RBM39 shapes innate immunity through transcriptional and splicing control of IRF3 and other key factors
RNA binding motif protein 39 (RBM39) is an RNA-binding protein involved in tumorigenesis, cell me... more RNA binding motif protein 39 (RBM39) is an RNA-binding protein involved in tumorigenesis, cell metabolism and development. Here, we performed a genome-wide CRISPR/Cas9 screen in two liver-derived cell lines and identified RBM39 as a regulator of cell intrinsic innate immune responses, affecting transcription and/or splicing of key pathway components, in particular interferon regulatory factor 3 (IRF3). Knockdown ofRBM39or treatment with Indisulam, an aryl sulfonamide drug targeting RBM39 for proteasomal degradation, strongly reduced the induction of interferon-stimulated genes (ISGs) in response to double-stranded RNA (dsRNA), lipopolysaccharide (LPS) and viral infections mediated by IRF3.RBM39knockdown further restrained the type III interferon (IFN) pathway, by reducing expression of the receptor subunit Interleukin 10 Receptor Subunit Beta (IL-10RB). RNAseq and mass spectrometry revealed altered expression of additional signaling factors, highlighting the importance of RBM39 in o...
Background: The papaya mosaic virus (PapMV) vaccine platform is a rod-shape nanoparticle made of ... more Background: The papaya mosaic virus (PapMV) vaccine platform is a rod-shape nanoparticle made of the recombinant PapMV coat protein (CP) self-assembled around a non-coding ssRNA template. The PapMV nanoparticle induces innate immunity through stimulation of the toll-like receptors (TLR) 7 and 8. The display of the vaccine antigen at the surface of the nanoparticle, associated with the co-stimulation signal via TLR7/8, ensures a strong stimulation of the immune response, which is ideal for the development of candidate vaccines. In this study, we assess the impact of where the peptide antigen is fused, either at the surface or at the extremities of the nanoparticles, on the immune response directed to that antigen. Methods: Two different peptides from influenza A virus were used as model antigens. The conserved M2e peptide was chosen as the B-cell epitope, and a peptide derived from the nucleocapsid was chosen as the CTL epitope. These peptides were coupled at two different positions ...
The eradication of hepatitis C virus (HCV) infection is a public health priority. Despite the eff... more The eradication of hepatitis C virus (HCV) infection is a public health priority. Despite the efficiency of treatment with direct-acting antivirals, the high cost of the therapy and the lack of accurate data about the HCV-infected population worldwide constitute important factors hampering this task. Hence, an affordable preventive vaccine is still necessary for reducing transmission and the future disease burden globally. In this work, chimeric proteins (EnvCNS3 and NS3EnvCo) encompassing conserved and immunogenic epitopes from the HCV core, E1, E2 and NS3 proteins were produced in Escherichia coli, and their immunogenicity was evaluated in BALB/c mice. The impact of recombinant HCV E2.680 protein and oligodeoxynucleotide 39M (ODN39M) on the immune response to chimeric proteins was also assessed. Immunization with chimeric proteins mixed with E2.680 enhanced the antibody and cellular response against HCV antigens and chimeric proteins. Interestingly, the combination of NS3EnvCo with E2.680 and ODN39M as adjuvant elicited a potent antibody response characterized by an increase in antibodies of the IgG2a subclass against E2.680, NS3 and chimeric proteins, suggesting the induction of a Th1-type response. Moreover, a cytotoxic T lymphocyte response and a broad response of IFN-γ-secreting cells against HCV antigens were induced with this formulation as well. This T cell response was able to protect vaccinated mice against challenge with a surrogate model based on HCV recombinant vaccinia virus. Overall, the vaccine candidate NS3EnvCo/E2.680/ODN39M might constitute an effective immunogen against HCV with potential for reducing the likelihood of viral persistence.
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Papers by Santa Olivera