Brucella species utilize diverse virulence factors. Previously, Brucella abortus light sensing histidine kinase was identified as important for cellular infection. Here, we demonstrate that a Brucella melitensis LOV-HK (BM-LOV-HK) mutant strain has strikingly different gene expression than wild type. General stress response genes including the alternative sigma factor rpoE1 and its anti-anti sigma factor phyR were downregulated, while flagellar, quorum sensing, and type IV secretion system genes were upregulated in the ΔBM-LOV-HK strain versus wild type. Contextually, expression results agree with other studies of transcriptional regulators involving ΔrpoE1, ΔphyR, ΔvjbR, and ΔblxR (ΔbabR) Brucella strains. Additionally, deletion of BM-LOV-HK decreases virulence in mice. During C57BL/6 mouse infection, the ΔBM-LOV-HK strain had 2 logs less CFUs in the spleen 3 days post infection but similar levels 6 days post infection compared to wild type. Infection of IRF-1−/− mice more specifically define ΔBM-LOV-HK strain attenuation with fewer bacteria in spleens and significantly increased survival of mutant versus wild type infected IRF-1−/− mice. Upregulation of flagella, quorum sensing, and VirB genes, along with downregulation of rpoE1 and related sigma factor, rpoH2 (BMEI0280) suggest that BM-LOV-HK modulates both quorum sensing and general stress response regulatory components to control Brucella gene expression on a global level.