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The intracellular pathogenic bacterium  Brucella  generates a replicative vacuole (rBCV) derived from the endoplasmic reticulum via subversion of the host cell secretory pathway. rBCV biogenesis requires the expression of the Type IV secretion system (T4SS) VirB, which is thought to translocate effector proteins that modulate membrane trafficking along the endocytic and secretory pathways. To date, only a few T4SS substrates have been identified, whose molecular functions remain unknown. Here, we used an  in silico  screen to identify putative T4SS effector candidate proteins using criteria such as limited homology in other bacterial genera, the presence of features similar to known VirB T4SS effectors, GC content and presence of eukaryotic-like motifs. Using β-lactamase and CyaA adenylate cyclase reporter assays, we identified eleven proteins translocated into host cells by  Brucella , five in a VirB T4SS-dependent manner, namely BAB1_0678 (BspA), BAB1_0712 (BspB), BAB1_0847 (BspC), BAB1_1671 (BspE) and BAB1_1948 (BspF). A subset of the translocated proteins targeted secretory pathway compartments when ectopically expressed in HeLa cells, and the VirB effectors BspA, BspB and BspF inhibited protein secretion.  Brucella  infection also impaired host protein secretion in a process requiring BspA, BspB and BspF. Single or combined deletions of  bspA ,  bspB  and  bspF  affected  Brucella  ability to replicate in macrophages and persist in the liver of infected mice. Taken together, these findings demonstrate that  Brucella  modulates secretory trafficking via multiple T4SS effector proteins that likely act coordinately to promote  Brucella  pathogenesis.

Brucella Modulates Secretory Trafficking via Multiple Type IV Secretion Effector Proteins