Abstract
Correct timing of virulence gene expression is critical for successful disease outcomes and the persistence of pathogens within the host environment. The global transcriptional silencer H-NS is a nucleoid-associated protein (NAP) that is important for coordination of virulence in many bacteria including Escherichia coli, Shigella, Salmonella, and Vibrio. In these bacteria, H-NS-mediated silencing is overcome through direct antagonization via transcriptional counter-silencers that bind to gene promoter regions, displace H-NS, and permit transcriptional activation. Brucella spp. and related members of α-proteobacteria lack functional H-NS homologs, so it is unclear whether other proteins are involved in performing analogous functions during host-association and pathogenesis. We have identified the Zn finger protein MucR as a novel H-NS-like protein that is critical for virulence in Brucella spp. by binding to and directly repressing virulence gene promoters in an H- NS-like manner. We show that MucR specifically interacts with AT-rich DNA regions containing multiple TA steps. Building on previous work, we show that oligomerization is required for proper MucR activity. Further, we demonstrate the stress- responsive regulator and SlyA-homolog, MdrA, acts as a direct counter-silencer to MucR through competition on virulence gene promoters. Consistent with the role of MucR as an H-NS-like protein, hns from E. coli is able to functionally complement mucR mutants in Brucella spp. Together these data demonstrate the role of MucR as a novel H-NS-like protein and highlight the importance of silencer/counter-silencer interactions in the pathogenesis of Brucella spp. and related bacteria.
