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

LIS N. VELÁSQUEZ; M. AYELÉN MILILLO; M. VICTORIA DELPINO; ALDANA TROTTA; M. FLORENCIA MERCOGLIANO; ROBERTO G. POZNER; ROXANA SCHILLACI; PATRICIA V. ELIZALDE; GUILLERMO H. GIAMBARTOLOMEI

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+ T-cell responses. We have recentlyreported the ability of B. abortus to inhibit the interferon-γ-induced major histocompatibility complex (MHC)-I cell surfaceexpression on human monocytes. This phenomenon was due to the B. abortus-mediated retention of MHC-I molecules within theGolgi apparatus and was dependent on bacterial viability. However, the implications of bacterial virulence or replicative capacityand the signaling pathways remained unknown. Here we demonstrated that the B. abortus mutant strains RB51 and virB10 − areable to inhibit MHC-I expression in the same manner as wild-type B. abortus, even though they are unable to persist insidehuman monocytes for a long period of time. Consistent with this, the phenomenon was triggered early in time and could beobserved at 8 h postinfection. At 24 and 48 h, it was even stronger. Regarding the signaling pathway, targeting epidermal growthfactor (EGF) receptor (EGFR), ErbB2 (HER2) or inhibition of tumor necrosis factor-α-converting enzyme, one of the enzymeswhich generates soluble EGF-like ligands, resulted in partial recovery of MHC-I surface expression. Moreover, recombinant EGFand transforming growth factor-α as well as the combination of both were also able to reproduce the B. abortus-induced MHC-Idownmodulation. Finally, when infection was performed in the presence of an extracellular signal?regulated kinase 1/2 (Erk1/2)inhibitor, MHC-I surface expression was significantly recovered. Overall, these results describe how B. abortus evades CD8+T-cell responses early during infection and exploits the EGFR-ERK signaling pathway to escape from the immune system and favor chronicity.