Copper Sensing Transcription Factor ArsR2 Regulates VjbR to Sustain Virulence in <i>Brucella abortus</i>

Brucellosis, caused by the intracellular pathogen <i>Brucella</i>, is a major zoonotic infection that promotes reproductive disease in domestic animals and chronic debilitating conditions in humans. The ArsR family of transcriptional regulators plays key roles in diverse cellular processes, including metal ion homeostasis, responding to adverse conditions, and virulence. However, little is known about the function of ArsR family members in <i>Brucella</i>. Here, we identified ArsR2 as a nonclassical member of the family that lacks autoregulatory function, but which nevertheless plays a vital role in maintaining copper homeostasis in <i>B. abortus</i>. ArsR2 is a global regulator of 241 genes, including those involved in the VirB type IV secretion system (T4SS). Significantly, ArsR2 regulates T4SS production in <i>B. abortus</i> by targeting VjbR which encodes a LuxR-type family transcriptional regulator. Moreover, copper modulates transcriptional activity of ArsR2, but not of VjbR. Furthermore, deletion of <i>arsR2</i> attenuated virulence in a mouse model. Collectively, these findings enhance understanding of the mechanism by which ArsR proteins regulate virulence gene expression in pathogenic <i>Brucella</i> species.