Estudio de los mecanismos y componentes de Brucella abortus involucrados en la disminución de MHC-I y la respuesta T CD8+ citotóxica
Brucella abortus can persist inside the host despite the potent T cell responses. B. abortus infection of human monocytes down-modulates the IFN-?-induced MHC-I cell surface expression by retaining these molecules in the Golgi apparatus (GA). However, several aspects of this phenomenon remained unkn...
Guardado en:
| Autor principal: | |
|---|---|
| Otros Autores: | |
| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
| Publicado: |
Facultad de Farmacia y Bioquímica
2018
|
| Materias: | |
| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2803 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2803.dir/2803.PDF |
| Aporte de: |
| Sumario: | Brucella abortus can persist inside the host despite the potent T cell responses. B. abortus infection of human monocytes down-modulates the IFN-?-induced MHC-I cell surface expression by retaining these molecules in the Golgi apparatus (GA). However, several aspects of this phenomenon remained unknown. Here we demonstrated that MHC-I down-modulation is dependent on bacteria viability but not mediated by well-known Brucella virulence factors. Instead, B. abortus RNA, a viability-associated PAMP (vita-PAMP) is the component involved in this phenomenon. Surprisingly, completely degraded RNA was also able to diminish MHC-I expression. Accordingly, B. abortus RNA and its degradation products caused MHC-I retention within the GA. We further demonstrated that human TLR8 is the receptor involved. Regarding the signalling pathway, the phenomenon was triggered early on during infection. Moreover, targeting epidermal growth factor receptor (EGFR) pathway resulted in partial recovery of MHC-I surface expression. Regarding the mechanisms of MHC-I retention, we observed that an improper acidification of GA caused by monensin prevents MHC-I transport to the cell surface. Finally, we showed that B. abortus RNA-treated macrophages display diminished capacity of antigen presentation to CD8+ T cells. Overall, our results indicate that B. abortus RNA constitutes a novel virulence factor whereby this bacterium, by a TLR8-dependent mechanism and through the EGFR pathway, inhibits MHC-I surface expression. Thus, bacteria can hide within monocytes/macrophages and avoid the immunological surveillance, establishing a chronic infection. |
|---|