RESUMEN
Despite the emergence of new direct-acting antivirals, hepatitis C virus (HCV) chronic infection and its consequent fibrosis and hepatocarcinoma remain a significant burden for public health, thus requiring an effective preventive vaccine. Our group previously showed that a subunit vaccine based on recombinant soluble E2 (sE2) can induce broadly neutralizing antibodies. To improve the immunogenicity of sE2, we designed and produced a fusion protein (sE2-ferritin) comprising sE2 and a ferritin unit in Drosophila S2 cells, which self-assembled into a nanoparticle with sE2 displayed on the surface. The sE2 moiety on the sE2-ferritin nanoparticle not only had nearly natural conformation but also had better affinities than the unfused sE2 to neutralizing antibodies, receptor, and patient serum. Mouse immunization studies showed that sE2-ferritin was more potent than sE2 in inducing anti-HCV broadly neutralizing antibodies. Our results demonstrate that sE2-ferritin is a vaccine candidate superior to previously developed sE2, providing a new possibility for controlling HCV.
Asunto(s)
Hepacivirus/inmunología , Hepatitis C Crónica/microbiología , Nanopartículas/química , Vacunas contra Hepatitis Viral/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Drosophila/inmunología , Genotipo , Anticuerpos contra la Hepatitis C/inmunología , Hepatitis C Crónica/virología , Inmunización/métodos , Ratones , Proteínas Recombinantes/inmunología , Vacunas de Subunidad/inmunología , Proteínas del Envoltorio Viral/inmunología , Vacunas contra Hepatitis Viral/químicaRESUMEN
Chronic hepatitis C infection is a leading cause of liver cirrhosis, which is linked to chronic hepatic inflammation. While there are multiple studies detailing the proinflammatory role of interleukin-1ß (IL-1ß) in HCV-induced inflammasome signaling, the antiviral capacity of this cytokine has not been adequately investigated in the context of HCV infection or other members of Flaviridae. Our data indicated that IL-1ß alone does not inhibit HCV replication, yet when in combination with IFN-α, it can boost the anti-HCV activity of IFN-α, which is mediated by augmented STAT1 tyrosine 701 phosphorylation. Through signaling inhibitor screening, we found that ERK2 kinase is directly linked to the enhanced activation of the STAT1 complex. Our study found that IL-1ß negatively affects ERK2 phosphorylation, which suggests that IL-1ß-mediated STAT1 tyrosine 701 phosphorylation employed kinase machinery of ERK2 other than JNK or P38 kinase. Our results identify IL-1ß as a proinflammatory cytokine possessing wide spectrum synergistic antiviral capability via enhancing IFN-α-induced interferon-stimulated genes (ISGs) expression. A more nuanced understanding of the antiviral mechanisms of this important cytokine could facilitate the development of new therapeutic options.