Brucella targets host USP8 through the effector protein TcpB to facilitate infection of macrophages

Brucella species are Gram-negative intracellular bacterial pathogens that cause the worldwide zoonotic disease brucellosis. Brucella can infect many mammals, including humans and domestic and wild animals. Brucella manipulates various host cellular processes to invade and multiply in professional and non-professional phagocytic cells. However, the host targets and their modulation by Brucella to facilitate the infection process remain obscure. Here, we report that the host Ubiquitin Specific Protease, USP8 negatively regulates the invasion of Brucella into macrophages through the plasma membrane receptor, CXCR4. Brucella suppressed the expression of USP8 at its early stage of infection in the infected macrophages. Subsequent studies revealed that the Brucella effector protein, TIR-domain containing protein from Brucella, TcpB plays a significant role in downregulating the expression of USP8 by targeting the CREB pathway. Treatment of mice with USP8 inhibitor resulted in enhanced survival of B. melitensis, whereas mice treated with CXCR4 or 14-3-3 antagonist showed a diminished bacterial load. Our experimental data demonstrate a novel role of USP8 in the host defence against microbial intrusion and microbial subversion of host defences.