Informe Final
Elucidating the mechanisms of pathogenicity used by the human respiratory syncytial virus to prevent t cell activation and cause central nervous system inflammation.
Fecha
2019Autor
Pontificia Universidad Católica de Chile
Institución
Resumen
This aim was completed and successfully executed. First, to evaluate whether the T cell activation inhibition due to hRSV infection of Dendritic Cells (DCs), described in our previous studies, could be restored with the improvement of the TCR-pMHC signaling, DCs were infected with hRSV or treated with purified N protein and then co-cultured with T cells and costimulatory molecules. We observed that the addition of anti-CD3/anti-CD28 antibody, anti-TCRß and the Staphylococcus aureus Super Antigen A was enough to restore T cell activation when Dcs were treated with N protein, although this was not found when DCs were infected with hRSV. Therefore, additional hRSV proteins are acting together to prevent T cells activation by infected DCs. To identify the proteins involved on T cell inactivation, we developed recombinant lentiviruses (Lv) encoding N, NS1, NS2, P, SH and M2-1. Then, we evaluated whether the transduction of DCs with these Lv reproduced the inability of these cells to prevent T cell activation. Firstly, lentiviruses transduced efficiently DCs, with no impact in their cell viability. We did not observe that DCs transduced with Lv expressing the the hRSV proteins had problems to differentiate efficiently. Importantly, we observed that DCs transduced with LV harboring the gene encoding N, NS-1, P and M2-1 prevent. Therefore, we demonstrated that several hRSV proteins can prevent DCs from activating T cells. We plan to evaluate whether the co expression of these proteins promote T cells inactivation in a synergistic way. As part of the development of this aim, we have published the following articles: Céspedes, P.F. et al. Vaccine, 2017Rey-Jurado, E. et al.Vaccines & Immunotherapeutics,2017; Canedo-Marroquín, G. et al. Frontiers in Cellular and Infection Microbiology, 2017, Gómez, R.S. et al. Immunology, 2016) proteins of the human respiratory syncytial virus (hRSV).