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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Brucellosis caused by Brucella melitensis is a worldwide zoonotic disease, yet the role of the c-di-GMP phosphodiesterase BpdB in virulence remains incompletely understood. This study aimed to investigate the function of BpdB in B. melitensis pathogenicity and its involvement in host STING signaling. A bpdB deletion strain (\u0394bpdB) and a complemented strain (CbpdB) were constructed in B. melitensis M5. Bacterial growth, stress tolerance, intracellular survival in macrophages, cytokine expression, and mouse virulence were evaluated. Deletion of bpdB did not affect in vitro growth but significantly attenuated virulence in BALB\/c mice, reducing splenomegaly, splenic bacterial load, and hepatic granuloma formation. The \u0394bpdB strain exhibited enhanced sensitivity to oxidative stress, whereas resistance to acid, polymyxin B, and SDS remained unchanged. Intracellular survival of \u0394bpdB in RAW264.7 macrophages was reduced at 72 h post infection, a defect that was completely abrogated in STING-knockout RAW264.7 cells. \u0394bpdB infection induced higher transcriptional levels of IFN-\u03b2 and IL-1\u03b2, with IFN-\u03b2 induction strictly dependent on STING. In C57BL\/6J mice, the virulence attenuation of \u0394bpdB was partially STING-dependent, as the reduction in splenic bacterial load was smaller in STING-knockout than in wild-type mice. These findings demonstrate that BpdB contributes to B. melitensis virulence by enhancing oxidative stress resistance and dampening STING-dependent host responses, providing new insights into c-di-GMP-mediated host\u2013pathogen interactions.<\/jats:p>","DOI":"10.3390\/ijms27156585","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:38:41Z","timestamp":1784889521000},"page":"6585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deletion of the c-di-GMP Phosphodiesterase BpdB Attenuates Brucella melitensis Virulence by Enhancing Oxidative Stress Sensitivity, Partially via the Host STING Signaling Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Na","family":"Li","sequence":"first","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"},{"name":"Hebei Key Laboratory of Preventive Veterinary Medicine, College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao 066600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiumei","family":"Shi","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Preventive Veterinary Medicine, College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao 066600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simin","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Feng","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengsi","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"},{"name":"Hebei Key Laboratory of Preventive Veterinary Medicine, College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao 066600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaohui","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3259-1637","authenticated-orcid":false,"given":"Yanqing","family":"Bao","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Qi","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4410-427X","authenticated-orcid":false,"given":"Tonglei","family":"Wu","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Preventive Veterinary Medicine, College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao 066600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6794-2639","authenticated-orcid":false,"given":"Mingxing","family":"Tian","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/S1369-5274(00)00165-X","article-title":"Brucellosis: A worldwide zoonosis","volume":"4","author":"Boschiroli","year":"2001","journal-title":"Curr. 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