Inhibition of MHC-I by Brucella abortus is an early event during infection and involves EGFR pathway

VELASQUEZ LN; TROTTA A; SCHILLACI R; BARRIONUEVO, P; MILILLO MA; MERCOGLIANO MF; ELIZALDE PV; DELPINO MV; POZNER RG; GIAMBARTOLOMEI GH

IMMUNOLOGY AND CELL BIOLOGY

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2017 vol. 95 p. 388 - 398

0818-9641

Brucella abortus is able to persist inside the host despite the development of potent CD8+ Tcell responses. We have recently reported the ability of B. abortus to inhibit the IFN-γ-induced MHC-I cell surface expression on human monocytes. This phenomenon was due tothe B. abortus-mediated retention of MHC-I molecules within the Golgi apparatus and wasdependent on bacterial viability. However, the implications of bacterial virulence orreplicative capacity and the signaling pathways remained unknown. Here, we demonstratedthat the B. abortus mutant strains RB51 and virB10- are able to inhibit MHC-I expression inthe same manner as wild type B. abortus, even though they are unable to persist inside humanmonocytes for a long period of time. Consistent with this, the phenomenon was triggeredearly in time and could be observed at 8 h post-infection. At 24 h and 48 h it was evenstronger. Regarding the signaling pathway, targeting EGF receptor (EGFR), ErbB2 (HER2) orinhibition of TACE, one of the enzymes which generates soluble EGF-like ligands, resulted inpartial recovery of MHC-I surface expression. Moreover, recombinant EGF and TGF-α aswell as the combination of both were also able to reproduce the B. abortus-induced MHC-Idown-modulation. Finally, when infection was performed in the presence of an Erk1/2inhibitor, MHC-I surface expression was significantly recovered. Overall, these resultsdescribe how B. abortus evades CD8+ T cell responses early during infection and exploits theEGFR-ERK signaling pathway to escape from the immune system and favor chronicity.