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We herein investigated gene expression and the importance of this protein during infection. Our data support that <jats:italic>bb0556<\/jats:italic> forms an operon with five other genes. A transcriptional start site and the associated \u03c3<jats:sup>70<\/jats:sup>\u2010type promoter were identified in the sequences upstream of <jats:italic>bb0554<\/jats:italic>, and luciferase reporter assays indicated that this promoter is functional in <jats:italic>B. burgdorferi<\/jats:italic>. Furthermore, the sequences upstream of <jats:italic>bb0556<\/jats:italic> contain an internal promoter to drive gene expression. <jats:italic>bb0556<\/jats:italic> expression was affected by various environmental factors such as changes in temperature, pH, and cell density when <jats:italic>B. burgdorferi<\/jats:italic> was grown in\u00a0vitro. Surprisingly, significant differences were observed for <jats:italic>bb0556<\/jats:italic> expression between <jats:italic>B. burgdorferi<\/jats:italic> strains B31\u2010A3 and CE162, likely due to the different <jats:italic>cis\u2010<\/jats:italic> and <jats:italic>trans<\/jats:italic>\u2010acting factors in these strains. Moreover, <jats:italic>bb0556<\/jats:italic> was found to be highly expressed by <jats:italic>B. burgdorferi<\/jats:italic> in infected mice tissues, suggesting that this gene plays an important role during animal infection. To test this hypothesis, we generated a <jats:italic>bb0556<\/jats:italic> deletion mutant in a virulent bioluminescent <jats:italic>B. burgdorferi<\/jats:italic> strain. The mutant grew normally in the medium and displayed no defect in the resistance to environmental stresses such as reactive oxygen species, reactive nitrogen species, and osmotic stress. However, when the infectivity was compared between the mutant and its parental strain using in\u00a0vivo bioluminescence imaging as well as analyses of spirochete recovery and bacterial burdens in animal tissues, our data showed that, contrary to the parental strain, the mutant was unable to infect mice. Complementation of <jats:italic>bb0556<\/jats:italic> in <jats:italic>cis<\/jats:italic> fully restored the infectious phenotype to wild\u2010type levels. Taken together, our study demonstrates that the hypothetical protein BB0556 is a novel virulence factor essential for <jats:italic>B. burgdorferi<\/jats:italic> mammalian infection.<\/jats:p>","DOI":"10.1111\/mmi.15319","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T20:26:46Z","timestamp":1734640006000},"page":"831-846","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Analysis of <i>bb0556<\/i> Expression and Its Role During <i>Borrelia burgdorferi<\/i> Mammalian Infection"],"prefix":"10.1111","volume":"122","author":[{"given":"Sierra","family":"George","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor","family":"Waldron","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7427-1856","authenticated-orcid":false,"given":"Zhiming","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1180"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2020.11.022"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(05)80360-2"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/461941"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens10030281"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-6445(03)00036-6"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05895.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/162.1.133"},{"key":"e_1_2_9_10_1","first-page":"263","article-title":"Kinetics of Borrelia burgdorferi Dissemination and Evolution of Disease After Intradermal Inoculation of Mice","volume":"139","author":"Barthold S. 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