Suppression of the key immune pathways in primary human macrophages by cooperation of Yersinia effectors

In order to suppress the host immune system, numerous bacterial pathogens utilize a type 3 secretion system (T3SS) to inject effector proteins into target cells. We investigated Yersinia enterocolitica effectors (Yops) for their individual and combined effects on gene expression, inflammasome formation and Ca ++ signaling in primary human macrophages. The up- or down-regulation of thousands of macrophage genes by Yersinia inflammatory stimuli was effectively suppressed by YopP, and this correlated with suppression of histone-3 serine-10 phosphorylation. Surprisingly, YopM and YopQ counteracted selected YopP effects on gene expression. Inflammasome formation was reduced by a combination of YopP and YopQ, but not by any single effector or combinations of them. Finally, Ca ++ transients in infected macrophages were completely blocked by YopH alone. We conclude that the T3SS effectors of Yersinia antagonistically, synergistically or individually control major immune pathways of human macrophages to jointly suppress the host immune response.