Replication of Brucella melitensis inside primary human monocytes depends on mitogen activated protein kinase signaling

The clinical course of infections caused by Brucella is linked to its capacity to modulate the initial immune response of macrophages in order to ensure its intracellular replication. Signal transduction pathways implicated in the survival of Brucella in human cells are not completely elucidated. We herein investigated the involvement of the TLR-MAPK-dependent signaling pathways in the survival of Brucella in primary human monocytes using live clinical strains of Brucella melitensis. B. melitensis caused a delayed, TLR2 dependent MAPK activation. Specific MAPK inhibitors for p38 (SB203580), ERK1/2 (PD98059) and JNK (SP600125) or the anti-TLR2 blocking Ab inhibited both inflammatory and anti-inflammatory responses characterized by TNF-α, IL-6 and IL-10 production. Intracellular replication of B. melitensis was mainly dependent on p38 and JNK activation and not affected by IL-10 levels. These are the first evidence to support that survival of B. melitensis inside human monocytes depends on interplay among the different MAPK family members, activated through TLR2, in spite of an initial pro-inflammatory response.