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In the intracellular pathogen <jats:styled-content style=\"fixed-case\"><jats:italic>Brucella ovis<\/jats:italic><\/jats:styled-content>, the orphan HWE\u2010family histidine kinase PhyK has been implicated in processes that influence cell envelope homeostasis, yet its function remains largely uncharacterized. We show that deletion of <jats:italic>phyK<\/jats:italic> (\u2206<jats:italic>phyK<\/jats:italic>) disrupts cell size control, increases resistance to anionic detergents, enhances sensitivity to cationic envelope disruptors, and triggers broad transcriptional changes, including reduced expression of aerobic respiration genes and increased expression of genes involved in transport and lipid metabolism. This transcriptional profile mirrors that of wild\u2010type <jats:styled-content style=\"fixed-case\"><jats:italic>B. ovis<\/jats:italic><\/jats:styled-content> exposed to an anionic detergent, indicating that loss of PhyK function primes cells to resist this stress. Despite its altered cell envelope properties, the \u2206<jats:italic>phyK<\/jats:italic> mutant exhibits no fitness defect in ex\u00a0vivo macrophage infection models. However, it elicits a significantly reduced pro\u2010inflammatory cytokine response in activated murine macrophages compared to the wild\u2010type strain. We further show that purified PhyK can form multiple stable oligomeric species in solution, reflecting the structural plasticity observed in other HWE\u2010family kinases and likely contributing to its signaling function in\u00a0vivo. Our results establish PhyK as a key regulator of <jats:styled-content style=\"fixed-case\"><jats:italic>B. ovis<\/jats:italic><\/jats:styled-content> cell envelope properties that can modulate host immune interactions.<\/jats:p>","DOI":"10.1111\/mmi.70006","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T01:45:49Z","timestamp":1750988749000},"page":"245-258","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An <scp>HWE<\/scp>\u2010Family Histidine Kinase Modulates <i>Brucella<\/i> Cell Envelope Properties and Host Innate Immune Response"],"prefix":"10.1111","volume":"124","author":[{"given":"Xingru","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Microbiology, Genetics, and Immunology Michigan State University  East Lansing Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics, and Immunology Michigan State University  East Lansing Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleanor C.","family":"Scheeres","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics, and Immunology Michigan State University  East Lansing Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosemary","family":"Northcote","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics, and Immunology Michigan State University  East Lansing Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aretha","family":"Fiebig","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics, and Immunology Michigan State University  East Lansing Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Olive","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics, and Immunology Michigan State University  East Lansing Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1727-322X","authenticated-orcid":false,"given":"Sean","family":"Crosson","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics, and Immunology Michigan State University  East Lansing Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)38417-0"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-032521-013159"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00444-09"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.08.011"},{"key":"e_1_2_9_6_1","first-page":"27","article-title":"Epididymitis in Rams. 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