immunopathology after RSV infection and has potential for development as novel therapeutic and prophylactic strategies.IMPORTANCE In the past decades, respiratory syncytial virus (RSV) has still been a major health concern worldwide. The vaccine-enhance disease (VED) hindered the RSV vaccine development. A truncated hepatitis B virus core protein vaccine containing conserved region (aa 144-204) of the RSV G protein (HBc-tG) had previously been shown to induce effective immune responses and confer protection against RSV infection in mice, but also lead to VED. In this study, we investigated the effect of IL-35 on host response and immunopathology following RSV infection in vaccinated mice. Our results indicated that HBc-tG together with IL-35 elicited balanced immune response and protected mice against RSV infection without vaccine-enhanced immunopathology. Applying a system biology method, we identified Il10 was the key regulator in reducing the excessive lung inflammation. Our study provides new insight into the function of IL-35 and its regulatory mechanism of VED at a network level.